Section A

Allergy - mechanisms

* What is allergy * B cells

* The discovery of IgE * Immunoglobulin E and other antibodies in allergy
* Allergens: structure and function; mechanisms of * Role of superantigens in allergic diseases
allergenicity; allergens and cross-reactivity; house dust * Cytokines in allergy
mite allergens; pet allergens; tree pollen allergens; grass * Cell migration and chemokines
pollen allergens; weed pollen allergens; food allergens; * Complement-mediated regulation of the allergic response
venom allergens; emerging allergens; pollen allergens and * Lipid mediators of hypersensitivity and inflammation
geographical factors * Lipid mediators in resolution of allergic inflammation
* The underlying mechanisms in allergy * Allergy and the epithelial barriers
* Innate immune response in allergy * Epithelial proteases and allergic diseases
* Dendritic cells * Mechanisms of immune regulation in allergy
* Natural killer cells and natural killer-T cells * Neuro-immune regulation of allergic inflammation
* Innate lymphoid cells * United airways and immune regulation
* Mast cells * Genetics of allergy
* Basophils * Epigenetics of allergy
* Eosinophils * Endotypes of allergic diseases
* T cells * Animal models of allergic disease
 Global atlas oF allergy

1 WHAT IS ALLERGY

Johannes Ring 
Technische Universität München
München, Germany

The term “Allergy” was born on

July 24, 1906 in the Münchener Ke y m essag es
Medizinische Wochenschrift as
Section A - Allergy - from genetics to mechanisms

“specifically altered reactivity of • The term “Allergy” was first coined on July 24, 1906 as
the organism”. Today, we define al- “specifically altered reactivity of the organism
lergy as immunological hypersen- • Today, we define allergy as an immunologically-mediated and
sitivity that can lead to a variety allergen-specific hypersensitivity
of different diseases via different • Allergies can be seen in almost every organ, most commonly in
pathomechanisms and thus differ- the skin and the mucous membranes
ent approaches in diagnosis, ther- • Allergology is the science regarding allergic diseases and their
apy and prevention can be taken. differential diagnoses and mechanisms
(Table 1). Several misconceptions
can be delineated (Table 2).

Allergology is the science regard-

ing allergic diseases and their
differential diagnoses and mech-
anisms. It requires clinical experi-
ence in allergic diseases, basic un-
derstanding of the immune system
in physiology and pathology and
finally extensive knowledge of en-
vironmental factors in eliciting or
modulating allergic reactions.
Allergy is not a disease itself, but
a mechanism leading to disease.
In clinical practice, allergy mani-
fests in form of various different
conditions such as anaphylaxis,
urticaria, angioedema, allergic rhi-
noconjunctivitis, allergic asthma,
serum sickness, allergic vasculitis,
Figure 1  The word “allergy” first appeared on July 24, 1906 in the Münchener
Medizinische Wochenschrift in an essay written by Clemens von Pirquet, a hypersensitivity pneumonitis, at-
pediatrician from Vienna. (Reproduced with permission from Ring J: Allergy in opic dermatitis (eczema), contact
Practice. Springer Berlin, Heidelberg, New York, 2005.) dermatitis and granulomatous

2 What is allergy
Global atlas oF allergy

TABLE 1
Definitions of terms frequently used in allergy TABLE 2

Sensitivity Normal response to a stimulus The most common misconceptions

of allergy
Hypersensitivity Abnormally strong response to a stimulus
Sensitation Development of increased sensitivity after repeated • natural reaction
contact • a symptom or sign (e.g. rhinitis)
Allergy Immunologically mediated hypersensitivity leading to • incompatibility of toxic/irritant
disease substances (e.g. tobacco smoke)
Anaphylaxis severe, life-threatening, generalized or systemic • psychological aversion
hypersensitivity reaction • incurable

Enviroment-induced disease

Toxicity Hypersensitivity

Section A - Allergy - from genetics to mechanisms

of a substance of the individuum

non- immune
immune mediated

Irritation,
Psycho-
Intoxication, Idio-
Intolerance neurogenic Allergy
chronic syncrasy
reaction
damage

Figure 2  Classification of environmentally related health these disorders. (Reproduced with permission from Ring J: Allergy
in Practice. Springer Berlin, Heidelberg, New York, 2005.)

reactions, as well as the colorful patients may out grow their al- allergy for global use: Report of the
spectrum of food- or drug – in- lergic disease spontaneously. We nomenclature committee of the
duced hypersensitivity reactions. should study these patients in- World Allergy Organization. J Al-
lergy Clin Immunol 2004; 113: 832-
Allergies can be seen in almost tensively, who spontaneously lose
836.
every organ. Most commonly, their allergy. Many allergic diseas-
3. Ring J. Allergy in Practice. Berlin:
however, it is the skin and the mu- es have a chronic course, but there
Springer, 2005.
cous membranes that are involved are ways to cure. Allergic diseases
4. Adkinson NF, Bochner BS, Burks
since they represent the frontier can be influenced by psychological
AW, Busse WW, Holgate ST, Le-
between the individual organism processes in a positive or in a neg- manske LF, O’Hehir RE. Middleton’s
and its environment. ative way. Allergy Principles and Practice.
8th edition. Philadelphia: Elsevier
Allergy often starts in the first Key References 2014.
three months of life but very 1. Bergmann KC, Ring J. History of Al- 5. Ring J, Akdis C, Behrendt H, Lauen-
rarely at birth, although there is a lergy. Basel:Karger, 2014 – in press. er RP, Schäppi G, Akdis M et al.
strong genetic background. Aller- 2. Johansson SGO, Bieber C, Dahl R, Davos declaration: allergy as a glob-
gy in some cases does not persist Friedmann PS, Lanier BQ, Lockey al problem. Allergy 2012;67:141-
over life-time; it starts and some RF et al. Revised nomenclature for 143.

What is allergy 3
 Global atlas oF allergy

2 The discovery of IgE

S.G.O. Johansson 
Karolinska Institute
Stockholm, Sweden

Allergic asthma and rhinitis were

already recognized in the 19th Ke y m essag es
century, but the mechanisms be-
Section A - Allergy - from genetics to mechanisms

hind the diseases were not under- • In 1921, Prausnitz and Küstner demonstrated passive
stood. In 1919 Ramirez noticed sensitization of the skin, since then referred to as the PK-test
that blood transfusion could trans- • In the 1960’s K. and T. Ishizaka published several articles
fer allergic asthma and passively describing an antiserum that could block the PK-test indicating
sensitize the recipient. In 1921, that it reacted with regain
Prausnitz and Küstner demon- • In 1965 S.G.O. Johansson in Uppsala detected in the serum of a
strated passive sensitization of myeloma patient an M-component that could not be identified as
the skin, since then referred to as any of the 4 known immunoglobulin classes
the PK-test. • The discovery of IgE and the understanding of the IgE-mediated
inflammation, allergic asthma and rhino-conjunctivitis, food
The search for reagin, the factor allergy and eczema has had a significant impact on diagnosis and
in plasma causing the positive PK- treatment of allergy
test, was unsuccessful for about
45 years and some rather confus-
ing proposals were published, e.g.
identifying reagin as IgA. In the
1960’s K. and T. Ishizaka published
several articles describing an an-
tiserum that could block the PK-
test indicating that it reacted with
reagin. They referred to this anti-
serum as anti-γE. Not surprisingly
considering the very low serum
concentration of IgE, they did not
succeed in isolating their γE.
In 1965 S.G.O. Johansson in
Uppsala detected in the serum of a
myeloma patient an M-component
that could not be identified as any
of the 4 known immunoglobulin
classes. Working with H. Bennich,
the unique immunological and
physicochemical characteristics

4 The discovery of IgE

Global atlas oF allergy

Section A - Allergy - from genetics to mechanisms

Figure 1  From left L. Wide, H. Bennich and S.G.O. Johansson presenting RAST in 1974.

of the new immunoglobulin, pro- port on the fifth immunoglobulin Key References
visionally labelled IgND after the class, IgE. 1. Ramirez MA. Horse asthma fol-
initials of the patient, were docu- lowing blood transfusion. JAMA
The discovery of IgE has had a 1919;73:984.
mented and published. Very small
significant impact on the diagno- 2. Prausnitz C, Küstner H. “Studien
amounts of IgND did, in dose-re-
sis and management of allergic über die Ueberempfindlichkeit”,
sponse, block the PK-test and the
disease, enabling clinicians to dif- Zentralbl Bakteriol 1921;86:160–
active structure was located in the
ferentiate between IgE-mediated 169.
Fc-fragment. A sensitive radio-im-
allergic diseases and other hyper- 3. Ishizaka K, Ishizaka T. Identifica-
muno assay was developed for
sensitivity reactions, and to man- tion of γE-antibodies as a carri-
IgND. Extremely low serum con-
age allergic diseases according er of reaginic activity. J Immunol
centrations, in the order of a few 1967;99:1187.
to their underlying mechanisms.
nanograms per ml, were found in
Tests became available that al- 4. Johansson SGO, Bennich H. Im-
healthy individuals but, interest- munological studies of an atypical
lowed a more simple and reliable
ingly, 10-100 fold higher levels (myeloma) immunoglobulin. Immu-
diagnosis covering a very broad
were found in allergic individuals. nology 1967;13:381-394.
spectrum of allergens. The char-
Purified IgND was sent to the acterization and standardization 5. Stanworth DR, Humphrey JH, Ben-
Ishizakas in 1967 and was found of allergen preparations for clini- nich H, Johansson SGO. Specific
to react with their anti-γE. In Feb- cal diagnosis and allergen specific inhibition of the Praunitz-Küstner
reaction by an atypical human my-
ruary 1968 the WHO Internation- immunotherapy, ASIT, improved
eloma protein. Lancet 1967;2:330-
al Reference Centre in Lausanne, although there is still much to do 332.
where studies on IgND had been in this area. An injectable mon-
6. Bennich H, Ishizaka K, Johans-
performed for some months, in- oclonal anti-IgE is now available son SGO, Rowe DS, Stanworth
vited the two groups to a meeting that eliminates IgE and has an im- DR, Terry WD. Immunoglobulin
to review comparative laboratory portant role in the management E, a new class of human immuno-
studies of IgND and γE, resulting of severe allergic asthma, severe globulins. Bull World Health Organ
in the publication of the official re- food allergy and chronic urticaria. 1968;38:151-152.

The discovery of IgE 5

 Global atlas oF allergy

3a Allergens – structure
and function
Ronald van Ree 
Academic Medical Center
Amsterdam, The Netherlands

Patients with type I allergy make

IgE antibodies against some, but Ke y m essag es
not against all environmental or
Section A - Allergy - from genetics to mechanisms

dietary proteins they are exposed • A protein capable of instructing the immune system to start
to. In fact, most allergens belong producing IgE antibodies is called a primary sensitizer
to a rather limited number of pro- • Pro-allergenic properties of a protein cannot be separated from
tein families. the individual being exposed or from the context of exposure
• Several structural and functional properties have been identified
Can we identify common struc- that contribute to allergenicity
tural or functional properties of • There is not a single common denominator for allergenicity
proteins that turn them into al-
lergens? Before answering this
question, it is important to clearly
define what an allergen is. An ab- potential endogenous pro-aller- immune system. Many known al-
solute prerequisite for a molecule genic properties of a protein can- lergens are indeed lipid binding
to be designated an allergen is for not be seen in isolation from the proteins (e.g. Bet v 1 and homo-
it to bind specific IgE antibodies. individual being exposed and from logues, house dust mite group 2
Not every protein fulfilling that the context of exposure, which allergens, lipocalins of pets, plant
requirement is however also ca- includes timing and dose of expo- lipid transfer proteins), and some
pable of instructing the immune sure, and the presence of co-fac- are glycoproteins (e.g. peanut Ara
tors that may act as pro-allergenic h 1 and grass pollen Phl p 1). Their
system to start producing these
or anti-allergenic adjuvants (Fig- lipid ligands and conjugated gly-
IgE antibodies, i.e. of being a pri-
ure 2). cans have been shown to interact
mary sensitizer (Figure 1). Clear
with pathogen recognition recep-
examples of allergens not able to With that in mind, are there com- tors such as Toll-like receptors and
do so are those in fruits, nuts and mon endogenous structural or C-type lectins on antigen-present-
vegetables that are cross-reactive functional properties that deter- ing cells, thereby skewing the im-
with the major birch pollen Bet v mine allergenicity? Glycosylation mune systems towards Th2-type
1. Their allergenicity is dependant per se has often been mentioned responses and IgE production
on their structural (and functional) as marker for allergenicity, but (Figure 3). In addition, protease
similarity to their “parent” mole- convincing evidence for such a activity such as of the cysteine
cule Bet v 1, the primary sensitizer. general claim cannot be found. protease Der p 1 has been shown
The more intriguing question is Some properties of proteins, in- to drive Th2 inflammation. It is
however, what determines wheth- cluding specific types of glycosyla- important to note that all these in-
er a protein is capable of being the tion and binding of lipids, seem to nate Th2-skewing properties may
primary sensitizer. The answer to determine their role as allergens also turn other proteins without
this question is complex, because via interaction with the innate these pro-allergenic properties

6 Allergens – structure and function

Global atlas oF allergy

PROTEIN PROTEIN
=
IgE ALLERGEN

PROTEIN
PROTEIN =
ALLERGEN
PROTEIN +
SENSITIZER
IgE

Section A - Allergy - from genetics to mechanisms

C PROTEIN 1
=
PROTEIN 1 PROTEIN 1 ALLERGEN
+
SENSITIZER
homologous cross-reactive
IgE PROTEIN 2
=
PROTEIN 2 PROTEIN 2 CROSS-REACTIV
ALLERGEN

Figure 1  Panel A illustrates the minimum requirements for a molecule to be designated as an allergen: it binds IgE
antibodies Panel B and C depict the two identities an allergen can have: it can itself act as primary sensitizer (orange in
panel B and C), or it cannot and binds IgE only based on cross-reactivity with the primary sensitizer (blue in panel C).

into allergens during simultane- KEY REFERENCES gens and pollen. Ann N Y Acad Sci
ous exposure. 1. Chapman MD, Pomés A, Breitened- 2002;964:47-68.
er H, Ferreira F. Nomenclature and 3. Thomas WR. Innate affairs of aller-
In summary, several structural and structural biology of allergens. J Al- gens. Clin Exp Allergy 2013;43:152-
functional properties have been lergy Clin Immunol 2007;119:414- 163.
identified that contribute to aller- 420. 4. Chapman MD, Wünschmann S,
genicity, but it is safe to say that 2. Vieths S, Scheurer S, Ballmer-We- Pomés A. Proteases as Th2 ad-
there is not a single common de- ber B. Current understanding juvants. Curr Allergy Asthma Rep
nominator for allergenicity. of cross-reactivity of food aller- 2007;7:363-367.

Allergens – structure and function 7

 Global atlas oF allergy

BIRTH
protein with protein without
genetic
endogenous allergenic endogenous allergenic
predisposition
properties properties

DOSE DOSE
low low

OR OR

risk & protective

risk & protective

context:

context:
factors

factors
high high

COMPLEX INTERPLAY
Section A - Allergy - from genetics to mechanisms

ALLERGY OR TOLERANCE

ELDERLY AGE

Figure 2  Sensitization is a complex interplay of the individual exposed (inherited risk of becoming allergic), the timing
of exposure (earlier in life the immune system is more susceptible to sensitization but also to induction of tolerance), the
dose (high early life exposure may skew towards tolerance), the context of exposure (environmental exposures such as
pollution, microbes, parasites, diet, lifestyle) and endogenous properties of the protein.

LIPID PRR Th-cell

GLYCAN DC
Th2
ALLERGEN

PAR
PROTEASE

B-cell

IgE

Figure 3  Allergens can interact via various mechanisms with dendritic cells skewing them towards a DC2 phenotype,
which in turn skews adaptive immunity towards Th2 and IgE production.

8 Allergens – structure and function

Global atlas oF allergy

Mechanisms of
3b allergenicity of
allergens
Heimo Breiteneder 
Medical University of Vienna
Vienna, Austria

Allergens interact with various

parts of the innate immune sys- Ke y m essag es
tem which plays a fundamental

Section A - Allergy - from genetics to mechanisms

role in shaping adaptive immune • The innate immune system plays a fundamental role in shaping
responses (Figure 1). The innate the response to potentially allergenic proteins
immune system comprises sever- • Allergic sensitization, a multifactorial process, is influenced by a
al cell types that express pattern protein’s biological and molecular features and by the interaction
recognition receptors (PRRs). pathway/s with the immune system
PRRs recognize pathogen- or • Proteins interact with Toll-like-, C-type lectin-, NOD-like-, and
damage-associated molecular protease-activated receptors (present on epithelial cells and
patterns (PAMPs, DAMPs) which dendritic cells) or with surfactant proteins (present in soluble
frequently accompany allergens. form) to manifest their allergenicity
• Lipids (directly bound by allergens, present in the allergen
Membrane-associated, source, or originating from microbial contaminations) modulate
cytoplasmic and soluble the immune response of predisposed individuals by interacting
PRRs with the innate immune system
Toll-like receptors (TLR) are a
conserved family of PRRs. The al-
lergens Der p 2 (house-dust mite), SIGN; Ara h 1, Der p 1 and 2, Fel d and Ambrosia artemisiifolia pollen
Fel d 1 (cat), and Can f 6 (dog) 1, Can f 1 and Bla g 2 (cockroach) extracts.
bind lipopolysaccharide (LPS) and with the mannose receptor. Pro-
Surfactant associated proteins
interact with TLR4, shifting the tease-activated receptors (PARs)
(SP), found in the alveoli of the
LPS-response curve to a Th2-in- signal in response to extracelluar
lungs, bind inhaled glycosylat-
ducing range. Bacterial contami- proteases. Allergens of house dust
ed allergens via a carbohydrate
nations present on pollen, shown mite (Der p 1, -3, -9) and mold (Pen
recognition domain. Der p 1 and
for ryegrass and Parietaria, are c 13) activate PAR-2 and induce IL-
Der f 1 degrade SP-A resulting in
responsible for triggering TLR2, 25 and thymic stromal lymphopoi-
increased degranulation of mast
TLR4 and TLR9 signaling. C-type etin (TSLP).
cells and basophils triggered by
lectin receptors contain carbohy- NOD-like receptors (NLRs) sense these allergens.
drate recognition domains that cytoplasmic PAMPs and DAMPs.
bind glycosylated allergens and Some NLRs are core components Cells of the innate immune
trigger pathways that determine of inflammasomes, protein com- system
T-cell polarization. Ara h 1 (pea- plexes involved in generating the Epithelial cells function as phys-
nut), Der p 1 (house dust mite) pro-inflammatory cytokines IL- ical barrier whose tight junction
and Can f 1 (dog) interact with 1β and IL-18. Inflammasomes are proteins are degraded by proteas-
the C-type lectin receptor DC- triggered by Der p 1, Api m 4 (bee), es including Der p 1 and Act d 1

Mechanisms of allergenicity of allergens 9

 Global atlas oF allergy

Der p 2 Bacterial contaminations Ara h 1 Ara h 1 Der p 1, -3, - 9 Lipids from

of pollen: Brazil nut
Fel d 1 Der p 1, -2 Der p 1 Pen c 13
LPS LTA Sphingomyelin
Can f 6 Bla g 2 Can f 1 Der p 1 from cow‘s milk
CpG-DNA
+ Fel d 1, Can f 1 Api m 1 Lipids from
LPS A. artemisiifolia pollen
pollen

N-terminus

C-terminus
TLR4-MD2 TLR2-TLR1/6 Mannose DC-SIGN PAR-2 CD1d
receptor
Section A - Allergy - from genetics to mechanisms

Endosome

Inflammasome
TLR9 complex

Figure 1  Simplified model of innate immune mechanisms activated by allergens. Examples are given for interactions
of allergens with Toll-like receptors (TLRs) via binding by the allergen or co-delivery of bacterial compounds (LPS:
lipopolysaccharide. LTA: lipoteichoic acid); with C-type lectin receptors via carbohydrate moieties present on allergens;
with protease-activated receptor (PAR) 2 via the allergens’ proteolytical activity; and with inflammasome complexes
(2-4). In addition, the presentation of lipids from the allergen source by CD1d to invariant natural killer T cells, which
enhances sensitization or in some cases even drives it, is shown.

(kiwi). Following allergen contact, certain lipids and potentially aller- in human keratinocytes. Allergy
epithelial cells produce TSLP, IL- genic proteins determine the out- 2012;67:1400-1407.
25 and IL-33 and instruct dendrit- come of the sensitization process. 4. Varga A, Budai MM, Milesz S,
ic cells to induce Th2 responses. Bácsi A, Tőzsér J, Benkő S. Rag-
Dendritic cells bridge innate and KEY REFERENCES weed pollen extract intensifies
adaptive immunity and polarize 1. Thomas WR. Innate affairs of aller- lipopolysaccharide-induced prim-
gens. Clin Exp Allergy 2013;43:152- ing of NLRP3 inflammasome in
the T helper cell response (5). Po-
163. human macrophages. Immunology
larization towards a Th2 response
2. Dai X, Sayama K, Tohyama M, Shi- 2013;138:392-401.
in dendritic cell-T cell co-cultures
rakata Y, Hanakawa Y, Tokumaru S 5. Hammad H, Lambrecht BN. Den-
has been shown for Bet v 1 (birch
et al. Mite allergen is a danger signal dritic cells and airway epithelial cells
pollen) and Pru p 3 (peach) when at the interface between innate and
for the skin via activation of inflam-
cells were derived from allergic masome in keratinocytes. J Allergy adaptive immune responses. Allergy
donors. Invariant natural killer T Clin Immunol 2011;127:806-814. 2011;66:579-587.
cells (iNKTs) recognize lipids pre- 3. Dombrowski Y, Peric M, Koglin 6. Brennan PJ, Brigl M, Brenner MB.
sented by CD1d (6). They secrete S, Kaymakanov N, Schmezer Invariant natural killer T cells: an
IL-4, -5 and -13 when presented V, Reinholz M et al. Honey bee innate activation scheme linked to
lipids from Brazil nut or sphingo- (Apis mellifera) venom induces diverse effector functions. Nat Rev
myelin from milk. Co-delivery of AIM2 inflammasome activation Immunol 2013;13:101-17.

10 Mechanisms of allergenicity of allergens

Global atlas oF allergy

3c Allergens and cross-

reactivity

Barbara Bohle 
Medical University of Vienna
Vienna, Austria

Allergens belong to a relatively low

number of different protein fami- Ke y m essag es
lies according to intrinsic features,

Section A - Allergy - from genetics to mechanisms

e.g. similar amino acid sequenc- • Members of the same protein family may share IgE and T cell
es and/or 3-dimensional folding. epitopes, which can cause allergic reactions by cross-reactivity
Members of the same protein fami- • Shared IgE epitopes between inhalant allergens and food
ly may share IgE and T cell epitopes, allergens can induce an immediate IgE-mediated reaction
which by cross-reactivity can cause confined to the oral cavity, known as the oral allergy syndrome
allergic reactions. In this context, • Cross-reactivity at the T cell level represents one of the
birch pollen-related food allergy mechanisms of worsening of atopic eczema in birch-pollen
has been well studied. This special allergic patients
form of food allergy affects more • Immunological cross-reactivity is explored as a possible cure
than 70% of birch pollen-allergic for allergy, by inducing cross-reactive regulatory T cells and/or
patients and is one of the most fre- cross-reactive blocking IgG4 antibodies
quent food allergies in adults.
Bet v 1, the single major birch pol- recognized by Bet v 1 - specific IgE depends on amino acid sequence
len allergen belongs to the patho- antibodies (Figure 1A). Although homologies. After uptake by anti-
genesis-related protein family 10 not all IgE-epitopes are shared, gen-presenting cells, allergens are
and homologous molecules are Bet v 1 - related food allergens degraded into short linear pep-
present in various foods, e.g. Mal d contain sufficient epitopes to tides, which are then loaded onto
1 in apple, Pru av 1 in cherry, Gly m achieve cross-linkage of IgE bound MHC class II molecules to be pre-
4 in soy and Ara h 8 in peanut. Al- to the surface of mast cells and sented to T cells (Figure 1B). Pro-
though these proteins derive from basophils. In most cases, this in- teins with homologous amino acid
plant species non-related to birch duces the oral allergy syndrome, sequences are processed in analog
trees, their primary and tertiary an immediate IgE-mediated re- fashion resulting in similar pep-
structures are highly homologous action confined to the oral cavity. tides. These activate cross-reac-
with Bet v 1. Destruction of the 3-dimensional tive T cells to proliferate and pro-
protein structure, e.g. by gastroin- duce cytokines. Clinically, T cell
Bet v 1 contains mainly confor-
testinal degradation or heat pro- activation by Bet v 1-related food
mational IgE-epitopes, as destruc-
cessing, reduces IgE cross-reac- allergens may result in a worsen-
tion of its 3-dimensional structure
tivity, which explains why cooked ing of atopic eczema in birch pol-
leads to a dramatic reduction of
foods containing Bet v 1-related len-allergic patients.
its IgE-binding capacity. Due to
proteins usually are tolerated by
similar protein folding, Bet v 1 - The analysis of the immune mech-
birch pollen-allergic patients.
homologs contain surface patch- anisms underlying birch pollen-re-
es forming epitopes that may be Cross-reactivity at the T cell level lated food allergy has markedly

Allergens and cross-reactivity 11

 Global atlas oF allergy

A Bet v 1

Pru av 1

B Bet v 1 Mal d 1
N C N C
Section A - Allergy - from genetics to mechanisms

TLLRAVESYLLAHSDAYN GLFKLI ESYLKDHPDAYN

IL-4
IL-5
IL-13

Figure 1  A. Homologous conformational epitopes cause IgE cross-reactivity. A putative IgE epitope defined on Bet v
1 and Pru av 1, the Bet v 1-homolog in cherry is shown in green (3). Protein models (pdb 1BV1 and 1E09, respectively)
are displayed using Polyview3D. B. Homologous linear epitopes cause T cell cross-reactivity. Proteins with similar amino
acid sequences (indicated as red and green lines) are processed in a similar manner by antigen-presenting cells leading
to the generation of linear peptides. The highly cross-reactive C-terminal immunodominant T cell epitope of Bet v 1 and
the homolog peptide of Mal d 1 are shown (4). Identical amino acid residues are highlighted in bold, similar residues are
underlined. T cell activation by either epitope induces proliferation and cytokine production.

contributed to our understanding Mari A, Breiteneder H. Allergens naboyina SC, Valenta R, Keller W.
how immunological cross-reac- are distributed into few protein Prediction of IgE-binding epitopes
tivity can induce allergy. Birch families and possess a restricted by means of allergen surface com-
number of biochemical functions. J parison and correlation to cross-re-
pollen-related food allergy is now
Allergy Clin Immunol 2008;121:847- activity. J Allergy Clin Immunol
currently investigated as a disease 852. 2011;128:872-879.
model to elucidate whether immu-
2. Bohle B, Zwolfer B, Heratizadeh A, 4. Jahn-Schmid B, Radakovics A,
nological cross-reactivity can cure Jahn-Schmid B, Antonia YD, Alter Luttkopf D, Scheurer S, Vieths S,
allergy, e.g. by cross-reactive reg- M et al. Cooking birch pollen-relat- Ebner C et al. Bet v 1142-156 is the
ulatory T cells and/or cross-reac- ed food: divergent consequences dominant T-cell epitope of the ma-
tive blocking IgG4 antibodies. for IgE- and T cell-mediated reac- jor birch pollen allergen and impor-
tivity in vitro and in vivo. J Allergy tant for cross-reactivity with Bet v
KEY REFERENCES Clin Immunol 2006;118:242-249. 1-related food allergens. J Allergy
1. Radauer C, Bublin M, Wagner S, 3. Dall’Antonia F, Gieras A, Deva- Clin Immunol 2005;116:213-219.

12 Allergens and cross-reactivity

Global atlas oF allergy

House dust mite

3d allergens
Wayne R. Thomas 
University of Western Australia
Perth, Australia

House dust mites are the most

ubiquitous source of indoor al- Ke y m essag es
lergens inducing allergies, highly

Section A - Allergy - from genetics to mechanisms

associated with asthma. They are • Many house dust mite proteins elicit IgE antibody synthesis, but
of paramount importance in all for most the titres are low
but the few regions of the world, • The group 1,2 and probably the newly recognized group 23
where they do not survive due to allergens are the major allergens for Dermatophagoides species
aridness, extreme cold or high al- • As found for D. pteronyssinus, the group 4, 5, 7 and 21 allergens
titude. are quantitatively the next most important, or mid-tier, allergens
• Blomia tropicalis is an important source of allergens in some
IgE binding studies have found tropical and subtropical regions with the major specificities Blo
that while a wide range of mite t 5 and Blo t 21
proteins can elicit antibodies most • Mite proteases other than the group 1 allergens induce only low
induce low or sporadically de- levels of sensitisation and very few allergens from other sources
tectable titres (Table 1). Taking D. are cysteine proteases
pteronyssinus as the exemplar, only
3 allergens bind IgE from most
people at high titre, Der p 1&2 and the amino-acid sequence of tropo- studies conducted in urban tem-
the recently recognized Der p 23. myosin group 10 makes them a po- perate regions.
The allergens Der p 4, 5, 7 and 21 tential source of cross reactivity
each elicit IgE antibodies in 30- The main species that cause al-
with allergens from a wide range lergic sensitisation are D. ptero-
50% of mite-allergic subjects and of species. In most regions of the
collectively, and sometimes indi- nyssinus and D. farinae. The most
world, however, they only induce abundant, D. pteronyssinus (Figure
vidually, induce titres of a magni- IgE in about 10% of mite-allergic
tude considered important for the 1), is essentially the only species
subjects. There are possible ex- found in Australasia and the Unit-
induction of disease. The group ceptions mentioned in uncorrobo- ed Kingdom and mixed species
1&2 allergens can be readily de- rated reports from Zimbabwe and are found elsewhere except for D.
tected in dust and proprietary Japan showing high titre binding, farinae-rich regions of central and
house dust mite extracts made suggesting regional importance. In northern Korea, northern Italy
from mites cultured in optimized another example of a regional ef- and high-latitude areas of east-
allergen-producing conditions. fect, aboriginals in northern Aus- ern USA, where mites are found
The distribution of other allergens
tralia do not have IgE to Der p 1, 2 in low abundance. The allergens
in the environment is largely un-
or 10, but instead have high titres from these species cross react
known and frequently cannot be
to the amylase, Der p 4. The profile extensively so species-specificity
detected in proprietary extracts.
of allergens responsible for sensi- cannot be determined by skin test.
The evolutionary conservation of tisation, thus might vary from the The possibility that the biochemi-

House dust mite allergens 13

 Global atlas oF allergy

Figure 1   Stereomicroscopic
view of Dermatophagoides
pteronyssinus on fabric cover. Scale:
mites are 0.3 mm long. Attribution:
Gilles San Martin from Namur,
Belgium (By Gilles San Martin from
Namur, Belgium (House dust mites
Uploaded by Jacopo Werther) [CC-BY-
SA-2.0], via Wikimedia Commons.)
Section A - Allergy - from genetics to mechanisms

TABLE 1
KEY REFERENCES
Known important house dust mite allergens
1. Thomas WR. House dust allergy
Species Allergen Biochemical Category and immunotherapy. Hum Vaccin
Immunother 2012;8:1469-1478.
D. pteronyssinus Der p 1 cysteine protease Major
Der p 2 ML Lipid binding Major 2. Thomas WR, Hales BJ, Smith WA.
House dust mite allergens in asth-
Der p 23 peritrophin Major
ma and allergy. Trends Mol Med
Der p 4 amylase Mid tier 2010;16:321-328.
Der p 5 unknown Mid tier 3. Weghofer M, Grote M, Resch Y,
Der p 7 LPS/BPI family Mid tier Casset A, Kneidinger M, Kopec J et
Der p 21 Der p 5-related Mid tier al. Identification of Der p 23, a peri-
D. farinae Der f 1 cysteine protease Major trophin-like protein, as a new major
Dermatophagoides pteronyssinus
Der f 2 ML Lipid binding Major
allergen associated with the peri-
Other not investigated not investigated trophic matrix of mite fecal pellets.
B. tropicalis Blo t 5 unknown Major J Immunol 2013;190:3059-3067.
Blo t 21 Blo t 5-related Major 4. Thomas WR. Geography of house
Blo t 7 LPS/BPI family Mid tier dust mite allergens. Asian Pac J Al-
lergy Immunol 2010;28:211-224.
The table lists allergens shown to have IgE-binding titres expected to make significant
contributions to the total anti-house dust mite titres. 5. Casset A, Mari A, Purohit A, Resch
LPS/BPI: lipopolysaccharide binding/bacterial permeability increasing protein Y, Weghofer M, Ferrara R, et al.
Varying allergen composition and
cal functions of the allergens might glycyphagoide mite found with D. content affects the in vivo aller-
help promote their allergenicity pteronyssinus in some tropical and genic activity of commercial Der-
has been mooted especially the subtropical environments pro- matophagoides pteronyssinus
cysteine protease activity of Der extracts. Int Arch Allergy Immunol
vides another source of allergens
p 1, the lipopolysaccharide bind- 2012;159:253-262.
ing activity of Der p 2 and the chi- where Blo t 5 and Blo t 21 are the
6. Thomas WR. Innate affairs of al-
tin-binding of Der p 23, but this re- most important allergens and Blo t lergens. Clin Exp Allergy 2013;43:
mains unproven. Blomia tropicalis a 2 is a minor specificity. 152-163.

14 House dust mite allergens

Global atlas oF allergy

3e Pet allergens

Hans Grönlund 
Karolinska Institutet
Stockholm, Sweden

Pets of mammalian origin are com-

mon in society and kept for social, Ke y m essag es
recreational or occupational rea-

Section A - Allergy - from genetics to mechanisms

sons. In the United States alone • Exposure to pet allergens is ubiquitous in every-day life
the number of dog and cat own- • 10-15% of the population in affluent areas show pet allergen
ers is estimated to be 77.5 and specific IgE
93.6 million, respectively. Pets are • Allergy to pets is among the most common cause of asthma
among the most common causes and polysensitisation to several pets a risk factor for severe
of allergy: scattered information problematic asthma
suggests to 10-15% of the popu- • Allergen-specific immunotherapy for cat is efficacious, while
lation in affluent countries. Sen- extracts from dog and horse needs improvement
sitization is thought to depend on
seeding of airborne particles from
the pelt, saliva or urine. Upon in- to many identified components, dog and horse is more complex. Fel
halation and mucosal uptake these Table 1, however there are many d 1 is a secretoglobin glycoprotein
particles induce IgE antibodies more to be identified. Allergy to composed of 10-20% carbohy-
pets is a risk factor for symptoms drates, which has been suggested
of asthma, rhinoconjunctivitis and to increase allergenicity via man-
eczema and in some areas is con- nose receptor uptake. Yet another
sidered the most common cause of mechanism by which Fel d 1 exerts
childhood asthma. its allergenicity is via signaling
through the innate Toll-like recep-
To date eight cat (Felis domesti-
tors 4 and 2.
cus), six dog (Canis familiaris), four
horse (Equus caballus) and addi- Polysensitization between pets
tional allergens from less common is extensive and a risk factor for
sources have been identified, Ta- severe asthma. The most prom-
ble 1. The major allergens in cat, inent group of cross-reactive al-
dog and horse extracts are Fel d lergens is the lipocalin family, in-
1, Can f 1 and Equ c 1, with serum cluding e.g. cat Fel d 4, horse Equ
IgE-reactivity in allergic patients c 1, dog Can f 6 and rat Rat n 1.
Figure 1   Traditionally allergens of about 95, 50 and 75%, respec- A second cross-reactive cluster
from pets are extracted from the hair.
tively. However their proportions are serum albumins, responsible
There is a growing awareness that
other sources, such as saliva (Can f may vary between different ge- for the pork-cat syndrome, a rare
2) or urine (Can f 5) may contribute ographic regions. The serum IgE phenomenon that can lead to se-
critically to the IgE profile of in dog profile in cat allergy is dominated vere reactions. IgE to the galac-
allergic patients. by Fel d 1, whereas the profile in tose- α1,3- galactose carbohydrate

Pet allergens 15
 Global atlas oF allergy

TABLE 1 moiety, present in ticks bites,

helminths and mammals, but
Current list of characterized allergens from pets (www.allergen.org)
not humans, has convincingly
Animal Allergen Protein Source MW Sensitized been shown to induce severe
Family (kDa) (%) reactions after treatment with
certain biopharmaceuticals
Cat Fel d 1 Secretoglobin Saliva 30-38 80-95
and furthermore was linked to
Dander, Sera, red meat food allergy.
Fel d 2 Albumin 68 20-35
Urine
The accuracy of pet allergy
Fel d 3 Cystatin Dander 11 10 diagnostics and success of im-
munotherapy depends largely
Fel d 4 Lipocalin Saliva 20 63 on the quality of the allergen
source and the allergy profile
Fel d 5 IgA Saliva, Serum 28, 64 38
of the patient. Thus, specific
Fel d 6 IgM Saliva, Serum 28, 94 immunotherapy of patients
with IgE sensitization to cat
Fel d 7 Lipocalin Saliva 18 38 has proven efficacious, while
specific immunotherapy of
Fel d 8 Latherin Saliva 24 19
dog and horse allergy are not
Section A - Allergy - from genetics to mechanisms

Dog Can f 1 Lipocalin Saliva, Dander 22-25 45-55 equally established.

Can f 2 Lipocalin Saliva, Dander 22-27 20-30 KEY REFERENCES

1. Portnoy J, Kennedy K, Sub-
Dander, Sali- lett J, Phipatanakul W, Mat-
Can f 3 Albumin 69 15-35
va, Serum sui E, Barnes C et al. Envi-
ronmental assessment and
Can f 4 Lipocalin Saliva, Dander 18 15-30
exposure control: a practice
Can f 5 Kallikrein Urine 28 70 parameter--furry animals.
Ann Allergy Asthma Immunol
Can f 6 Lipocalin Dander 27, 29 38 2012;108:223.e1-15.
2. Brunekreef B1, Von Muti-
Equ c 1 Lipocalin Dander, Saliva 22 76 us E, Wong G, Odhiambo J,
García-Marcos L, Foliaki S;
Equ c 2§ Lipocalin Dander 16 50 ISAAC Phase Three Study
Group. Exposure to cats
Dander, Meat,
Horse Equ c 3 Albumin 65 18 and dogs, and symptoms of
Sera
asthma, rhinoconjunctivitis,
Equ c 4 Latherin Dander, Saliva 17-19 and eczema. Epidemiology
2012;23:742-750.
Equ c 5 Latherin Dander 17 3. Nilsson OB, van Hage M,
Grönlund H. Mammalian-de-
Cav p 1§ Lipocalin Dander, Urine 20 70-87 rived respiratory allergens -
Guinea- Implications for diagnosis and
Cav p 2 Lipocalin Dander, Tears 17-19 55-65
pig therapy of individuals aller-
Cav p 3 Lipocalin Saliva 18-19 54 gic to furry animals. Methods
2014;66:86-95.
Ory c 1§ Lipocalin Dander, Saliva 17-18 4. Zuberbier T, Bachert C,
Bousquet PJ, Passalacqua G,
Rabbit Ory c 2§ Lipocalin Dander, Saliva 21 Walter Canonica G, Merk H
et al. GA² LEN/EAACI pock-
Ory c 3 Secretoglobin Dander, Saliva 18-19 77 et guide for allergen-specific
immunotherapy for allergic
Rat Rat n 1 Lipocalin Urine 17-21 66
rhinitis and asthma. Allergy
2010;65:1525-1530.

16 Pet allergens
Global atlas oF allergy

A B

Figure 2   A) Saliva (n=14) from different dogs and breeds show variable allergen expression by IgE immunoblot using
a pool of dog allergic patients. Molecular marker, left lane (Reproduced with permission from Polovic N, Wadén K, Binnmyr
J, et al. Dog saliva – an important source of dog allergens. Allergy, 2013;68:585-92, with permission from Willey Blackwell.). B)
Variability in protein content of dog dander extracts commercially available for skin prick test. Left hand lane in-house
extract control, right hand side molecular markers (Reproduced with permission from Curin M, Reininger R, Swoboda I, et
al. Skin prick test extracts for dog allergy diagnosis show considerable variations regarding the content of major and minor dog

Section A - Allergy - from genetics to mechanisms

allergens. Int Arch Allergy Immunol 2011;154:258–263; with permission from Karger Publishers.)

rFel d1
(kUA/L)
1000

100

10

0.35

0.35 1 10 100 1000

Cat dander extract (kUA/L)

Figure 3   As opposed to dog and horse dander, one allergen, Fel d 1 (y-axis), is dominating in cat dander extracts (x-axis)
as illustrated by IgE correlation analysis of 100 cat sensitized subjects using ImmunoCAP system (Reproduced with
permission from Grönlund H, Adédoyin J, Reininger R et al. Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-
allergic children with asthma compared with rhinoconjunctivitis. Clin Exp Allergy. 2008 ;38:1275-81, with permission from Willey
Blackwell.)

Pet allergens 17
 Global atlas oF allergy

Tree pollen
3f allergens
Fatima Ferreira Gabriele Gadermaier Michael Wallner
University of Salzburg
Salzburg, Austria

GEOGRAPHICAL
DISTRIBUTION AND CLINICAL Ke y m essag es
RELEVANCE
Section A - Allergy - from genetics to mechanisms

Trees belonging to the Fagales, • The most clinically relevant sources of tree pollen allergens are
Oleaceae, and Cupressaceae com- found among Fagales, Oleaceae, and Cupressaceae plants, which
prise the clinically most relevant are widely distributed worldwide
sources of allergenic pollen in • Bet v 1-like proteins, Ole e 1- like proteins, and pectate lyases/
many regions around the world. polygalacturonases represent the major pollen allergens of
This approach to the classification Fagales, Oleaceae, and Cupressaceae, respectively
of allergenic trees according to • Bet v 1-like allergens are responsible for allergic cross-reactions
their phylogeny provides useful among Fagales pollen and various fruits and vegetables, a clinical
guidance both for their geograph- condition referred to as oral allergy syndrome
ical distribution and typical flow- • Ole e 1-like allergens and pectate lyases/polygalacturonases are
ering seasons (Figure 1). Thus, Fa- responsible for extensive IgE cross-reactivity between Oleaceae
gales trees are widely distributed and Cupressaceae plants, respectively
within the temperate climate zone
of the Northern hemisphere and
predominantly flower in spring. elicited by the Bet v 1-like aller- OLEACEAE POLLEN ALLERGENS
Oleaceae trees grow in the Medi- gens, which belong to the family Ole e 1-like glycoproteins repre-
terranean areas as well as in oth- 10 of plant pathogenesis-related sent the major allergen of aller-
er parts of the temperate climate proteins. Besides cross-reactiv- genic Oleaceae trees, including
zone. Their flowering season vary ity between Fagales trees, Bet v olive, ash, and privet (Table 1). It
according to regions, ranging from has been shown that exposure to
1 sensitization often leads to al-
early January to June. Cupres- high loads of olive pollen can lead
lergic reactions to various fruits
saceae plants are widely distrib- to increased sensitization rates
and vegetables due to homolo-
uted in parts of Europe, Asia and to minor allergens (lipid-transfer
gous proteins found in certain
Northern America, with pollina- proteins, 1,3-beta-glucanase) and
tion periods occurring between plant families, including Rosaceae,
correlates with more severe aller-
January and April, depending on Apiacea, and Fabaceae (Figure
gic symptoms, including asthma.
the region. Figure 2 shows sensiti- 3). Furthermore, pan-allergens
zation rates to representative tree belonging to the families of calci- CUPRESSACEAE POLLEN
pollen allergen sources in four- um-binding proteins and profilin ALLERGENS
teen European countries. contribute to the extensive food The major pollen allergens from
and pollen cross-reactive patterns Cupressaceae trees (e.g. cypress,
FAGALES POLLEN ALLERGENS observed among Fagales-sensi- mountain cedar, Japanese cedar)
Fagales pollen allergies are mainly tized patients. belong to the family of pectate

18 Tree pollen allergens

Global atlas oF allergy

Betula ssp Quercus ssp

Olea ssp Fraxinus ssp

Section A - Allergy - from genetics to mechanisms

Cryptomeria ssp Juniperus ssp

Figure 1   Word maps showing the distribution of trees causing respiratory allergic reactions. Representative members
of the Fagales family (Betula and Quercus), the Oleaceae family (Olea and Fraxinus), and the Cupressaceae family
(Cryptomeria and Juniperus) are depicted in the maps as density of registered data (increasing density from yellow to
orange) within the Global Biodiversity Information Facility (www.gbif.org), a free and open access data infrastructure
funded by governments.

Tree pollen allergens 19

 Global atlas oF allergy

Figure 2  Sensitization (colored)

and clinically relevant sensitization
rates (striped) to tree pollen allergens
from the GA2LEN skin test study II.
Patients (n=3034) referred to allergy
clinics in 14 European countries
were diagnosed using skin prick test
extracts of birch, olive and cypress.
In Northern and central European
countries, a high prevalence to
birch pollen was observed while
reactivity to cypress was generally
low. Sensitization to olive was most
abundant in Switzerland and Greece
suggesting an involvement of cross-
reactive ash-tree pollen. The majority
of sensitized patients (66%-75%)
displayed clinical symptoms to the
allergen elicitor. (Reproduced with
permission from Burbach GJ, Heinzerling
LM, Edenharter G, et al. GA(2)LEN
Section A - Allergy - from genetics to mechanisms

skin test study II: clinical relevance

of inhalant allergen sensitizations in
Europe.Allergy 2009,64:1507-1515,
with permission from Willey Blackwell.)

lyases and polygalacturonases. Oleaceae, and Cupressaceae be- few protein families and show
Natural purified Cupressaceae long to distinct families of pro- distinct patterns of species dis-
allergens display extensive IgE teins, and thus represent ideal tribution. J Allergy Clin Immunol
cross-reactivity, which is partly tools for molecule-based diagno- 2006;117:141–147.
due to the presence of cross-reac- sis and therapy of tree pollen al- 3. Villalba M, Rodriguez R, Batane-
tive carbohydrate determinants. lergies. ro E. The spectrum of olive pollen
In addition, the overlap of flower-
allergens. From structures to di-
ing period with winter flu seasons KEY REFERENCES
agnosis and treatment. Methods
complicates the clinical diagnosis 1. Mothes N, Valenta R. Biology of
2013;66:44-54.
of Cupressacea pollen allergies. tree pollen allergens. Curr Allergy
Asthma Rep 2004;4:384-390. 4. Charpin D, Calleja M, Lahoz C, Pi-
CONCLUSION 2. Radauer C, Breiteneder H. Pol- chot C, Waisel Y. Allergy to cypress
The major allergens of Fagales, len allergens are restricted to pollen. Allergy 2005;60:293-301.

20 Tree pollen allergens

Global atlas oF allergy

Tree pollen allergens Cross-reactive allergens

Oleaceae
Fagales pollen Cupressaceae
pollen Pollen Fruits Vegetables Other
allergens pollen allergens
allergens

Major allergens

Alder (Aln g 1) Gold kiwi (Act c 8) Celery (Api Hazelnut (Cor

Birch (Bet v 1) Kiwi (Act d 8) g 1) a 1)
Bet v 1-related proteins

Hornbeam (Car Kiwi (Act d 11) Carrot (Dau Soy (Gly m 4)

b 1) Peanut (Ara h 8) c 1) Mung bean (Vig
Chestnut (Cas Strawberry (Fra a 1) Tomato r 1)
s 1) Apple (Mal d 1) (Sola l 4)
Hazel (Cor a 1) Apricot (Pru ar 1)
Beech (Fag s 1) Sweet cherry (Pru av 1)
Hophornbeam Peach (Pru p 1) Bet v 1-associated
(Ost c 1) Pear (Pyr c 1) oral allergy syndrome
Oak (Que a 1) Red raspberry (Rub i 1)

Ash (Fra e 1) Sweet beet (Beta v 1)

Ole e 1-related

Privet (Lig v 1) Pigweed (Che a 1)

proteins

Lilac (Syr v 1) Privet (Lig v 1)

Rye grass (Lol p 11)
Timothy grass (Phl p 11)
English plantain (Pla l 1)
Russian thistle (Sal k 5)

Section A - Allergy - from genetics to mechanisms

Japanese cypress (Cha o 1) Ragweed (Amb a 1)
Pectate lyases

Japanese cedar (Cry j 1) Mugwort (Art v 6)

Cypress (Cup a 1)
Common cypress (Cup s 1)
Mountain cedar (Jun a 1)
Eastern red cedar (Jun v 1)
Japanese cypress (Cha o 2)
galacturonases

Japanese cedar (Cry j 2)

Mountain cedar (Jun a 2)
Poly-

English plane tree (Pla a 2)

English plane tree (Pla a 2)

Minor allergens
Birch (Bet v 2) Olive (Ole e 2) Ragweed (Amb a 8) Kiwi (Act d 9) Celery (Api Hazelnut (Cor
Redroot pigweed (Ama r 2) Pineapple (Ana c 1) g 4) a 2)
Mugwort (Art v 4) Peanut (Ara h 5) Bell pepper Saffron crocus
Sweet beet (Beta v 2) Sweet orange (Cit s 2) (Cap a 2) (Cro s 2)
Turnip (Bra r 5) Melon (Cuc m 2) Carro (Dau Soy (Gly m 3)
Pigweed (Che a 2) Strawberry (Fra a 4) c 4) Latex (Hev b 8)
Profilins

Bermuda grass (Cyn d 12) Litchi (Lit c 1) Tomato Barley (Hor v 12)
Sunflower (Hel a 2) Apple (Mal d 4) (Sola l 1) Rice (Ory s 12)
Annual mercury (Mer a 1) Banana (Mus a 1) Almond (Pru
Wall pellitory (Par j 3) Sweet cherry (Pru av 4) du 4)
Timothy grass (Phl p 12) Peach (Pru p 4) Yellow mustard
Date palm (Pho d 2) Pear (Pyr c 4) (Sin a 4)
Russian thistle (Sal k 4) Wheat (Tri a 12)
Maize (Zea m 12)

Alder (Aln g 4) Olive (Ole e 3) Prickly juniper (Jun o 4) Ragweed (Amb a 9)

Birch (Bet v 3) Olive (Ole e 8) Ragweed (Amb a 10)
Polcalcins

Birch (Bet v 4) Lilac (Syr v 3) Mugwort (Art v 5)

Pigweeed (Che a 3)
Bermuda grass (Cyn d 7)
Wall pellitory (Par j 4)
Timothy grass (Phl p 7)
Birch (Bet v 6) Olive (Ole e 4) Common cypress (Cup s 3)
Hazel (Cor a 6) Olive (Ole e 5) Mountain cedar (Jun a 3) Figure 3  Major and minor allergens identified in pollen from
Other minor
allergens

Birch (Bet v 7) Olive (Ole e 6) Eastern red cedar (Jun v 3) Fagales, Oleaceae, and Cupressaceae trees. Cross-reactive
Olive (Ole e 7) Prickly juniper (Jun a 4)
Olive (Ole e 9)
allergens identified in other allergen sources are shown in the
Olive (Ole e 10) left panel. IgE cross-reactivity between Bet v 1-like proteins
Olive (Ole e 11) found in pollen, fruits, and vegetables can cause a clinical
condition referred to as Oral Allergy Syndrome.

Tree pollen allergens 21

 Global atlas oF allergy

Grass Pollen
3g Allergens
Jörg Kleine-Tebbe  Janet Davies 
Allergy & Asthma Center Westend The University of Queensland
Berlin, Germany Brisbane, Australia

Botanical relationship
Grasses are ubiquitous plants in Ke y m essag es
most parts of the world. The grass
Section A - Allergy - from genetics to mechanisms

family (Poaceae) includes >600 • Pollens from diverse grass plants are main contributors to
genera and >11,000 recognized seasonal inhalant allergies worldwide
species with a wide distribution. • Grass group 1 and 5 allergens represent highly cross-reactive
Over 95% of allergy-relevant and potent major allergens, group 5 present only in temperate
grass species belong to three sub- climate grasses (Pooideae)
families; Pooideae, Chloridoideae • Depending on climate and region, global sensitization rates to
and Panicoideae (Figure 1 and 2). grass pollen vary between 1% to 30% of the general population
• Strong evidence supports specific immunotherapy with grass
Global distribution pollen extracts
Depending on climate and geogra-
phy, grass pollens represent major consist of major (>50% sensitiza- been adopted by the European
contributors of airborne allergens tion rate, SR) and minor allergens Medicines Agency (EMA).
during spring as well as summer. (<50% SR). Due to their abun-
They grow on all continents and dance and potency, grass group Clinical allergy based on
represent 25% to 35% of the 1 and 5 allergens are considered sensitizations
earth´s vegetation. Pooideae dom- immunodominant major Pooideae Sensitizations to grass pollen al-
inate temperate climate zones; pollen allergens (Figure 4). While lergens, indicated by grass pollen
Chlorodoideae cover the North group 5 allergens are restricted allergen (extract) positive skin
American, African and Australian to the Pooideae subfamily, group test or specific IgE, reflect regional
continents and Panicoideae grow 1 allergens are present through- plant distribution and pollen ex-
in tropical and subtropical envi- out the subfamilies of Poaceae. In posure. Population based sensiti-
ronments of Asia, Australia, Africa contrast, pan-allergens profilin zation rates are mainly available
and South America (Figure 3). (group 12) and polcalcin (group 7) for Europe and the US and vary
contribute to ubiquitous cross-re- considerably between and within
Allergens of grass pollen activity between grass, tree and countries (Figure 5). Grass pollen
Grass pollen allergens are grouped weed pollen in 10 – 15% of grass allergy is a global problem (Figure
according to their protein struc- pollen sensitized subjects. Present 5c). At least half of grass pollen
ture and function (Table 1). They concepts of homologous allergen allergen sensitized subjects will
are named according to the offi- groups, are based on similar bio- suffer from symptoms of allergic
cial nomenclature (www.allergen. chemical composition, homology rhinoconjunctivitis and/or bron-
org), i.e.: Phl p 1 = grass group 1 al- and immune cross-reactivity re- chial asthma, particularly during
lergen from Phleum pratense (tim- flecting in most cases their close the warm seasons in moderate cli-
othy grass). Ten designated groups taxonomic relationship and have mate regions.

22 Grass pollen allergens

Global atlas oF allergy

a b

Section A - Allergy - from genetics to mechanisms

Figure 1   Pictures of different grass species and their pollen : a - Timothy grass (Phleum pratense), subfamily Pooideae;
b-Bermuda grass (Cynodon dactylon), subfamily Chloridoideae; c - Bahia grass (Paspalum notatum), subfamily Panicoideae.

Family Subfamily Tribe Genus Common name (US)

Poaceae Bambusoideae Oryzeae Oryza (Rice)

Arundinoideae Arundineae Phragmites (Common reed)

Chloridoideae Chlorideae Cynodon (Bermuda grass)

Paniceae Paspalum (Bahia grass)

Panicoideae
Sorghum (Johnson grass)
Andropogoneae
Zea (Corn, maize)

Dactylis (Orchard grass)

Festuca (Meadow fescue)
Poeae
Lolium (Perennial rye)
Poa (Kentucky bluegrass)

Anthoxanthum (Sweet vernal grass)

Avena (Cultivated oat)
Aveneae
Pooideae Holcus (Velvet grass)
Phleum (Timothy grass)

Bromeae Bromus (Smooth brome grass)

Hordeum (Barley)
Triticeae Secale (Cultivated rye)
Triticum (Wheat)

Figure 2   Taxonomy of grasses (important subfamilies within colored boxes). Overlapping circles (colored lines) indicate
partial cross-reactivity between neighboring subfamilies (modified from (2), (4) and (10)).

Grass pollen allergens 23

 Global atlas oF allergy

In: Lockey RF, Ledford DK, ed-

itors. Allergens and Allergen
Immunotherapy. 4th Edition ed:
Informa Healthcare, New York;
2008. p. 107-126.
2. Andersson K, Lidholm J. Charac-
teristics and immunobiology of
grass pollen allergens. Int Arch Al-
lergy Immunol 2003;130:87-107.
3. Hrabina M, Peltre G, van Ree R,
a Moingeon P. Grass pollen allergens.
Clin Exp Allergy Rev 2008;8:7-11.
4. Gangl K, Niederberger V, Va-
lenta R. Multiple grass mixes as
opposed to single grasses for
allergen immunotherapy in al-
lergic rhinitis. Clin Exp Allergy
2013;43:1202-1216.
5. Lorenz AR, Lüttkopf D, May S,
Scheurer S, Vieths S. The princi-
Section A - Allergy - from genetics to mechanisms

ple of homologous groups in reg-

b ulatory affairs of allergen prod-
ucts--a proposal. Int Arch Allergy
Immunol 2009;148:1-17.
6. European Medicines Agen-
cy (EMA). Guideline on aller-
gen products:production and
quality issues. (EMEA/CHMP/
BWP/304831/2007) 2009.
7. Newson RB, van Ree R, Forsberg
B, Janson C, Lotvall J, Dahlen SE
c et al. Geographical variation in
the prevalence of sensitization to
common aeroallergens in adults:
the GA2LEN survey. Allergy
Figure 3  Global distribution of selected grass species (10): a- Timothy grass
2014;69:643-651.
(Phleum pratense), subfamily Pooideae; b-Bermuda grass (Cynodon dactylon), sub-
family Chloridoideae; c-Bahia grass (Paspalum notatum), subfamily Panicoideae. 8. Salo PM, Arbes SJ Jr, Jaramillo R,
Calatroni A, Weir CH, Sever ML,
Diagnosis and treatment gual home use of droplets or tab- et. al Prevalence of allergic sen-
Positive skin prick tests and ele- lets with monopreparations of one sitization in the United States:
vated specific serum IgE to grass grass species, but also grass mixes Results from the National Health
pollen preparations indicate al- and Nutrition Examination Sur-
(mainly Pooideae), with or without
vey (NHANES) 2005-2006. J Al-
lergic sensitizations, being clini- adjuvants. lergy Clin Immunol 2014 (in press).
cally relevant only in case of cor-
responding symptoms. Measuring Acknowledgement: We kindly 9. Davies JM. Grass pollen aller-
acknowledge Andreas Nandy gens globally; the contribution of
IgE to major allergens (i.e. Phl p 1
(Allergopharma, Reinbek, Germa- subtropical grasses to burden of
and 5) increases analytical spec- allergic respiratory diseases. Clin
ificity for temperate grass pol- ny), Jonas Lidholm and Kerstin Wall Exp Allergy 2014;44:790-801.
len allergy, particularly in case of (ThermoFisher, Uppsala, Sweden)
10. Simon BK, Clayton WD, Harman
sensitizations to cross-reactive for additional information and KT, Vorontsova M, Brake I, Healy
pollen-panallergens. Specific im- helpful suggestions. D and Alfonso Y. 2011. Grass-
munotherapy is most successfully World, http://grassworld.mys-
applied for at least three years by Key References pecies.info/ (Accessed April 25,
subcutaneous injections or sublin- 1. Esch RE. Grass pollen allergens. 2014).

24 Grass pollen allergens

Global atlas oF allergy

TABLE 1
Grass pollen allergen groups
Allergen Biochemical Molecular- Member in IgE
Features
group function weight [kDa] Phleum pratense reactivity
Glycoprotein, major grass pollen allergen, >90%
1 β-expansin 27 - 35 Phl p 1
produced by every grass species 85-99%
highly homologous to group 3 and 35 - 50%
2 Unknown 11 Phl p 2
C-terminal portion of group 1 allergens 40-60 %
highly homologous to group 2 and 35 - 70%
3 Unknown 11 - 14 Phl p 3
C-terminal portion of group 1 allergens 57-67 %
Glycoprotein, Berberine bridge enzyme
Oxidoreduc- 50 - 75%
4 50 - 60 Phl p 4 family member, plant pathogen response
tase 45 - 88%
system
found in Pooideae grass species, associated
65 - 85%
5 Unknown 27 - 35 Phl p 5 with submicronic cytoplasmic starch
50 - 88 %
particles
homologous to internal group 5 sequences,
60 - 70%
6 Unknown 12 - 13 Phl p 6 only in Anthoxanthum odoratum, Phleum
45 - 70%
pratense and Poa pratensis

Section A - Allergy - from genetics to mechanisms

Polcalcin, Ca++- Panallergen, dimer assembly in grass 5 - 35%
7 8 - 12 Phl p 7
binding protein pollen, broad pollen-related crossreactivity 2 - 12%
Glycoprotein, similar structure to pollen
Ole e 1-related
11 16 - 20 Phl p 11 allergens from olive tree pollen (Ole e 1) 18 - 56%
protein
and lamb´s quarter (Che a 1)
Panallergen, highly conserved, broad pollen 10 - 40%
12 Profilin 13 - 14 Phl p 12
and plant food-related crossreactivity 9 - 32%
Polygalacturo- Glycoprotein, susceptible to protease 30 - 40%
13 45 - 60 Phl p 13
nase degradation 36 - 56 %
Modified from (1). Due to their taxonomic and biochemical relationship, many grasses contain similar allergens grouped accor-
ding to shared amino acid sequences. Specific allergens from timothy grass (Phleum pratense, see middle column) are given as
examples of the listed grass allergen groups.

Prevalence

Group
1
Group Figure 4   Involvement of
High
4 Group
grass pollen allergens in patient
5 sensitization (3).
Group
2/3
50% Group
Group 13
11

Low Group
12
Group
Group 7
10

Low 40% High Potency

(mean IgE level)

Grass pollen allergens 25

 Global atlas oF allergy

14.5 17
25

21
20
22

23.5
b
17
22 29.5
22.5
10
10 11
24.5 28.5 21.5

24 15.5
18
12.5
Section A - Allergy - from genetics to mechanisms

c
a

Saudi Arabia
Taiwan (AR, 419)
61%  AR (54)
▼ 10%,
Southern USA  2.1%
▲ 57% AR (429) Thailand (AR, 100)
▼21%,
▲16%
India
17%
12.5%, (AR/A, 48)
52% (GPA, 133)

Malaysia (A, 100)

20.5%,
SPT test:
▲6.5%
▼Johnson GP
▲Bahia Australia (GPA, 48)
Bermuda GP Zimbabwe ▼77%
(number tested) 50.4%  AR (341) ▲81%
Subject group: d 84%
A, asthma
AR, allergic rhinitis,
GPA, grass pollen allergic

Figure 5   Sensitization rates to grass pollen (Pooideae) in Europe (a: modified from (7)), to Ryegrass (b) and Bermuda
grass (c ) in the US (b and c: modified from (8)) and to Johnson, Bahia and Bermuda grass pollen elsewhere (d: limited
information, modified from (9)).

26 Grass pollen allergens

Global atlas oF allergy

Weed pollen
3h allergens
Richard W. Weber 
National Jewish Medical & Research Center
Denver, USA

Weeds can be defined as un-

wanted plants; as such, they may Ke y m essag es
be very variable in form. While

Section A - Allergy - from genetics to mechanisms

many are herbaceous, some have • The major weeds families inducing allergic rhinitis are the
greater or lesser woody stocks, Amaranthaceae, the Asteraceae and the Urticaceae
for example the sagebrushes, Ar- • Cross-reactivity between family members is frequent
temisia tridentata and A. frigida. • In most temperate regions the weeds pollen season is August
Some are prostrate and hug the and September, but climate change can be associated with a
ground, while others, such as giant lengthening of the pollination period
ragweed, Ambrosia trifida, may be
over 3 meters high. Herbaceous
varieties may be annuals or per- in arid floristic zones. Redroot can natives, but most of them have
ennials. Weeds found in numerous pigweed (A. retroflexus) is a ubiq- been introduced into Europe, and
botanical families can be inducers uitous cosmopolitan weed, found have rapidly expanded across the
of allergic rhinitis and asthma, but throughout temperate regions of Balkans, Ukraine, and into Poland.
a few families stand out with the the globe. Allergenic cross-reac- In most temperate regions the pol-
majority of aeroallergen sources. tivity is very strong amongst the len season is August and Septem-
Atriplex weeds, and likewise be- ber. Cross-allergenicity is strong
Amaranthaceae contains the pig-
tween the Amaranthus species ex- amongst the major ragweed spe-
weeds (Amaranthus), saltbush-
amined; cross-reactivity between cies. Other important members of
es (Atriplex), and tumbleweeds
other chenopod weeds is present Asteraceae are in the genus Arte-
(Salsola, Kochia, Bassia) as well as
but more variable. misia, the sages. There are about a
other chenopod weeds (Cheno-
dozen species found in the United
podium). The latter three groups Asteraceae (previously known as
States. The most prevalent in east-
were earlier placed in a separate Compositae) is the largest family
ern U.S. and Europe is mugwort
family, Chenopodiaceae. More of flowering plants (Angiosper-
(A. vulgaris). Fringed sagebrush (A.
recent systematics has, however, mae), and contains several noto-
frigida) is a common groundcover
redefined this group as a subfam- rious inducers of pollinosis. The
in the Siberian steppes. Cross-re-
ily of Amaranthaceae. The major genus Ambrosia contains all the
activity is very strong between Ar-
tumbleweeds of the North Amer- ragweeds, including several re-
temisia species.
ican Great Plains are Russian classified from the discarded ge-
thistle (Salsola kali) and burning nus Franseria. The four major rag- Urticaceae includes two members
bush (Kochia scoparia): both are weed (Artemisia) species are giant of significance: pellitory (Parietar-
introduced plants. Other species (A. trifida) (Figure 1), short (A. ar- ia) (figure 3) and nettle (Urtica).
of Salsola and Bassia are common temisiifolia) (Figure 2), western (A. Pellitory is a major seasonal aer-
throughout the Middle East. The psilostachya), and false (A. acanthi- oallergen of the Mediterranean
Atriplex saltbushes are common carpa). These are all North Ameri- Basin. Climate change is associat-

Weed pollen allergens 27

 Global atlas oF allergy

b
Section A - Allergy - from genetics to mechanisms

a c
Figure 1  a - Giant sagebrush (Artemisia); b - short ragweed; c- pellitory (Parietaria).

ed with a lengthening of its pollen 3. Smith M, Cecchi L, Skjøth CA, Ledoux RA, Westley CR, Weber
season to about ten months. Karrer G, Šikoparija B. Common RW. Mugwort and sage (Artemi-
ragweed: a threat to environmen- sia) pollen cross-reactivity: ELISA
KEY REFERENCES tal health in Europe. Environ Int inhibition and immunoblot evalu-
1. Judd WS, Campbell CS, Kellogg 2013;61:115-126. ation. Ann Allergy Asthma Immunol
EA, Stevens PF. Plant Systematics: 4. Leiferman KM, Gleich GJ, Jones RT. 1997;79:340-346.
A Phylogenetic Approach. Sun- The cross-reactivity of IgE antibod- 6. Ariano R, Canonica GW, Passa-
derland, MA, Sinauer Associates, ies with pollen allergens. II. Analy- lacqua G. Possible role of climate
1999:240-7. ses of various species of ragweed changes in variations in pollen
2. Weber RW. Cross-reactivity of and other fall weed pollens. J Aller- seasons and allergic sensitizations
plant and animal allergens. Clin Rev gy Clin Immunol 1976;58:140-148. during 27 years. Ann Allergy Asthma
Allergy Immunol 2001;21:153-202. 5. Katial RK, Lin FL, Stafford WW, Immunol 2010;104:215-222.

28 Weed pollen allergens

Global atlas oF allergy

3i Food allergens

Barbara Ballmer-Weber 
University Hospital Zürich
Zürich, Switzerland

Depending on the route of sen-

sitization, immediate-type food Ke y m essag es
hypersensitivities are either a

Section A - Allergy - from genetics to mechanisms

result of reactivity to food aller- • Differences in sensitization to food allergens across different
gens through the gastrointesti- geographic regions have been particularly observed for plant
nal tract (class I allergens) or the food allergens
result of secondary sensitization • 65% of plant food allergens are part of four protein families/
to cross-reactive food allergens superfamilies: the prolamin, cupin, Bet v 1 and profilin family
mainly due to primary sensitiza- • In Europe, the prevalence of IgE to foods significantly correlates
tion to homologous pollen aller- with the prevalence of sensitization to birch-pollen-associated
gens via the respiratory tract (class allergens Bet v 1 and Bet v 2
II allergens, Figure 1). Class I aller- • Food allergic patients from Mediterranean countries show a
gens are often resistant to heat, higher sensitization rate to profilin and non-specific lipid transfer
degradation and digestion. Class II proteins compared to Central, Western or Eastern Europe
allergens are mainly labile and eas-
ily degradable. According to these
characteristics the clinical mani- More than 65% of plant food al- 6.6% (Iceland) to 23.6% (Switzer-
festation is influenced by the type lergens are members of just four land) and was significantly corre-
of allergens to which an individual protein families/superfamilies: lated with the prevalence of sensi-
is sensitized. The class I allergens the prolamin, cupin, Bet v 1 and tization to birch-pollen-associated
have a higher potential to induce profilin family (Table 1). Animal allergens Bet v 1 and Bet v 2 (pro-
severe reactions compared to the derived food allergens mainly be- filin), whereas IgE sensitization to
easily degradable class II food al- long to three protein families: the non-pollen-related plant allergens
lergens, which induce often symp- tropomyosins, parvalbumins and were more evenly distributed.
toms restricted to the oral cavity. caseins. These results confirmed the find-
Due to such reasons, great efforts At school age, adolescence and ings from studies evaluating the
have been made in the last few adulthood cross-reactive food al- sensitisation pattern to food aller-
years to identify and characterize lergy is dominating. According to gens across Europe. Sensitization
individual food allergen molecules new epidemiologic data sensitiza- rates to the Bet v 1 homologous
in the most prevalent allergenic tion to the respective food aller- proteins in apple (Mal d 1), kiwi
foods (http://www.allergen.org/; gens is heavily dependent on the (Act d 8), carrot (Dau c 1) or ha-
http://www.allergome.org/; http:// exposure and sensitization to in- zelnut (Cor a 1) were significantly
www.meduniwien.ac.at/allergens/ halant allergens. In a recent study higher in countries with high birch
allfam/) and to compare sensiti- including adult participants from pollen exposure such the Neth-
zation patterns between different eight European centres the preva- erlands, Austria, Northern Italy,
geographic regions. lence of IgE to foods ranged from Switzerland and Denmark com-

Food allergens 29
Section A - Allergy - from genetics to mechanisms Global atlas oF allergy

Figure 1  Homology between the major birch pollen allergen Bet v 1 and homologous food protein. High structural
homology between the major birch pollen allergen Bet v 1 (top) and homologous food protein (here as an example the
cherry allergen Pru av 1, bottom) explains the phenomenon of cross-sensitization between birch pollen and plant foods
and the high prevalence of sensitization to foods in birch pollen exposed regions of Europe.

TABLE 1
Most important protein families for plant food allergies

Protein Thaumatin-like
Prolamin Cupin Profilin Bet v 1
family protein

Biochemical 7S-globulin 11S-globulin

2S albumin nsLTP
structure vicilin legumin

pathogen
storage plant storage storage actin pathogen
function resistance
protein defense protein protein binding resistance PR-5
PR-10

Rosaceae Rosaceae cherry, apple,

peanut, soy,
fruits, peanut, soy, fruits, peach, tomato,
examples of tree nuts, peanut, soy, all plant
nuts, pea, lentil, nuts, orange, grape,
foods sesame, nuts foods
seeds, nuts, sesame legumes, kiwi, bell
mustard
vegetables vegetables pepper

30 Food allergens
Global atlas oF allergy

70
Northern Europe

60 Central/Western Europe

Eastern Europe
% of kiwi allergics (n=311)

50
Southern Europe

40

30

20

10

Section A - Allergy - from genetics to mechanisms

0
Act d 1 Act d 5 Act d 8 Act d 9 Act d 10

Figure 2  Sensitization pattern to kiwi allergens. Sensitization pattern to kiwi allergens Act d 1 (Actinidin), Act d 5
(Kiwellin), Act d 8 (Bet v 1 homologous protein), Act d 9 (Profilin) and Act d 10 (non-specific LTP) in four European regions
(northern: Iceland; central/western: France, northern Italy, Switzerland, The Netherlands, United Kingdom; eastern:
Bulgaria, Poland, Czech Republic, Lithuania, southern: Spain, Greece). Patients from Iceland were mainly sensitized to
Act d 1 (32%), those from western/central and eastern Europe to Act d 8 (58% and 44%, respectively), and those from
southern Europe to Act d 9 (profilin, 31%) and Act d 10 (non-specific LTP, 22%) (Le et al., J Allergy Clin Immunol 2013).

pared to that observed in Medi- Differences in the sensitization 3. Le TM, Bublin M, Breiteneder H,
terranean countries such as Spain pattern were also demonstrated Fernández-Rivas M, Asero R, Ball-
or Greece (Figure 2: sensitization for children with peanut allergy mer-Weber BK, et al. Kiwifruit
from three different geographic allergy across Europe: clinical
pattern to kiwifruit allergens
regions. Spanish patients were manifestation and IgE recognition
across Europe). Spanish and Greek patterns to kiwifruit allergens. J Al-
patients, however, showed a high- mainly sensitised to non-specific
lergy Clin Immunol 2013;131:164-
LTP (Ara h 9), Swedish patients to
er sensitization rate to profilin and 171.
the Bet v 1 homologous allergen
non-specific Lipid transfer protein 4. Ballmer-Weber BK, Skamstrup
Ara h 8 and US patients to the
(LTP). A similar association of sen- Hansen K, Sastre J, Andersson K,
storage proteins in peanut Ara h 1,
sitisation to pollen from the Betu- Ara h 2 and Ara h 3. Bätscher I, Ostling J et al. Com-
laceae family, particular alder, and ponent-resolved in vitro diagno-
the development of fruit allergy sis of carrot allergy in three dif-
KEY REFERENCES
was observed in Japan. Sensitiza- ferent regions of Europe. Allergy
1. Breiteneder H, Mills EN. Molecular
properties of food allergens. J Aller- 2012;67:758-766.
tion to food LTP is highly prevalent
in Mediterranean countries and gy Clin Immunol 2005;115:14-23. 5. Vereda A, van Hage M, Ahlstedt S,
2. Burney PG, Potts J, Kummeling I, Ibañez MD, Cuesta-Herranz J, van
associated with a higher rate of
Mills EN, Clausen M, Dubakiene R, Odijk J et al. Peanut allergy: Clini-
systemic reactions. Also in China cal and immunologic differences
et al. The prevalence and distribu-
sensitization to peach LTP, Pru p 3, tion of food sensitization in Euro- among patients from 3 different
was associated with a high rate of pean adults. Allergy 2014;69:365- geographic regions. J Allergy Clin
systemic reactions. 371. Immunol 2011;127:603-607.

Food allergens 31
 Global atlas oF allergy

3j Venom allergens

Franziska Ruëff 
Ludwig-Maximilian University
Munich, Germany

Insects
For allergic sting reactions, main- Ke y m essag es
ly social Aculeatae are important
Section A - Allergy - from genetics to mechanisms

elicitors. Social insects have de- • 12 molecular allergens of honey bee venom, and five of Vespula
veloped a division of labour with venom are known and have been sequenced
sterile females forming a work- • Use of molecular allergens has improved testing of venom-
ing class. Female workers have a specific IgE antibodies
stinger by which venom is injected • Further research on the clinical role of individual molecular
during a sting into the skin. Within insect venom allergens is needed
the Aculeatae, Vespidae (vespids), • Allergen components of the venoms should be available for
Apidae (bees), and Formidaceae routine testing
(ants) are social insects (Figures
1 and 2). Vespidae are divided into
the subfamilies Polistinae and Ves- eliciting an allergic reaction. Mi-
pinae. The latter contains three nor allergens may also induce sIgE,
genera: Vespula, Dolichovespula however, this occurs in a small
and Vespa. percentage of venom allergic pa-
tients.
Insect venoms Phospholipase A2, hyaluronidase,
Insect venoms contain a complex and acid phosphatase are the ma-
mixture of toxic proteins and pep- jor bee venom allergens. Major
tides, of which some may induce allergens of Vespula venom are
IgE-mediated sensitisation. Today, Phospholipase A1, Hyaluronidase, a
12 molecular allergens of hon- and Antigen 5. Some allergens of
ey bee venom, and 5 of Vespula
Vespula and bee venom share mi-
venom are known and have been
nor to moderate sequence iden-
sequenced (Table 1). For some of
tity and show a corresponding
these allergens, isoforms have
cross-reactivity. However, the
been detected.
closer is the taxonomic relation-
Major allergens are characterized ship of insects the greater is the
by the fact that there is corre- overlap of biochemical structures
sponding specific IgE-antibodies of molecular venom allergens. b
(sIgE) in the blood of the majority Honey bee venom allergens show
of allergic patients. Major aller- more cross-reactivity with bumble
gens are probably more important bee allergens compared to aller- Figure 1  a - Apidae (bee); b-
than minor allergens in terms of gens of the venoms from Vespula Vespidae (vespids).

32 Venom allergens
Global atlas oF allergy

TABLE 1 Testing sIgE to single venom al-

lergens is of major importance for
Most important protein families for plant food allergies
improving sensitivity and specific-
Molecular weight Percent of ity of in-vitro diagnostics. Using
Allergen Name / Function
(KDa) dry weight recombinant allergens improved
Honey bee venom allergens the value of assays testing sIgE to
the whole venom.
Api m 1 Phospholipase A2* 16 12
Api m 2 Hyaluronidase* 39 2 Another problem for the diagnosis
of insect venom allergy is the dou-
Api m 3 Acid phosphatase 43 1-2
ble positivity although presuma-
Api m 4 Melittin* 3 50 bly the patient only suffers from
Api m 5 Dipeptidylpeptidase IV 100 <1 one allergy. Double positivity may
Api m 6 8 1-2 be due to true double allergy, to
Api m 7 CUB serine protease 39 ? cross reactivity between allergen
compounds of honey bee and Ves-
Api m 8 Carboxylesterase 70 ?
pula venoms, and to sensitization
Api m 9 Serine carboxypeptidase 60 ? to widespread cross-reactive car-

Section A - Allergy - from genetics to mechanisms

Icarapin variant 2, car- bohydrate determinants (CCD),
Api m 10 50- <1
bohydrate-rich protein which are present in many aller-
50 (deglycosylated gen sources from plants and ani-
Api m 11 Major royal jelly protein ?
form) mals. The latter, however, usually
Api m 12 Vitellogenin 200 ? do not act as allergens. Allergen
compounds, which are free from
Vespula venom allergens
CCD improve the specificity of in
Ves v 1 Phospholipase A1* 34 6-14 vitro testing.
Ves v 2 Hyaluronidase* 28 1-3
Ves v 3 Dipeptidylpeptidase IV 100 ? KEY REFERENCES
1. Eberlein B, Krischan L, Darsow U,
Ves v 5 Antigen 5* 23 5-10 Ollert M, Ring J. Double positivity
Ves v 6 Vitellogenin 200 ? to bee and wasp venom: improved
diagnostic procedure by recombi-
(IUIS Allergen Nomenclature Sub-Committee. www.allergen.org). Major allergens are
nant allergen-based IgE testing and
indicated by an asterix (*)
basophil activation test including
species. Venom allergens from ey bee venom (Api m 1) and two of data about cross-reactive carbo-
Polistinae or Dolichovespula are Vespula venom (Ves v 1 and 5) are hydrate determinants. J Allergy Clin
more related to Vespula venoms. available for routine diagnostics. Immunol 2012;130:155-161.
It is assumed that in the near fu- 2. Vos B, Köhler J, Müller S, Stretz E,
In-vitro diagnostics of ture more molecular compounds Ruëff F, Jakob T. Spiking venom
venom sensitization will be available to identify venom with rVes v 5 improves sensitivity
Demonstration of venom-specific sIgE. of IgE detection in patients with
sensitization is essential for diag- allergy to Vespula venom. J Aller-
nosing an insect venom allergy and In contrast to certain food al- gy Clin Immunol 2013;131:1225-
is also a prerequisite to select the lergies, where the sensitization 1227.
proper venom for immunothera- patterns were found to be associ- 3. Seismann H, Blank S, Braren I,
py. To identify venom-specific IgE ated with mild or severe allergic Greunke K, Cifuentes L, Grunwald
in human blood, insect venoms reactions and can be used for risk T, et al. Dissecting cross-reactivi-
are in use since the seventies. In assessment, for venom allergy, ty in hymenoptera venom allergy
the late eighties, purified allergens the clinical relevance of a certain by circumvention of alpha-1,3-
were produced. Today, one recom- pattern of venom sIgE remains un- core fucosylation. Mol Immunol
binant allergen component of hon- clear. 2010;47:799-808.

Venom allergens 33
 Global atlas oF allergy

Emerging
3k allergens
Karin Hoffmann-Sommergruber 
Medical University of Vienna
Vienna, Austria

In the recent past, great efforts

have been undertaken to charac- Ke y m essag es
terise allergens. This in turn has
Section A - Allergy - from genetics to mechanisms

revolutionized in vitro diagnosis, • Only a minority of known proteins exert an allergenic activity
by determining the range of cross • Allergen panels contribute to improve in vitro diagnosis of allergy
reactivities and establishing aller- • While some allergens rather induce mild symptoms, others are
gen panels. Of special interest is known to be linked with severe symptoms (marker allergens)
the identification of marker aller- • Depending on environmental exposure and dietary habits IgE
gens: allergens that tend to induce recognition patterns may vary in different patients groups
rather severe symptoms versus
allergens that rather account for
mild symptoms. allergens from mites and cock- sensitization event. This highlights
roaches. that alternative exposures have
It is only a minority of proteins
to be considered if new and unex-
that exert allergenic activity. To Parvalbumins share an EF-hand
domain binding Ca2+ and thus are pected cases of allergies occur.
date allergens can be assigned to
2% of all known protein families. involved in signaling pathways or
Plant-derived food
According to allergen databases, Ca2+ transport. These major food
the dominating protein families allergens were identified from allergens
among animal-derived food aller- fish and amphibians, but not from The non-specific lipid transfer
gens are tropomyosins, parvalbu- higher vertebrates. proteins (LTP) and the 2S albumins
mins and caseins. Similarly, pro- belong to the prolamin superfam-
Caseins are a major heterogenous ily. Both types of proteins display
lamins, cupins and PR10 proteins
protein fraction in mammalian a rigid tertiary structure and are
are the 3 most important plant
milk displaying a random-coiled resistant to enzymatic and ther-
protein families (Table 1).
structure. They function as Ca2+ mal treatment. Non-specific-LTPs
binders and allergenic caseins and are involved in plant defense, and
Animal-derived food
are highly cross-reactive among are relevant allergens in various
allergens
mammalian species. fruits, nuts and pollens. 2S albu-
Tropomyosins are highly con-
served eukaryotic proteins with a So far sensitization to carbohy- mins are seed storage proteins
typical coiled-coil structure that drates has been regarded as of and together with the proteins
are necessary for regulating mus- low clinical importance in allergic from the cupin superfamily they
cle contraction. So far, allergenic diseases. However, recently, aller- represent important allergens in
tropomyosins have been identi- gic reactions to alpha-gal epitopes seeds and nuts, usually evoking
fied from e-vertebrates, highly were observed in meat allergy. severe symptoms in patients. The
cross-reactive among crustaceans Previous administration of mono- PR10 proteins, involved in plant
and mollusks, as well as inhalant clonal antibody doses induced the defense, are present in pollen as

34 Emerging allergens
Global atlas oF allergy

TABLE 1 well as in plant food, usually evok-

ing mild oral symptoms. Eventual-
Overview of 3 most important plant and animal food allergen protein
ly, they can induce severe symp-
families
toms as in soy allergy.
Protein su- Protein Biological Molecular Allergens Structure
perfamily family function mass (kDa) known from In conclusion, a number of aller-
gens are now available for compo-
Animal food allergens
nent-resolved in vitro diagnosis.
Analysis of their physicochemical
features, especially their 3D struc-
Muscle Crustaceans,
Tropomyosin 36-38 ture contributes to our under-
contraction molluscs
standing of protein stability, range
PDB: 1C1G of cross reactivity and changes in
allergenicity during thermal or en-
zymatic treatment.
Ca2+ Fish,
Parvalbumin 12 KEY REFERENCES
binding amphibians
1. Radauer C, Bublin M, Wagner S,
PDB:1B8R Mari A, Breiteneder H. Allergens
Ca2+ Mammalian are distributed into few protein

Section A - Allergy - from genetics to mechanisms

Casein 20-30 Not available families and possess a restricted
binding milk
number of biochemical functions. J
Plant food allergens Allergy Clin Immunol 2008:121:847-
852.
2. Hoffmann-Sommergruber K, Mills
Prolamin 2S Seed Peanut, tree ENC. Food allergen protein families
15-17
superfamily Albumin storage nuts, seeds and their structural characteristics
and application in component-re-
PDB: 1PNB solved diagnosis: new data from
the EuroPrevall project. Anal Bio-
anal Chem 2009:395:25-35.
Plant 3. Ballmer-Weber B, Hoffmann-Som-
ns-LTP 7-9 Plant food
defense mergruber K. Molecular diagno-
sis of fruit and vegetable allergy.
PDB: 2B5S Curr Opin Allergy Clin Immunol
2011:3:229-235.
4. Alessandri S, Sancho A, Vieths S,
Cupin 7/8S Seed Legumes, Mills CE, Wal JM, Shewry PR, Rig-
150-190
superfamily globulin storage nuts, seeds by N, Hoffmann-Sommergruber K.
High-throughput NMR assessment
PDB: 3SMH of the tertiary structure of food al-
lergens. PLos One 2012:7:e39785.

11S Seed Peanut, tree

60
globulin storage nuts, seeds

PDB:3FZ3

Plant
PR10 17 Plant food
defense

PDB: 2BKO
(ns-LTP – non-specific Lipid transfer protein; PR10 – pathogenesis related protein
family 10; structures retrieved from pdb)

Emerging allergens 35
 Global atlas oF allergy

3l Pollen allergens and

geographical factors
Jeroen Buters 
Technische Universität München and Helmholtzzentrum
Munich, Germany

Allergies to pollen are the most

frequent type 1 allergies, surpass- Ke y m essag es
ing the prevalence of allergies to
Section A - Allergy - from genetics to mechanisms

house dust mite. Their prevalence • Pollen exposure varies between geographical regions
have been increasing since dec- • The same amount of olive pollen releases 12-fold variable
ades and an end is not in sight. amounts of Ole e 1, 10-fold differences in Bet v 1 is documented
for birch pollen, while Phl p 5 from grass pollen can show even
Pollen is a natural product and higher variations
shows a large geographical and • Pollen allergen release potency is not geographically fixed and
climatic variability. Indeed, natural changes between years
variability is so large that a simple • Pollen allergen release potency is determined in the week before
prediction of pollen load depend- pollination by two simultaneous competing ripening processes:
ing on the year long experience is anther development and individual pollen ripening
not possible. This has led to the im-
plementation of pollen monitoring
networks. Climate change is reported to conditions at source, which var-
influence pollen season for the ies with the geographical location.
Geographic factors and starting date and for the intensi- The amount of allergen released
pollen exposure ty for early blooming species. The per pollen is variable between
Few pollen monitoring networks natural yearly variability in pollen years, locations and even days. In
exist worldwide (Figure 1). In addi- exposure is large, making the ef- a EU-wide project (www.hialine.
tion, rotorod samplers are used in fect of climate change difficult to eu) the allergen release potency
USA, while Hirst-type pollen traps predict. An elongation of the birch for olive, birch and grass pollen
are frequent in Europe making pollen season was reported only was analyzed with standardized
quantitative comparison between in a few random places. Pollen methods. Across Europe, pollen
continents challenging. exposure is mostly dependent on potency varied 12-fold for olive
However, similar results emerge: short-term local weather, making pollen, 10-fold for birch pollen
pollen exposure varies substan- on the spot monitoring an essen- and even more for grass pollen.
tially. For Europe, according to a tial instrument in determining ex- Also, potency of pollen from olive
20-year average, birch pollen is posure. and birch depended on the origin
the dominant pollen with 2-times of emission as potency is deter-
higher counts than grass pollen Geographical factors and mined by weather at the place of
in almost all reported locations. pollen potency emission, not at the place of meas-
Between locations, a 10-fold dif- Pollens are natural products and uring the pollen. Within Germany,
ference of pollen load was noted like wine and strawberries their a constant 3-fold gradient of birch
(Figure 2). “quality” depends on the climatic pollen potency is observed, with

36 Pollen allergens and geographical factors

Global atlas oF allergy

Rotorod
Durham
Hirst-type

Section A - Allergy - from genetics to mechanisms

Figure 1  Pollen monitoring networks across the world. Current pollen monitoring sites running for more than 6 years.
Three different types of pollen counters are in use worldwide: Rotorod, Durham and Hirst-type traps. This makes pollen
counts difficult to compare. Data from Europe were provided by U. Berger, European Aerobiology Network (EAN),
Medical University Vienna, from USA by Jerome Schultz (AAAAI), from Russia by E. Severova, from Japan by R. Kishikawa,
from South Africa by D. Byrman, from Israel by A. Eshel, from Saudi Arabia by H. Syed, from Azores by Rui Brandao, from
Canada by F. Coates and from Australia by Janet Davies. For some countries data was not available.

southern pollen being more po- Conclusion 3. Smith M, Jäger S, Berge U, Sikopari-
tent that northern pollen. In the All investigated aeroallergens:pol- ja B, Hallsdottir M, Sauline I et al.
len from birch, olive and grass, but Geographic and temporal varia-
same line, olive pollen from Spain
also from cat, dog and horse vary tions in pollen exposure across Eu-
released 5 times more Ole e 1 than rope. Allergy, In press 2014.
Portugese olive pollen. at least 10-fold in allergen release
within the same species. We ex- 4. Buters JTM, Thibaudon M, Smith
The difference in pollen potency pect the same for other sources. M, Kennedy R, Rantio-Lehtimaa-
could be due to two competing rip- ki A, Albertini R, et al. Release of
Bet v 1 from birch pollen from 5
ening processes: allergen expres- KEY REFERENCES
European countries. Results from
sion in pollen increases from zero 1. Langen U, Schmitz R, Steppuhn H.
the HIALINE study. Atmos Environ
[Prevalence of allergic diseases in
in the week before pollination to 2012;55:496-505.
Germany: results of the German
high numbers upon pollination Health Interview and Examina- 5. Galan C, Antunes C, Brandao R,
(ripening of Bet v 1). Concomitant- tion Survey for Adults (DEGS1)]. Torres C, Garcia-Mozo H, Caeiro E,
ly the anthers ripen too, and will Bundesgesundheitsblatt Gesund- et al. Airborne olive pollen counts
release pollen when they are ripe heitsforschung Gesundheitsschutz are not representative of exposure
2013;56:698-706. to the major olive allergen Ole e 1.
and weather is suitable. Thus, bad
2. Haahtela T, Holgate S, Akdis C. The Allergy 2013;68:809-812.
weather can result in late opening
biodiversity hypothesis and allergic 6. Buters JTM, Kasche A, Weichen-
of anthers and consequently long disease: world allergy organization meier I, Schober W, Klaus S,
ripening periods for the allergen, position statement. WAO Journal Traidl-Hoffmann C, et al. Year-to-
resulting in more potent pollen. 2013;6:3. Year Variation in Release of Bet

Pollen allergens and geographical factors 37

 Global atlas oF allergy

Bet v 1
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5

Reykjavik 0,0

Leiden C

Siauliai
4,0
3,5
3,0
Bet v 1 Neustrelitz 9

2,5
2,0
Derby
1,5
6
1,0
1 4
0,5
G
0,0 3

11
E

13
Lodz
D 2

F
Section A - Allergy - from genetics to mechanisms

10

Strasbourg
5
12 Prague
A

Zurich Asteraceae
Asteraceae
Sofia
4,0
3,5 Ole e 1
4,0
3,5 Ole e 1
4,0
3,5 Bet v 1
4,0
3,5 Bet v 1
4,0
3,5 Bet v 1
Betulaceae
Betulaceae
3,0 3,0 3,0
Oleaceae
3,0 3,0
Oleaceae
Thessaloniki
2,5 2,5 2,5 2,5 2,5
2,0 2,0 2,0 2,0 2,0
1,5
1,0
1,5
1,0
1,5
1,0
1,5
1,0
1,5
1,0 Poaceae
Poaceae
0,5 0,5 0,5 0,5 0,5
0,0 0,0 0,0 0,0 0,0

Madrid
Figure 2  Pollen distribution and pollen potency across Europe. Size of the circles represents quantitative differences in
the pollen index, colors represent different pollen species (families). Bar graphs represent the amount of allergen released
per pollen (potency) for the indicated locations.

v 1 Allergen from Birch Pollen:

Evidence for Geographical Differ-
ences between West and South
Germany. Int Arch Allergy Immunol
2008;145:122-130.
7. Buters JTM, Weichenmeier I, Ochs
S, Pusch G, Kreyling W, Boere AJ, et
al. The allergen Bet v 1 in fractions
of ambient air deviates from birch
pollen counts. Allergy 2010;65:850-
858.

38 Pollen allergens and geographical factors

Global atlas oF allergy

4 The underlying
mechanisms in allergy

Cezmi A. Akdis 
Swiss Institute of Allergy and Asthma Research
Davos, Switzerland

The immune system forms an in-

teractive network with tissues and Ke y m essag es
makes its decisions on the basis of

Section A - Allergy - from genetics to mechanisms

signals coming from resident tissue • The early development of memory T and B cell responses and IgE
cells, infectious agents, commensal production represent the sensitization phase of allergic reaction
bacteria and almost any environ- • IL-4 and IL-13 are essential to induce class switching to IgE in B
mental agents. The immunologic cells and for the production of allergen-specific IgE antibodies
basis of allergic diseases (Table 1) • Cross-linking of the IgE-FcεRI complexes on basophils and mast
is observed in two phases: sensiti- cells and subsequent release of anaphylactogenic mediators is
responsible for the immediate hypersensitivity reaction
zation and development of mem-
• Effector T and B cell and eosinophil infiltration of the affected
ory T and B cell responses and IgE
tissues is controlled by a chemokine network
production and effector functions
• Type 2 innate lymphoid cells play a role in eosinophilic inflammation
related to tissue inflammation, tis-
in mouse models and are observed in nasal polyp tissue in humans
sue injury, tissue remodeling and
• There is strong evidence on the defective allergen tolerance
chronicity in asthma, atopic derma-
mechanisms by T and B regulatory cells
titis (AD) and allergic rhinitis (AR). • Epithelial barrier is leaky in asthma, chronic rhinosinusitis and
Different disease endotypes may atopic dermatitis
become apparent with different • Different disease endotypes show different dominant molecular
dominant molecular mechanisms, mechanisms, biomarkers and therapy response to biologicals
related biomarkers and response
to biological therapy.
In the sensitization phase, during tion. In the effector phase, when nosinusitis (CRS) patients as well
the development of allergic dis- a new encounter with the allergen as keratinocytes in the skin of AD
eases, effector Th2 cells produce causes cross-linking of the IgE- patients. Recent studies suggest
IL-4, IL-5, and IL-13. IL-4 and IL- FcεRI complexes on sensitized ba- that tissue integrity is disturbed
13 induce class switching to the sophils and mast cells, they are ac- and allows penetration of aller-
ε immunoglobulin heavy chain tivated and subsequently release gens, bacterial toxins and other
in B cells and the production of anaphylactogenic mediators that particles through the epidermis,
allergen-specific IgE antibodies are responsible for the immediate the lung and sinus epithelium,
(Figure 1). Innate lymphoid cells hypersensitivity reaction. where they may activate the im-
(ILC2) also provide Th2 cytokines. Defective epithelial barrier func- mune system leading to severe
Allergen-specific IgE binds to the tion has been demonstrated for chronic inflammation in these dis-
high-affinity FcεRI on the surface bronchial epithelial cells in the eases. Activation of the epithelial
of mast cells and basophils, thus asthmatic lung, epithelial cells cells and release of IL-25, IL-31,
leading to the patient’s sensitiza- in the sinus tissue of chronic rhi- IL-33 and TSLP contribute to type

The underlying mechanisms in allergy 39

 Global atlas oF allergy

TABLE 1 2 responses of T cells and innate

lymphoid cells (Figure 2). These
Cellular and molecular events in allergic inflammation
cytokines play a role in the pro-
• Epithelial barrier defect in the skin and affected mucosas duction of allergen-specific IgE,
eosinophilia, permissiveness of
• Epithelial cell activation and their proinflammatory cytokines and
chemokine production that induces inflammation and contributes to Th2 endothelium for the recruitment
response: TNF-α, IL-13, IL-25, IL-31, IL-33, TSLP of inflammatory cells to inflamed
tissues, production of mucus and
• Chemokine release attracting Th2 cells and eosinophils
decreased threshold of contrac-
• Epithelial apoptosis and shedding in AD and asthma: IFN-γ, TNF-α, IL-32 tion of smooth muscle cells.
• Innate lymphoid cell type 2 response: IL5, IL13 The discovery of ILCs has changed
• Th2 response: IL-4, IL-5, IL-13, our perception of T cells as the
major cytokine-secreting effec-
• Eosinophilia: IL-5, IL-25, IL-33
tors of immunity and made us
• Local and systemic IgE production: IL-4, IL-13 aware of completely unappreci-
• Cross-linking of IgE receptor FcεRI on the surface of mast cells and baso- ated innate immune cell sources
phils and their degranulation of effector cytokines. Particularly
type 2 ILCs can contribute to Th2
• Smooth muscle, myofibroblasts activation, bronchial hyperreactivity in
type inflammation similar to Th2
Section A - Allergy - from genetics to mechanisms

asthma: IL-4, IL-9, IL-13, IL-25, IL-33

cells in mouse models. Th1 cells
• Angiogenesis in chronic inflammation: VEGF, IL-32 also efficiently contribute to the
• Survival and reactivation of migrating inflammatory cells and their inter- effector phase in allergic diseases
action with resident tissue cells and other inflammatory cells: IL-2, IL-4 with their role in apoptosis of the
• Activation of other effector T cell subsets, such as Th9, Th17 and Th22 epithelium in asthma and AD.
cells and their contribution to mucus production, tissue inflammation and In recent years, induction of im-
regeneration.
mune tolerance has become a

Th2
IgM Figure 1  In the sensitization phase
allergen-specific IgE antibodies
are produced and bind to the
IL-4
naive IL-13
high-affinity FcεRI on the surface
IgE B cell of mast cells and basophils, thus
memory leading to the patient’s sensitization.
B cell IgE class When a new encounter with the
switching
ILC2 allergen causes cross-linking of the
IgE-FcεRI complexes on sensitized
IgE+memory memory basophils and mast cells, they release
B cell B cell anaphylactogenic mediators that
expansion are responsible for the immediate
allergens hypersensitivity reaction.
B cell epitopes
IgE
Vasoactive amins
FcεRI
(histamine)
IgE Lipid mediators
(PGD2, PAF
production LTC4, LTD4, LTE4)
by plasma cells Cytokines
degranulation (IL-3, IL-4, IL-5, IL-13)
basophil Chemokines
type 1 hypersensitivity

40 The underlying mechanisms in allergy

Global atlas oF allergy

Section A - Allergy - from genetics to mechanisms

Figure 2  Pathogenic mechanisms in allergic inflammation. Epithelial leakiness and activation and their proinflammatory
cytokines and chemokines (TNF-α, IL-13, TSLP, IL-31, IL-33) production induces inflammation and contributes to Th2 re-
sponse. Highly activated epithelial cells undergo apoptosis and shedding takes place. Chemokines are essential players for
the recruitment of inflammatory cells, which is followed by survival and reactivation of migrating inflammatory cells and
their interaction with resident tissue cells and other inflammatory cells. Innate lymphoid cells (ILC2) play a role in T and
B cell activation and recruitment and are early providers of Th2 and T cell recruitment cytokines. Th2 type of an immune
environment is characterized by IL-4, IL-5, IL-9, IL-13, IL-25, IL-33 production coming from Th2 cells and tissue cells. Eosin-
ophilia is induced by IL-5, IL-25, IL-33. Local and systemic IgE production takes place in allergic patients with the involve-
ment of IL-4, IL-13. Other effector T cell subsets, such as Th9, Th17 and Th22 cells also play partial roles in inflammation,
mucus production and tissue healing. Smooth muscle, myofibroblasts activation and bronchial hyperreactivity is related
to IL-4, IL-9, IL-13, IL-25, IL-33. Several chemokines, and arachidonic acid pathway molecules and other small molecules
play roles in the inflammatory cell recruitment and further augmentation of the inflammatory cascades.

The underlying mechanisms in allergy 41

 Global atlas oF allergy

Immune
tolerance Allergy
Autoimmunity IL-4
IL-5
IFN-γ TReg IL-9
TNF-α,β IL-17 IL-13

Th1 Th17 Th2

T-bet GATA-3 Figure 3  Concept development

in T cell tolerance in allergy and
autoimmunity. After the discovery
Fox P3 of Th1 and Th2 cell subsets in 1986,
it was thought that Th1 cells play a
Th1 Treg Th2 role in infections and autoimmunity
and Th2 cells in allergic disease. Both
Transcription
T-bet FoxP3 GATA-3 subsets were considered to have
factors
reciprocal roles in counter regulating
Delayed type of hy- inhibition of Th1 and Th2 each other. After the introduction
chronic
persensitivity, mac- cells of Treg cells, it was demonstrated
Section A - Allergy - from genetics to mechanisms

Major eosinophilic
rophage activation inhibition of mo/mac that although there is reciprocal
functions inflammation
limited B cell help/ inhibition of DC matura- regulation between individual Th cell
with high IgE
inhibition tion peripheral tolerance subsets, Treg cells play a major role in
the induction of immune tolerance
Chronic intracellu- immunotherapy trans- arthritis
in allergy, autoimmunity, organ
Beneficial lar infections: leish- plantation autoimmunity autoimmunity
transplantation, cancer, pregnancy,
role maniasis, leprosy, allergy/asthma preg- helminth inf.
chronic infections.
virus infections nancy pregnancy

prime target for prevention and KEY REFERENCES immune responses in asthma. Nat
treatment strategies for allergic 1. Akdis CA. Therapies for allergic Med 2012;18:673-683.
diseases. Immune tolerance to inflammation: refining strate- 6. De Benedetto A, Rafaels NM,
allergens can be defined as estab- gies to induce tolerance. Nat Med McGirt LY, Ivanov AI, Georas SN,
lishment of a long-term clinical 2012;18:736-749. Cheadle C, et al. Tight junction
2. Akdis M, Akdis, AC. Immune Tol- defects in patients with atopic
tolerance against allergens, which
erance. In: N Franklin Adkinson dermatitis. J Allergy Clin Immunol
immunologically implies changes 2011;127:773-786.
in memory type allergen-specific Jr BSB, Wesley Burks, William W
Busse, Stephen T Holgate, Robert 7. Soyka MB, Wawrzyniak P, Eiwegger
T and B cell responses as well as T, Holzmann D, Treis A, Wanke K, et
F Lemanske Jr, Robyn E O’Hehir, ed.
mast cell and basophil activation al. Defective epithelial barrier in
Middleton’s Allergy, 8th Edition,
thresholds that do not cause al- 2013. chronic rhinosinusitis: The regula-
lergic symptoms anymore (Figure tion of tight junctions by IFN-gam-
3. Akdis M, Akdis CA. Mechanisms
3). T and B regulatory cells and ma and IL-4. J Allergy Clin Immunol
of allergen-specific immunother-
production of allergen-specific 2012;130:1087-1096.
apy: multiple suppressor factors
IgE-blocking IgG4 isotype anti- at work in immune tolerance to 8. Rebane A, Zimmermann M, Aab
bodies play an essential role in A, Baurecht H, Koreck A, Karelson
allergens. J Allergy Clin Immunol
allergen tolerance. Similar mech- M et al. Mechanisms of IFN-gam-
2014;133:621-631.
ma-induced apoptosis of human
anisms of immune tolerance take 4. Akdis M, Burgler S, Crameri R, Ei- skin keratinocytes in patients with
place in high dose allergen ex- wegger T, Fujita H, Gomez E, et al. atopic dermatitis. J Allergy Clin Im-
posed bee-keepers and cat owners Interleukins, from 1 to 37, and in- munol 2012;129:1297-1306.
(who do not develop allergy), after terferon-gamma: receptors, func- 9. Scanlon ST, McKenzie AN. Type 2
allergen-specific immunotherapy, tions, and roles in diseases. J Allergy innate lymphoid cells: new players
and in individuals who naturally Clin Immunol 2011;127:701-721. in asthma and allergy. Curr Opin Im-
outgrow allergic diseases. 5. Holgate ST. Innate and adaptive munol 2012;24:707-712.

42 The underlying mechanisms in allergy (overview)

Global atlas oF allergy

5 Innate immune
response in allergy
Michael N. Teng  Richard F. Lockey
University of South Florida
Tampa, USA
While the underlying inflamma-
tion in allergic asthma, allergic Ke y m essag es
rhinitis and atopic dermatitis is

Section A - Allergy - from genetics to mechanisms

thought to result from the activity • Bronchial epithelial cells and skin keratinocytes play an important
of Th2 cells, the innate (non-anti- role in asthma and atopic dermatitis
gen specific) response to these in- • Type 2 innate lymphoid cells are essential for asthma progression
sults provides key triggers for the • Dendritic cell subsets may play both pro and anti-inflammatory
initiation of the chronic inflamma- roles
tion. • Epithelial cells, dendritic cells and innate lymphoid cells play a
crucial role during the chronic phase of the allergic inflammation
Innate immune responses begin by producing pro-inflammatory cytokines and chemokines that
with sensing of insults by airway attract other inflammatory cells to affected tissues
and skin epithelial cells. Non-spe- • Non-antigen specific innate immunity serves as the bridge to
cific antigen recognition by epi- adaptive immune responses
thelial cells occurs via pattern rec-
ognition receptors (PRR), which
include both soluble (collectins) production are important for cells (ILC2, Neucytes) are impor-
and cellular [Toll-like receptors antiviral defense. Airway epithe- tant for asthma pathogenesis.
(TLR)] PRRs. Soluble PRRs recog- lial cells from subjects with asth- ILC2 are derived from a common
nize the carbohydrate moieties ma have decreased levels of IFN lymphoid progenitor and related
of microbes and can activate the production after viral infection, to NK and RORγt innate lymphoid
complement cascade, initiating suggesting that IFN may play a cells (Figure 2). ILC2 respond to IL-
inflammatory responses. Cellular protective role in preventing viral 25, IL-33, and TSLP stimulation by
PRRs are better known for their asthma exacerbations. Production producing high levels of “Th2-type”
interaction with pathogen-associ- of pro-inflammatory cytokines / cytokines (i.e., IL-5, -9, and -13)
ated molecular patterns (PAMPs). chemokines (e.g., TNFα, IL-1, IL-6, upon stimulation. These cytokines
Although TLRs are best known for IL-25, IL-33, TSLP) from epithelial can then activate eosinophils (via
binding to products of microbes cells is the result of PRR activation IL-5, -13) and mast cells (via IL-9)
and viruses, allergens also inter- of NFκB. as well as B and T lymphocytes
act with TLRs (e.g., house dust Epithelial cells responding to aller- (Figure 1). In addition, secretion
mite protein, Der p2 with TLR4). gen insult also produce IL-25, IL-33 of IL-13 induces mucus produc-
Binding of TLRs and other cellular and thymic stromal lymphopoietin tion, smooth muscle contractility,
PRRs triggers the production of (TSLP) (Figure 1). These cytokines and alternative activation of alve-
interferon (IFN) and pro-inflam- have downstream effects on in- olar macrophages, which leads to
matory cytokines and chemok- nate and adaptive immune cells. In amplification of IL-33 production.
ines. Both type I and type III IFN particular, type 2 innate lymphoid ILC2 also secrete amphiregulin,

Innate immune response in allergy 43

 Global atlas oF allergy

Allergens
IFN Mucus
Viruses

Airway
epithelium

IL-25
IL-33
TSLP
Areg Eosinophil
IL-13
IL-9
DC IL-5
ILC2
IgE
which may be involved in airway
Mast cell remodeling. TSLP also drives the
IL-4
maturation of immature lung den-
dritic cells (DC) to conventional
CD4+ T T h2 B DC capable of presenting antigen
to T cells. These allergen-activat-
Section A - Allergy - from genetics to mechanisms

Figure 1  Innate immune response in asthma. Exposure to allergens or viruses ed DC then initiate the adaptive
induces innate immune responses in airway epithelial cells. Viral infection in-
immune responses characteristic
duces type I and type III interferon (IFN) responses. Epithelial cells also secrete
IL-25, IL-33, and TSLP, which activate type 2 innate lymphoid cells (ILC2) and of atopic airway disease.
dendritic cells (DC). ILC2 cells produce “Th2-like” cytokines (e.g., IL-5, IL-9, and In summary, innate immunity plays
IL-13). These cytokines then active eosinophils, mast cells, and goblet cells to a key role in initiating asthma. Rec-
cause disease. ILC2 also produce amphiregulin (Areg) to induce airway remod-
ognition of insults by AEC leads
eling. Activated DC traffic to lymphoid organs to initiate T cell responses to the
allergens/viruses to further disease pathogenesis. Adapted from ref. 3. to activation of ILC2, which pro-
duce Th2-type cytokines, and DC,
RORγt
which stimulate allergen-specific
NK
CD4+ T cell responses is necessary
for asthma progression.

KEY REFERENCES
IL-7
1. Deckers J, Branco Madeira F, Ham-
IL-15 mad H. Innate immune cells in asth-
ma. Trends Immunol 2013;34:540-
Id2
547.
GATA3 2. Hirota JA, Knight DA. Human air-
RORα way epithelial cell innate immunity:
CLP ILCP γc cytokine ILC2 relevance to asthma. Curr Op Immu-
Notch nol 2012;24:740-746.
3. Licona-Limon P, Kim LK, Palm MW,
Flavell RA. Th2, allergy and group 2
GATA3 IL-4 innate lymphoid cells. Nat Immunol
IL-5 2013;14:536-542.
IL-9
4. Minnicozzi M, Sawyer RT, Fenton
IL-13
CD4+ T T h2 MJ. Innate immunity in allergic dis-
ease. Immunol Rev 2011;242:106-
Figure 2  Differentiation of ILC2 cells. ILC precursors (ILCP) are derived from 127.
the common lymphoid progenitor (CLP) cells in an Id2-dependent process. ILCP 5. Vercelli D, Gozdz J, von Mutius E.
are further differentiated into RORγt, NK, and ILC2 cells through the activities Innate lymphoid cells in asthma:
of transcription factors (GATA3, RORα) and cytokines (IL-7, IL-15). CLP cells when innate immunity comes in a
also differentiate into Th2 cells through thymic maturation. ILC2 and Th2 cells Th2 flavor. Curr Op Allergy Clin Im-
secrete an overlapping set of cytokines. Adapted from ref. 3. munol 2014;14:29-34.

44 Innate immune response in allergy

Global atlas oF allergy

6 Dendritic cells

Bart N. Lambrecht 
Gent University,
Gent, Belgium

The adaptive immune response

Ke y m essag es

Section A - Allergy - from genetics to mechanisms

to allergens is characterized by a • Dendritic cells are one of the first immune cells that come into
humoral arm (production of IgE contact with allergens at mucosal surfaces and can sample
by B lymphocytes), and a cellular luminal antigens directly by extending dendrites across the
arm (CD8 and CD4 T lymphocytes epithelial barrier
that respond to the allergen in the • In the lymph node they report on the type of antigen encountered
context of MHCI and MHCII mol- and subsequently induce CD4 T helper cell differentiation and
ecules). Before adaptive immuni- CD8 T cell activation and transfer some of their encountered
ty is induced to environmental or antigens to B cells
food allergens, the allergen must • Lung and skin DCs also play a crucial role during the chronic
get through the natural barriers of phase of the allergic inflammation, by producing chemokines
the body (skin, mucus membranes) that attract other inflammatory cells to inflamed tissues
and reach the cells of the immune • Unraveling how DCs induce and maintain Th2 immunity will
system that are recirculating in provide new selective therapeutics targets for allergic diseases
the lymph nodes (LN). Dendritic
cells (DCs) are one of the first im-
mune cells that come into contact epithelial cells and can sample lu- DCs originating from the lungs
with allergens at mucosal surfac- minal antigens directly by extend- of house dust mite (HDM) al-
es. In the lungs, intestine and skin, ing dendrites across the epithelial lergen-exposed mice are neces-
DCs sit at the basolateral side of barrier (Figure 1). sary and sufficient to induce Th2
After antigen uptake, DCs migrate sensitization to HDM. Lung and
to the draining LN and present the skin DCs also play a crucial role
processed antigen to naïve T cells, during the chronic phase of the
leading to clonal expansion and allergic response, by producing
differentiation of antigen-specific chemokines that attract other in-
T cells (Figure 2). Dendritic cells flammatory cells back to periph-
arriving in the LN report on the eral tissues (Figure 2). In addition,
type of pathogen or allergen that allergen-specific IgE and IgG1,
has been encountered in the pe- through stimulation of FcεRI and
riphery, and they subsequently FcγRIII respectively, target aller-
induce CD4 T helper cell differen- gens to DCs thus boosting Th2
tiation (Figure 3), CD8 T cell acti- immunity further. During both
Figure 1  Dendritic cells across the vation and transfer some of their sensitization and challenge, DCs
epithelial barrier. encountered antigens to B cells. closely communicate with neigh-

Dendritic cells 45
Section A - Allergy - from genetics to mechanisms Global atlas oF allergy

Figure 2  Role of dendritic cells in inflammation and T-cell polarisation.

Surface ligand Secreted

high IL-6 IL-4

OX40L low IL-12 IL-5 Allergy/Parasites
Th2
CD86 T1/ST2L/IL-33 IL-13 Extracel, infections
Jagged CCL2 ? TNFα

ICOSL low IL-6

dim CD86 low IL-12
IL-2 IL-10 Tolerance
dim CD80 Th0 IL-10 Treg
TGFβ Fibrosis ?
Jagged ? TGFβ
PGD2

high IL-6 Fungal infections

Th17 IL-17
high TGFβ Autoimmunity

IL-23

high IL-6 IFN-γ

CD80 high IL-12 TNFα Intracel. Infections
high IL-18 Th1 Cancer
Delta
ICAM-1 CCL3
high IFNγ

Figure 3  Factors that affect T-cell differentiation.

46 Dendritic cells
Global atlas oF allergy

Section A - Allergy - from genetics to mechanisms

Th2
Figure 4  The interaction of dendritic cells and epitelial cells drives the inflammatory process.

boring epithelial cells. Triggering ing the function of DCs in allergy cells initiate and maintain T help-
of pattern recognition receptors constitutes a therapeutic avenue. er 2 cell-mediated immunity to
on epithelial cells like the Toll-like However, eliminating the function house dust mite allergen. Immunity
receptor 4 or protease activated of DCs completely would also in- 2013;38:322-335.
receptors by allergens leads to the duce immunodeficiency, and it is 3. Lambrecht BN, Hammad H. The
production of epithelial-derived much more important to unravel airway epithelium in asthma. Nat
chemokines and cytokines (Fig- how DCs induce and maintain Th2 Med 2012;18:684-692.
ure 4) that recruit DCs and that immunity selectively, to find new 4. Hammad H, Chieppa M, Perros F,
program the DCs to induce Th2 therapeutics for allergy. Willart MA, Germain RN, Lambre-
immune responses. Epithelial cells cht BN. House dust mite allergen
and other innate immune cells also KEY REFERENCES induces asthma via Toll-like recep-
make endogenous danger signals 1. Lambrecht BN, Hammad H. Lung tor 4 triggering of airway structural
like uric acid, ATP and High Mobili- dendritic cells in respiratory viral cells. Nat Med 2009;15:410-416.
ty Group Box 1 (HM-GB1) that can infection and asthma : from protec- 5. Kool M, Willart MA, van Nimwegen
have the same effect on DCs. tion to immunopathology Ann Rev M, Bergen I, Pouliot P, Virchow JC
Immunol 2012;30:243-270. et al. An unexpected role for uric
Patients with atopic dermatitis, al- 2. Plantinga M, Guilliams M, Van- acid as an inducer of T helper 2 cell
lergic rhinitis and asthma have in- heerswynghels M, Deswarte K, immunity to inhaled antigens and
creased numbers of activated DCs Branco-Madeira F, Toussaint W inflammatory mediator of allergic
armed with IgE in the inflamed et al. Conventional and mono- asthma. Immunity 2011;34:527-
tissues. Not surprisingly, target- cyte-derived CD11b(+) dendritic 540.

Dendritic cells 47
 Global atlas oF allergy

7 Natural killer cells and

natural killer-T cells

Günnur Deniz 
Istanbul University
Istanbul, Turkey

Besides the heterogeneity of asth-

ma pathogenesis, current knowl- Ke y m essag es
edge underlines the dominance
Section A - Allergy - from genetics to mechanisms

of a subgroup with Th2-like im- • Natural Killer (NK) cells display a potent regulatory function
mune response and eosinophil- by secreting various cytokines or cell-to-cell contact and thus,
ia. However allergic asthma may regulate innate and adaptive immune responses and maintain
additionally involve innate, T cell immune homeostasis
independent immune responses. • NK cells express subsets similar to T helper cells, such as NK1,
Several different populations of NK2 and NK regulatory cells
• Understanding the mechanisms enrolled in the development of
innate lymphoid cells (ILC), in-
allergic diseases are essential to develop strategies for treatment
cluding natural killer (NK) cells, γδ
and prevention
T cells, and CD1-restricted NK1
• Recent developments in NK cell subsets support their role in
cells have been previously impli-
allergic diseases
cated in the regulation of immune
responses in the respiratory tract.
NK cells are innate lymphocytes, secreting and IFN-non-secreting nificantly higher, while IFN-γ+ NK
which are a first line of defense NK cells strongly support this cells were not significantly lower
against infection and cancer. The concept (Figure 1). The IFN-γ se- in allergic rhinitis patients com-
airways are a major route of en- creting NK subset showed a typ- pared to nonatopic controls. Since
try of many important pathogens ical Th1-like cytokine pattern. In NK cells are important cells in in-
into the body and the ability of contrast, the IFN-γ-non-secreting nate immunity and the initiation
NK cells to respond rapidly to NK subset was composed of IL- of immune responses, their differ-
infection suggests an important 4, IL-5 and IL-13-producing NK ent cytokine patterns may be im-
role for these cells in acute pul- cells. These results demonstrate portant in changing the cytokine
monary infection. Recent devel- that circulating NK cells retain milieu and the induction of T cell
opments in our understanding effector subsets in humans with deviation.
of NK cell subsets support their distinct cytokine profiles and may Natural killer-T (NK-T) cells are
role in allergic diseases that may display different inflammatory unique CD1d-restricted T cells
contribute to allergen-specific properties. In addition, it has been with NK cell surface markers.
Th1 or Th2 cell generation as well reported that patients with aller- These cells may play an important
induction or suppression of IgE. gic rhinitis had a higher percent- role in the pathogenesis of asthma.
The in vivo and in vitro existence age and cytotoxicity of NK cells Invariant NK-T cells and not con-
of human NK cell subsets, simi- compared to nonatopic patients. ventional MHC class II-restricted
lar to Th1 and Th2 cells, with dis- The mean percentage of IL-4- and CD4+ T cells were found predomi-
tinct cytokine patterns as IFN-γ IL-13-secreting NK cells were sig- nant in the lungs and bronchoalve-

48 Natural killer cells and natural killer-T cells

Global atlas oF allergy

IL-22
NK22

IL-23 Protection of
epithelial cell bariers

NK
IL-2 NKreg IL-10, TGF-β

IL-12, IL-18 IL-4

Suppression of IgE
NK2 IL-5, IL-13 production

Section A - Allergy - from genetics to mechanisms

NK1

Stimulation of IgE
production

IFN-γ
Suppression of IgE
production

Figure 1  NK cells are divided into four different subsets according to their cytokine secretion. NK cells have been
detected in close contact to dendritic cells. NK cells grown in IL-12 and IL-18 (NK1) produce IFN-γ and inhibit IgE
production, whereas NK cells grown in IL-4 (NK2) produce IL-5 and IL-13 and stimulate IgE production. NK reg cells
produce IL-10 and TGF-β and suppress IgE production. IL-22 secreting NK22 subset might have a role in the protection
of epithelial cell barriers. (Reprinted from J Allergy Clin Immunol, 132/3, Deniz G,van de Veen W, Akdis M. Natural killer cells in
patients with allergic diseases, 527-35, Copyright 2013, with permission from Elsevier.)

olar lavage fluid of allergic asthma. 2. Pichavant M, Matangkasombut P, et al Regulatory NK cells suppress
Although CD1d-restricted NK-T Dekruyff RH, Umetsu DT. Natural antigen-specific T cell responses. J
cells might play a role in modulat- killer T cells regulate the develop- Immunol 2008;180:850-857.
ing the asthmatic phenotype, they ment of asthma. Expert Rev Clin Im- 5. Deniz G, van de Veen W, Akdis M.
are not the critical drivers of the munol 2009;5:251-260. Natural killer cells in patients with
asthmatic response and at most 3. Mesdaghi M, Vodjgani M, Salehi allergic diseases. J Allergy Clin Im-
play a modulatory role. E, Hadjati J, Sarrafnejad A, Bidad munol 2013;132:527-35.
K et al. Natural killer cells in aller- 6. Deniz G, Akdis M, Aktas E, Blaser
KEY REFERENCES gic rhinitis patients and nonatopic K, Akdis CA. Human NK1 and NK2
1. Scanlon ST, McKenzie AN. Type 2 controls. Int Arch Allergy Immunol subsets determined by purifica-
innate lymphoid cells: new players 2010;153:234-238. tion of IFN-gamma-secreting and
in asthma and allergy. Curr Opin Im- 4. Deniz G, Erten G, Kücüksezer UC, IFN-gamma-nonsecreting NK cells.
munol 2012;24:707-712. Kocacik D, Karagiannidis C, Aktas E Eur J Immunol 2002;32:879-884.

Natural killer cells and natural killer-T cells 49

 Global atlas oF allergy

Innate lymphoid
8 cells
Hirohisa Saito 
National Research Institute for Child Health & Development
Tokyo, Japan

Definition and ontogeny

Innate lymphoid cells (ILCs) are the Ke y m essag es
cells having lymphoid morphology,
Section A - Allergy - from genetics to mechanisms

but lacking recombination acti- • Innate lymphoid cells (ILCs) have lymphoid morphology, but lack
vating gene (RAG)-dependent re- rearranged antigen receptors and myeloid and dendritic cell
arranged antigen receptors. They markers
also lack myeloid and dendritic • ILCs are derived from a committed ILC precursor
cell markers (Lineage – (Lin-)). Ac- • Group 1 ILCs (ILC1s) release INF-γ, but not Th2 and Th17
cording to these definition, natural cytokines under the influence of IL-12 and IL-18
killer (NK) cells and lymphoid tis- • Group 2 ILCs (ILC2s) may play a role in allergic diseases and
sue-inducer (LTi) cells are included eosinophilic inflammation by releasing the Th2 cytokines IL-
into the ILC population. NK cells 5, IL-9 and IL-13, when stimulated with IL-25, IL-33 and thymic
mediate initial immune responses stromal lymphopoietin
against viruses and cancer cells. • Group 3 ILCs (ILC3s) may play a role in some chronic allergic
LTi cells are essential for the for- diseases by releasing the Th17 cytokines IL-17 and IL-22
mation of lymph nodes.
ILCs can be divided into three
but not IL-17, while NCR-‑ ILC3s ance against nematodes. Although
groups. Group 1 ILCs (ILC1s) are
are capable of producing IL-17, Th2 cells are a major source of
defined by their capacity to pro-
but not IL-22. However, it should type 2 cytokines during asthmatic
duce Th1 cytokine IFNγ and the
be noted that some NCR-‑ILC3s and allergic reactions, ILC2s also
inability to produce Th2 cell- and
can also produce IL-22. Recently, contribute to disease pathology,
TH17 cell-associated cytokines.
it was suggested that ILCs are de- especially where IL-25, IL-33 and
They develop under the influence
rived from a committed ILC pre- TSLP are released by inflamed and
of IL-12 and IL-18. Group 2 ILCs
cursor, which is developmentally damaged epithelia. Human ILC2s
(ILC2s) are capable of producing
unrelated to NK and LTi cells. have similar properties with their
Th2 cytokines (IL-5, IL-9 and IL-13)
murine counterparts. In addition,
in response to epithelium-derived
Role of ILCs in allergy human ILC2s express CRTh2 (che-
cytokines IL‑25, IL‑33 and thym-
ILC2s include Lin- SCA1+ natural moattractant receptor-homolo-
ic stromal lymphopoietin (TSLP).
helper cells found in fat-associat- gous molecule expressed on Th2
Group 3 ILCs (ILC3s) can produce
ed lymphoid clusters, Lin-SCA1+ cells) on their surface.
Th17 cytokines IL-17 and/or IL-22
in the presence of IL-1β and IL-23. nuocytes and Lin-SCA1- innate IL-17-producing ILC3s play a role
Some ILC3s express the natural helper 2 cells derived from lymph in neutrophilic inflammation in a
cytotoxicity triggering receptor nodes of IL-25 and/or IL-33-inject- particular endotype of asthma via
(NCR) NKp46 (NCR+ ILC3s). The ed or N. brasiliensis-infected mice. production of IL-1β by macrophag-
NCR+ ILC3s can produce IL-22, ILC2s are important in host resist- es stimulated with damage-associ-

50 Innate lymphoid cells

Global atlas oF allergy

CLP

B cell

α4β7+
T cell

α4β7?

Section A - Allergy - from genetics to mechanisms

ILCP PLZF
high
NKP LTiP RORγthigh

Gfi1 RORγt
T-bet RORγt GATA3
RORα
NCR+
IL-12 ILC3

IL-18 NCR-
NK LTi ILC2 ILC1 ILC3

IL-12 IL-23 IL-25 IL-12 IL-23

IL-18 IL-1β IL-33 IL-18 IL-1β
TSLP

IL-17 IL-5
IFNγ IL-22 IL-9 IFNγ IL-22 IL-17
IL-13

Figure 1  Ontogeny of innate lymphoid cells (ILCs). A committed ILC precursor (ILCP) having a high level of
transcriptional factor PLZF (2) can give rise to ILC1s, ILC2s and ILC3s, but not to LTi cells and NK cells, which originate
from a α4β7+ common progenitor shared with the three ILC lineages. Development of ILC2s depends on the transcription
factors Gfi1, GATA3 and RORα. ILC3s require the transcription factor RORγt for their development and function.
Although NCR+ ILC3s can give rise to ILC1s if stimulated with IL-12 and IL-18, the differentiation pathway of ILC1s is not
fully understood yet.

Innate lymphoid cells 51

 Global atlas oF allergy

Protease
PAMPs Allergen

Goblet cell
hyperplasia
DAMPs IL-25
IL-33 IL-13
TSLP
IL-22
Macrophage

IL-1β
ILC3 ILC2
Section A - Allergy - from genetics to mechanisms

IL-17 IL-5

Neutrophilic Eosinophilic
Inflammation Inflammation

Figure 2  The role of ILCs in allergy. Epithelial tissues can release IL-25, IL-33 and TSLP in response to protease allergens
such as house dust mites or papain, DAMPs, PAMPs and TH2 cytokines. In response to the epithelium-derived cytokines
ILC2s can release IL-13, which induces inflammation and remodeling (such as goblet cell hyperplasia) in the tissue, and IL-
5, which can induce eosinophilic inflammation. ILC3s release IL-17, which can induce neutrophilic inflammation, and IL-22,
which inhibits the release of ILC2-activating cytokines.

ated molecular patterns (DAMPs) KEY REFERENCES 3. Walker JA, Barlow JL, McKenzie
and/or pathogen-associated mo- 1. Spits H, Artis D, Colonna M, Diefen- AN. Innate lymphoid cells--how
lecular patterns (PAMPs). The bach A, Di Santo JP, Eberl G, et al. did we miss them? Nat Rev Immunol
expression of the IL-10 family Innate lymphoid cells-a proposal 2013;13:75-87.
for uniform nomenclature. Nat Rev
cytokine IL-22, which is capable 4. Kim HY, Lee HJ, Chang YJ, Picha-
Immunol 2013;13:145-149.
of being released from ILC3s, LTi vant M, Shore SA, Fitzgerald KA, et
2. Constantinides MG, McDonald BD,
cells or Th17 cells, is increased in al. Interleukin-17-producing innate
Verhoef PA, Bendelac A. A commit-
chronic allergic inflammation in ted precursor to innate lymphoid lymphoid cells and the NLRP3 in-
the lung and skin. IL-22 inhibits cells. Nature 2014 [Epub ahead flammasome facilitate obesity-as-
the production of ILC2-activating of print Feb 9] doi: 10.1038/na- sociated airway hyperreactivity.
cytokines, IL-25 and IL-33. ture13047. Nat Med 2014;20:54-61.

52 Innate lymphoid cells and allergy

Global atlas oF allergy

9 Mast cells

Stephen J. Galli 
Stanford University
Stanford, USA

What are mast cells?

In humans and other vertebrates, Ke y m essag es
mast cells reside in virtually all

Section A - Allergy - from genetics to mechanisms

tissues, often close to epithelial • Mast cells develop in essentially all tissues from precursors that
surfaces (e.g., the skin, respira- circulate in the blood
tory system, and gastrointesti- • Mast cells are major sources of histamine and other products
nal tract) and near blood vessels, (mediators) that contribute to anaphylaxis and other allergic
nerves, smooth muscle cells and disorders
fibroblasts. Mast cell precursors • Mast cells can be rapidly activated (within minutes) to release
are generated in the bone mar- mediators when allergens are recognized by IgE antibodies
row, circulate in the blood, and bound to IgE receptors (FcεRI) on the cells’ surface
then enter the tissues where they • Mast cells also can be activated to release mediators by many
complete their maturation, be- agents that act independently of IgE
coming cells with many prominent • Mast cells can have beneficial roles in enhancing resistance to
cytoplasmic granules (Figure 1A animal venoms and in host defense against certain parasites
& C). These granules are storage
sites for mast cell products (often
called “mediators”) that, when re- of allergic diseases or parasite in- of the IgE-bound FcεRIs, signaling
leased by the cell, have powerful fections, and in other settings. the cells to release their products
effects on other cell types. Mast (Figure 1B & D). Mast cells also can
cell granules contain most of the How can mast cells be be activated independently of IgE,
body’s histamine and virtually all activated to release their e.g., by products of microorgan-
of its heparin, as well as a variety products? isms, certain neuropeptides, and
of proteases (Table 1). When mast Mast cells express on their sur- compounds present in animal ven-
cells are “activated” (i.e., stimulat- face hundreds of thousands of oms (Table 2).
ed to release their products), they high affinity receptors (FcεRI) that When large numbers of mast cells
release histamine, heparin and strongly bind the Fc portion of IgE are rapidly activated by the sys-
proteases by “degranulation” (Fig- antibodies. Individual mast cells temic distribution of an allergen
ure 1B & D), and they also secrete can bind IgEs which recognize in subjects who have IgE recog-
many other mediators that are not any of a variety of different aller- nizing that allergen, anaphylaxis
stored, but are synthesized by the gens derived from pollens, foods, can occur within minutes. Such
activated cells, including leukot- dust mites, medicines, etc. Such IgE-dependent anaphylaxis is ab-
rienes, prostaglandins, cytokines, mast cells can be activated when sent or markedly diminished in
chemokines and peptide growth they encounter any antigens that mice genetically lacking mast cells
factors (Table 1). Mast cell num- cross-link two adjacent IgE mole- (even though they have basophils,
bers can increase in tissues at sites cules, which results in aggregation another bone marrow-derived cell

Mast cells 53
 Global atlas oF allergy

Figure 1  (A, C) A resting mast cell

(shown in a transmission electron
micrograph in A and as a cartoon in C)
contains many cytoplasmic granules
(indicated by arrows in A) and has
allergen-specific IgE (yellow symbols
in C) bound to FcεRI receptors (green
symbols in C) on its surface (B, D).
When allergen (red symbols in D) is
recognized by adjacent IgE antibodies
bound to the mast cell’s FcεRI
receptors, this aggregates the FcεRIs
on the cell’s surface, activating the mast
cell to release its granule contents at
points where the granules fuse with
the plasma membrane (indicated by
arrows in a transmission electron
micrograph in B and as a cartoon in D).
Such activated mast cells also secrete
newly synthesized products that are
not stored in the granules. (Modified
Section A - Allergy - from genetics to mechanisms

from Fig. 9.44 in Parham P. The Immune

System. 3rd edition, Copyright 2009
from The Immune System by Parham.
Reproduced by permission of Garland
Science/Taylor & Francis LLC. The
electron micrographs in A & B are
courtesy of Ann M. Dvorak.)

TABLE 1
Mast Cell Products

Products Biological effects*

Stored preformed in • Increases vascular permeability and blood vessel dilatation
granules and secreted • Contracts airway smooth muscle
Histamine
upon activation (in • Causes itching and pain
minutes) • Influences immune responses and the function of some nerves
• Anticoagulant
Heparin
• Required for storage of other products in granules
Proteases (e.g., • Degrade certain proteins and peptides, including components of
tryptase, chymase, animal venoms
carboxypeptidase • Regulate tissue remodeling
A3) • Converts angiotensin I to angiotensin II (chymase)
Synthesized and se- • Regulate migration and function of leukocytes
creted upon activation • Increase vascular permeability
Lipid mediators
(beginning in minutes • Induce constriction or dilatation of blood vessels (depending on
(e.g., leukotrienes,
for lipid mediators, the type of mediator)
prostaglandins)
extending over hours • Contract or relax smooth muscle (airways, gastrointestinal tract)
for peptide products†) • Enhance mucus secretion
Cytokines, chemok- • Many effects on other cells (both leukocytes and tissue structural
ines, peptide growth cells) that can promote or suppress inflammation and/or tissue re-
factors modeling
*
Only some of the many biological effects of these products are listed.
†
Some of these can be present in granules and therefore also can be released rapidly upon mast cell activation.

54 Mast cells
Global atlas oF allergy

TABLE 2
Mechanisms of mast cell activation*

Activation mechanisms† Settings in which this occurs Comments

Anaphylaxis, allergic rhinitis, The site of mast cell activation depends on the
Cross-linking of IgE bound to mast cell
atopic dermatitis, allergic site of exposure to the antigen; in anaphylaxis,
surface FcεRI by multivalent antigen
asthma, some types of urti- there is systemic distribution of the offending
recognized by the IgE
caria antigen throughout the body.

Reaction of microbial products or

products of damaged or dead cells Various types of viral or bac- Exposure of mast cells to some of these prod-
with receptors (Toll-like receptors or terial infections; diverse set- ucts cells can influence how the mast cells re-
other pattern recognition receptors) tings in which cell damage or spond to other activation signals, such as IgE
on the mast cell surface or inside the cell death occurs and antigen.
mast cell

Endogenous peptides that can activate some

Reaction of endogenous peptides Various disease processes or
types of mast cells include certain neuropep-
with receptors for those peptides on mechanisms of host defense
tides, endothelin-1, and products of comple-
the mast cell surface that maintain health
ment activation (C3a, C5a).

Section A - Allergy - from genetics to mechanisms

Some of these venom peptides are structur-
ally similar to endogenous peptides that can
Reaction of exogenous peptides with
Envenomation by venomous also activate mast cells; mast cell proteases
receptors on the mast cell surface
reptiles released when the activated mast cells de-
that recognize such peptides
granulate can degrade and thereby reduce the
toxicity of some components of the venoms.

*
In addition to mechanisms that activate mast cells, certain stimuli can diminish the extent of mast cell activation.
†
Mast cells activated by IgE and specific antigen can release many or all of the products listed in Table 1. By contrast, other acti-
vation mechanisms can result in the relatively selective release of granule-stored products (e.g., in response to certain peptides) or
cytokines, chemokines and growth factors (e.g., in response to certain microbial products).

type that can bind IgE), showing mast cells did not develop in order shansky K, Lichtman MA, Beutler
that mast cells importantly con- to cause disease. Likely beneficial E, Kipps TJ, Seligsohn U, Prchal JT,
tribute to this acute, catastroph- roles of mast cells include enhanc- eds. Williams Hematology, 8th ed.
ic and potentially fatal reaction. ing host resistance to some par- New York: McGraw-Hill Medical,
Through effects of released mast asites and other pathogens and 2010;63:915-932.
cell products on inflammation enhancing innate and acquired re- 2. Galli SJ, Tsai M. IgE and mast
and structural cells in the affected sistance to certain animal venoms. cells in allergic disease. Nat Med
tissues (Table 1), IgE-dependent Mast cells also have the potential 2012;18:693-704.
mast cell activation can contribute to limit the pathology associated
3. Reber L, Marichal T, Galli SJ. New
to late phase reactions (that devel- with certain innate or acquired
models for analyzing mast cell
op hours after allergen exposure) immune responses through the
functions in vivo. Trends Immunol
and to the features of chronic al- production of mediators with an-
2012;33:613-625.
lergic inflammation (e.g., in allergic ti-inflammatory or immunosup-
asthma). pressive effects. 4. Marichal T, Starkl P, Reber LL, Kale-
snikoff J, Oettgen HC, Tsai M, Metz
Do mast cells contribute KEY REFERENCES M, Galli SJ. A beneficial role for
to health, or only to 1. Galli SJ, Metcalfe DD, Arber DA, Immunoglobulin E in host defense
disease? Dvorak AM. Basophils and mast against honeybee venom. Immunity
From an evolutionary perspective, cells and their disorders. In: Kau- 2013;39:963-975.

Mast cells 55
 Global atlas oF allergy

10 Basophils

Hajime Karasuyama 
Tokyo Medical and Dental University
Tokyo, Japan

Basophils are the least abundant

granulocytes, and represent less Ke y m essag es
than 1% of peripheral blood leuko-
Section A - Allergy - from genetics to mechanisms

cytes. They were first document- • Basophils have long been neglected in immunological studies,
ed by Paul Ehrlich more than 100 owing to their small numbers and phenotypic similarity to mast
years ago, but their functional sig- cells
nificance remained enigmatic for a • The finding that basophils secrete large quantities of Th2
long time. Basophils share certain cytokines (IL-4 and IL-13) ended the long-held view of basophils
features with tissue-resident mast as minor relatives of mast cells with little function
• Basophils normally circulate in the blood, and are recruited to
cells, including the presence of ba-
affected tissues in various allergic disorders, including allergic
sophilic granules in the cytoplasm,
rhinitis, chronic urticaria, atopic dermatitis, and asthma
the surface expression of IgE re-
• Recent development of analytical tools in mouse models has
ceptor (FcεRI), and the release of
identified pivotal and nonredundant roles for basophils in a
chemical mediators in response
variety of immune responses, including allergy
to various stimuli (Table 1). There-
fore, they have often erroneously
been considered as minor and re-
mast cells may play distinct roles in allergic reactions. Indeed, baso-
dundant relatives or precursors of
in vivo, no definitive evidence for phils have been demonstrated to
tissue-resident mast cells. Indeed,
it has been provided until recently. infiltrate affected tissues in var-
in clinical settings, basophils have
Basophils release preformed his- ious allergic disorders, including
been used, as surrogates of less
tamine, newly synthesized leukot- allergic rhinitis, chronic urticaria,
accessible tissue mast cells, for the
in vitro quantification of immedi- riene C4, and Th2 cytokines (IL-4 atopic dermatitis, and asthma.
ate-type response to allergens in and IL-13), all of which are involved However, the overwhelming influx
allergic patients.
TABLE 1
Basophils circulate in the periph-
Difference between basophils and mast cells
eral blood, and are rarely present
in peripheral tissues under home- Basophils Mast cells
ostatic conditions, in contrast to Place of birth bone marrow bone marrow
mast cells. The half-life of circu-
lating basophils is estimated at Place of maturation bone marrow peripheral tissues
approximately 2 days, while mast Anatomical localization peripheral blood peripheral tissues
cells survive for months in periph- Life span short (several days) long (weeks or months)
eral tissues. Although these differ-
Proliferation capability - +
ences suggest that basophils and

56 Basophils
Global atlas oF allergy

Basophils Basophils in Basophils in

in diseases protective immunity regulation of immunity

Protection against Promotion of

Allergy
Ectoparasites Th2 cell differentiation

™™ Basophils function as IL-4

™™ Allergic rhinitis ™™ Tick infestation producers and antigen-pre-
senting cells
™™ Chronic cutaneous allergic
inflammation
™™ Systemic anaphylaxis Protection against Enhancement of
™™ Eosinophilic esophagitis Endoparasites humoral memory response
™™ etc.
™™ Basophil-derived factors
™™ Helminth infection stimulate memory B and T

Section A - Allergy - from genetics to mechanisms

cells

Generation of
Autoimmunity
M2-type macrophage

™™ Basophil-derived IL-4
™™ Lupus nephritis acts on monocytes and
macrophages

Figure 1  Previously unappreciated roles of basophils revealed by mouse studies.

of eosinophils in these responses parasites (ticks and intestinal hel- KEY REFERENCES
has long overshadowed the signif- minths), and regulation of innate 1. Karasuyama H, Mukai K, Obata K,
icance of basophil infiltration and Tsujimura Y, Wada T. Nonredun-
and acquired immunity (gener-
dant roles of basophils in immunity.
it has remained uncertain whether ation of Th2 cells and M2-type Annu Rev Immunol 2011;29: 45-69.
basophils play a crucial role or are macrophages, and enhancement 2. Falcon, F.H., Knol, E.F., Gibbs, B.F.
just redundant with mast cells.
of humoral immunity) (Figure 1). The role of basophils in the patho-
Recent development of analyti- Of note, the number of basophils genesis of allergic disease. Clin Exp
cal tools for basophil function in recruited to affected tissues of Allergy 2011;41:939-947.
vivo, including basophil-deficient model mice is much smaller than 3. Schroeder JT. Basophils: emerg-
mice, has identified pivotal and ing roles in the pathogenesis of
that of eosinophils, as observed in allergic disease. Immunol Rev
nonredundant roles for basophils allergic patients, suggesting that 2011;242:144-160.
in a variety of immune responses
basophils may also play key roles 4. Siracusa MC, Kim BS, Spergel JM,
in mouse models, such as allergic
in the development and exacerba- Artis D. Basophils and allergic in-
reactions (allergic rhinitis, chronic flammation. J Allergy Clin Immunol
cutaneous allergic inflammation, tion of human allergic disorders in
2013;132:789-801.
systemic anaphylaxis, and eosin- spite of their paucity. Therefore,
5. Voehringer D. Protective and
ophilic esophagitis), autoimmun- basophils and their products could
pathological roles of mast cells
ity (lupus nephritis), protective be promising targets for the treat- and basophils. Nat Rev Immunol
immunity against infections with ment of allergic disorders. 2013;13:362-75.

Basophils 57
 Global atlas oF allergy

11 Eosinophils

Hans-Uwe Simon 
University of Bern
Bern, Switzerland

Eosinophils are terminally differ-

entiated granulocytic effector Ke y m essag es
cells that produce and store bio-
Section A - Allergy - from genetics to mechanisms

logically active molecules, includ- • Eosinophils are multifunctional cells

ing cytotoxic proteins, lipid medi- • Eosinophilia in allergic diseases is largely mediated by IL-5-
ators, chemotactic peptides, and producing T cells
cytokines. They are considered as • Eosinophils can cause organ dysfunction by both cytotoxicity
multifunctional cells able to mod- and fibrosis
ulate both innate and adaptive • Specific anti-eosinophil therapies have been shown to be
effective in asthma
immunity (Fig. 1). Eosinophils are
generated in the bone marrow
under the influence of eosinopoie-
tins (IL-3, IL-5, GM-CSF), released
to peripheral blood upon matura- that reduce eosinophil numbers bronchoconstriction. Moreover,
are usually effective in allergic dis- eosinophils can amplify T helper
tion, and mainly reside in the he-
eases. Moreover, the numbers of 2 immune reactions by the gener-
matopietic and lymphatic organs,
eosinophils in sputum have been ation of cytokines. A role for eo-
such as the bone marrow, spleen,
shown to predict the success of sinophils in experimental asthma
lymph nodes, and thymus. The
anti-eosinophil therapies in asth- has been demonstrated in eosino-
normal eosinophil blood count
matic patients. For example, tai- phil-deficient mice, which demon-
ranges from 50 to 500 x 109/L.
loring of asthma treatment based strated reduced T cell recruitment
Eosinophil numbers can increase on sputum eosinophils is effective and mucus production, as well as
in various inflammatory reactions, in decreasing asthma exacerba- reduced bronchial hyperreactivity.
including allergic diseases. Several tions.
proposals for the classification of Eosinophils also play a role in tis-
eosinophil-related disorders have The exact role of eosinophils in sue repair and remodeling pro-
been published. In allergic diseas- the pathogenesis of allergic dis- cesses. Specific anti-eosinophil
es, eosinophilia is largely mediat- eases is currently a topic of inten- treatment by using anti-IL-5 an-
ed by IL-5 - producing T cells. sive research. In asthma, eosin- tibodies was associated with re-
ophil-derived cytotoxic proteins duced fibrosis in allergic asthma
Clinical observations point to a and reactive oxygen species have and eosinophilic esophagitis. The
potential role of eosinophils in the been shown to damage bronchial peribronchial fibrosis was also
pathogenesis of allergic diseases. epithelial cells, leading to a bar- reduced in experimental asthma
Eosinophil numbers in blood and rier defect. Eosinophils are also a induced in eosinophil-deficient
eosinophil tissue infiltration of- source of lipid mediators, such as mice. Therefore, eosinophils can
ten correlate with the severity of leukotriene C4 and platelet-ac- contribute to organ dysfunction
the disease. Therefore, therapies tivating factor, which can cause by both cytotoxicity and fibrosis.

58 Eosinophils
Global atlas oF allergy

A Bone
marrow Blood Tissue
B
Activation

IL-5
GM-CSF
IL-3

Section A - Allergy - from genetics to mechanisms

Granule proteins Killing of pathogens
DNA &
ROS tissue damage

Activation Cytokines Immune regulation

Lipid mediators

Cytokines
Remodeling
MMP-9

Figure 1  Tissue infiltration and role of eosinophils in diseases. (A) Eosinophils originate from multipotent and lineage-
restricted hematopoietic progenitor cells. They mature in the bone marrow under the influence of eosinophilopoietic
cytokines (IL-3, IL-5, and GM-CSF). Mature eosinophils are released in the peripheral blood and can infiltrate
inflammatory tissues as it occurs in allergic diseases. At sites of inflammation, eosinophils are activated and their
apoptosis is delayed (reviewed by Geering B, Stoeckle C, Conus S, Simon HU. Living and dying for inflammation:
neutrophils, eosinophils, basophils. Trends Immunol 2013;34:398-409). Under non-inflammatory conditions, eosinophils
undergo apoptosis without infiltration of organs outside the hematopoietic and lymphatic systems. (B) An example of
eosinophil tissue infiltration: Eosinophil infiltration of the dermis in a patient with drug allergy. The tissue section was
stained with hematoxylin and eosin (original magnification x63). (C) Eosinophils are multifunctional cells. Following
activation of eosinophils, they release granule proteins and reactive oxygen species (ROS), which are able to kill
pathogens, but also tissue cells possibly causing organ dysfunction. Eosinophils additionally release mitochondrial DNA,
which forms together with granule proteins eosinophil extracellular traps (reviewed by Simon D, Simon HU, Yousefi
S. Extracellular DNA traps in allergic, infectious, and autoimmune diseases. Allergy 2013;68:409-416). By releasing
cytokines and lipid mediators, eosinophils are further involved in immune regulation and remodeling events.

KEY REFERENCES al on criteria and classification of allergy. Ann Rev Pharmacol Toxicol
1. Simon D, Simon HU. Eosinophilic eosinophilic disorders and related 2014;55:in press.
disorders. J Allergy Clin Immunol syndromes. J Allergy Clin Immunol
2007;119:1291-1300. 2012;130:607-612. 4. Rosenberg HF, Dyer KD, Foster PS.
3. Radonjic-Hoesli S, Simon HU. Eosinophils: changing perspectives
2. Valent P, Klion AD, Horny HP, Rou-
fosse F, Gotlib J, Weller PF et al. Novel targeted therapies for eo- in health and disease. Nat Rev Im-
Contemporary consensus propos- sinophil-associated diseases and munol 2013;13:9-22.

Eosinophils 59
 Global atlas oF allergy

12 T cells

Carsten B. Schmidt-Weber 
Technical University Munich and Helmholtz Center
Munich, Germany

Immune memory - good

against bugs, bad for Ke y m essag es
allergic and autoimmune
Section A - Allergy - from genetics to mechanisms

diseases • Allergy is dependent on the immunologic memory as it re-occurs

The potency of the immune mem- regularly
ory is assumed to be a key event • Allergic symptoms correlate with T cell activation particularly of
in the evolution that allowed the the Th2 type
success of larger organisms over • T cells do also react to allergens in asymptomatic patients and
smaller sized creatures and gen- may mediate allergen tolerance by active immune suppression
erated longer-lived organisms.
However, the ability to remember
pathogens has also its downsides. variability and, thus, an extend- memory cells are able to quickly
ed repertoire of TCRs that cover expand and reproduce an immune
A key feature of allergy is that most determinants of our environ- response that has been proven to
the symptoms occur again every ment is generated. Apart from the be successful. It is anticipated that
season. This is similar to the im- sophisticated structure of TCRs, the generation of memory cells is
munologic feature that memoriz- the activation and differentiation underlying successful immuniza-
es determinants on pathogens or of these cells is integrating mul- tions (vaccination) against infec-
other harmless structures such tiple signals from the tissue, the tious agents. Hyposensitisation
as autoantigens or allergens. The immune system and the external by allergen-specific immunother-
inappropriate immune response environment. This integration pro- apy (AIT) may also be governed by
caused by dysregulation of the im- cess involves antigen-presenting memory populations.
munologic tolerance is underlying cells (APC) that need to digest the
autoimmune and allergic diseases. environmental allergen/antigen Decision making in the
Both memory and immune toler- and present it in a molecule with immune system
ance are mediated by T lympho- similar high diversity as the TCR. The decision making process is
cytes, which recognize immu- Major histocompatibility com- subject of immunology research
nogenic structures by the T-cell plexes, (MHC) bring the digested and has the intention to solve the
receptor (TCR). This receptor is peptides to the surface of the APC “black box” of immune tolerance
characterized by a very high varia- and also deliver additional signals mechanisms. The goals are to
bility that is generated by multiple that are essential for the activa- prevent the loss of immune tol-
gene-segment cassettes that are tion or deactivation of T cells. The erance by means of public health
alternatively rearranged to gen- successful activated T cell will di- initiatives (e.g. pollution control,
erate a final gene product. Further vide and after the termination of dietary advices etc.), to increase
variation is introduced by a flexi- an immune response some cells effectiveness of specific immuno-
ble fusion process that increases (memory cells) will remain. These therapy and similar vaccination

60 T cells
 Global atlas oF allergy

spec. spongiosis remodeling, bronchiale itch immediate type acute inflammation asymptomatic
immunity unspec. immunity hypersensitivity reactions anti- "remodeling"? reactions
shedding inhibition of MHC airway - microbial tissue

Section A - Allergy - from genetics to mechanisms

I & II "remodelling" homeostatis

Figure 1  Different T cell phenotypes arise from naïve (resting, not antigen-experienced T cells) upon activation by
antigen-presenting cells and by decision cytokines (not shown). The figure highlights a variety of responding cells both of
the immune system as well as from non-immune (mesenteric) origin.

strategies and to develop new Terminating immune immunology. J Allergy Clin Immunol
therapies that prevent severe tis- responses 2007;120:247-254.
sue damage as it occurs in the gut, This holds particularly true for 2. Stott B, Lavender P, Lehmann S,
skin and airways. The decision of the immune system. T regulatory Pennino D, Durham S, Schmidt-We-
the immune system is reflected by (Treg) cells represent a key discov- ber CB. Human IL-31 is induced by
the T lymphocyte activity, mainly ery that falls into this category, as IL-4 and promotes TH2-driven in-
by their secreted mediators, in- they are actively suppressing oth- flammation. J Allergy Clin Immunol
terleukins (IL). Interleukins are er immune cells particularly Th1, 2013;132:446-54 e5.
typically of the “Th2”-type includ- -2 and-17 cells. In fact, healthy 3. Eyerich S, Onken AT, Weidinger
ing IL-4, IL-5 and IL-13, whereas individuals are showing immune S, Franke A, Nasorri F, Pennino D,
autoimmune or pathogen-trigged activation in vitro, suggesting that et al. Mutual antagonism of T cells
T cells usually express “Th1- or mechanisms exist that keep these causing psoriasis and atopic ecze-
Th17-type” IL’s and interferons processes under asymptomatic ma. N Engl J Med 2011;365:231-
(IFN) such as IFN-γ or IL-17. IL-4 control. Novel immune regulato- 238.
produced by T cells is essential for ry T cell phenotypes are hypothe- 4. Akdis M, Verhagen J, Taylor A, Kar-
the production of IgE, the diagnos- sized to mediate anti-inflammato- amloo F, Karagiannidis C, Crameri
tic key parameter in the detection ry signals also to tissue cells. AIT is R, et al. Immune responses in
of allergies. The interleukins have assumed to generate Treg cells and healthy and allergic individuals are
various functions and are charac- future research and novel phar- characterized by a fine balance be-
terizing the regulatory impact of maceutical strategies are aiming tween allergen-specific T regulato-
T cells on other immune cells and to reinforce these mechanisms in ry 1 and T helper 2 cells. J Exp Med
on tissue cells. The exploration order to re-construct immune tol- 2004;199:1567-1575.
of T cell mediated signals on tis- erance under minimal influence on 5. Pennino D, Bhavsar PK, Effner R,
sue cells is just beginning and it is anti-pathogen responses. Avitabile S, Venn P, Quaranta M,
already revealed that T cells can et al. IL-22 suppresses IFN-gam-
directly mediate tissue pathology KEY REFERENCES ma-mediated lung inflammation
such as epithelial damage or colla- 1. Schmidt-Weber CB, Akdis M, Akdis in asthmatic patients. J Allergy Clin
gen deposition (Figure 1). CA. TH17 cells in the big picture of Immunol 2013;131:562-570.

T cells 61
 Global atlas oF allergy

13 B cells

Azza Abdel-Gadir Talal Chatila

Harvard Medical School
Boston, USA
B cells are crucial in allergic dis-
eases by virtue of their production Ke y m essag es
of allergen-specific IgE antibodies,
Section A - Allergy - from genetics to mechanisms

which play a key role in instigat- • By their production of allergen-specific IgE antibodies B cells
ing immediate hypersensitivity contribute to the pathophysiology of a wide range of allergic
reactions and contribute to the diseases
pathophysiology of a wide range • CD4+ Th2 cells that produce IL-4 and express CD40L orchestrate
of allergic diseases ranging from the IgE-switch and differentiation of B cells
asthma, atopic dermatitis, food • The recently described B regulatory cells inhibit over-activated
immune responses
and drug allergy, amongst others.
• Elucidating mechanisms regulating the bifurcation of B cell
IgE-production by B cells entails
responses into B regulatory versus IgE-producing cells holds
class-switch recombination at the
promise for therapeutic interventions
immunoglobulin heavy chain locus
into the IgE heavy chain (Cε). CD4+
Th2 cells that produce IL-4 and
of each pathway to the generation given to regulatory B (Breg) cells
express CD40L orchestrate the
of disease-promoting pathogenic that inhibit over-activated im-
differentiation of IgE-switched B
IgE antibodies remains to be es- mune responses. Several groups
cells. It has been suggested that
tablished (Figure 1). have proposed that a reduction
there are two pathways for IgE
in Breg cells worsens symptoms
production after secondary expo- The highly variable correlation be-
of allergic disease such as contact
sure to antigen. tween the levels of allergen-spe-
hypersensitivity and anaphylax-
cific IgE antibodies and suscepti-
The first involves the differen- is. Breg cells are characterized by
bility to anaphylaxis indicates that
tiation of IgE-switched plasma their production of the negative
other factors, such as IgG antibod-
cells from IgG1+ precursors by regulatory cytokines, IL-10 and
ies, have profound influences on
sequential switching from Cγ1 TGF-β. An increased number of
IgE-mediated responses. Immuno-
to Cε, leading to the production IL-10-producing B cells has been
therapy to aeroallergens has been
of high affinity IgE antibodies by found in S. mansoni worm infection
shown to stimulate the production
somatic hypermutation (affinity and the in vivo transfer of these
of allergen-specific IgG1 and IgG4
maturation). The second pathway cells prevents recipient mice from
antibodies, that protect against
involves the direct differentiation anaphylaxis. Breg cells proliferate
disease by inhibiting allergen in-
of IgE+ memory B cells generated when stimulated with the milk an-
teraction with FcεRI-bound IgE on
during the primary immune re- tigen casein in milk tolerant but
mast cells and basophils, thus pre-
sponse into plasma cells, leading not in milk allergic patients. Akdis
venting their degranulation.
to a robust recall IgE antibody re- and colleagues recently found in-
sponse. The relative contribution Recently, much attention has been creased suppressive IL10+ Breg

62 B cells
Global atlas oF allergy

cells in non-allergic beekeepers

undergoing allergen-specific im-
munotherapy and high-dose ven-
om exposure. They revealed that
Breg cells are specifically devel-
oping into IgG4-producing plasma
cells (Figure 2). Thus, elucidating
mechanisms regulating the bi-
furcation of B cell responses into
Breg versus IgE producing cells
holds promise for therapeutic in-
terventions.

KEY REFERENCES
1. Larché M, Akdis CA, Valenta R. Im-
munological mechanisms of aller-
gen-specific immunotherapy. Nat
Rev Immunol 2006;6:761-771.
2. Xiong H, Dolpady J, Wabl M, Cu-

Section A - Allergy - from genetics to mechanisms

rotto de Lafaille MA, Lafaille JJ.
Figure 1  Pathways for the generation of memory B cells. The interaction of Sequential class switching is re-
Th2 cells with allergen-specific B cells may lead to switching into either IgE+ or quired for the generation of high
IgG1+ memory B cells. The former would differentiate directly to IgE+ plasma affinity IgE antibodies. J Exp Med
cells upon recall responses, while the latter would first undergo switching from 2012;209:353-364.
Cγ1 to Cε before further differentiating into plasma cells. 3. Talay O, Yan D, Brightbill HD,
Straney EE, Zhou M, Ladi E, et al.
IgE+ memory B cells and plasma
cells generated through a germi-
nal-center pathway. Nat Immunol
2012;13: 396–404.
4. Lee JH, Noh J, Noh G, Choi WS,
Cho S, Lee SS. Allergen-specific
transforming growth factor-β-pro-
ducing CD19(+)CD5(+) regulatory
B-cell (Br3) responses in human
late eczematous allergic reactions
to cow’s milk. J Interferon Cytokine
Res 2011;31: 441–449.
5. Amu S, Saunders SP, Kronenberg
M, Mangan NE, Atzberger A, Fal-
lon PG. Regulatory B cells prevent
and reverse allergic airway inflam-
mation via FoxP3-positive T reg-
ulatory cells in a murine model.
J Allergy Clin Immunol 2010;125:
1114–1124.
6. van de Veen W, Stanic B, Yaman G,
Wawrzyniak M, Sollner S, Akdis DG,
et al. IgG4 production is confined to
Figure 2  Opposing actions of IgE and IgG4 in allergic responses. Allergen- human IL-10-producing regulatory
specific IgG4, generated during immunotherapy, blocks the interaction of B cells that suppress antigen-spe-
allergens to IgE and abrogates IgE-dependent effector responses. Regulatory cific immune responses. J Allergy
B cells may promote tolerance by differentiating into allergen-specific IgG4- Clin Immunol 2013;131:1204–
producing plasma cells. 1212.

B cells 63
 Global atlas oF allergy

Immunoglobulin E and
14 other antibodies in
allergy
Hannah Gould Yih-Chih Chan
King’s College London
London, United Kingdom
Immunoglobulin E (IgE) is one of
five antibody classes, IgM, IgD, Ke y m essag es
IgG, IgA and IgE, in mammals (Fig-
Section A - Allergy - from genetics to mechanisms

ure 1). There are four subclasses • Antibodies of the IgE class are central to the allergic response.
of IgG (IgG1-4) and two of IgA • IgE antibodies are synthesized and secreted by allergen-specific
(IgA1, IgA2), making a total of 9 B cells that have undergone heavy-chain class switching to IgE
nine different classes including and differentiated into IgE-secreting plasma cells
the subclasses in humans. • IgE binds to FcεRI on mast cells and antigen (in this case allergen)-
presenting cells to sensitize the cells for allergen activation
Every person can produce an anti- • The immediate symptoms of allergy are caused by the release
body to recognize virtually any po- of potent physiological mediators produced by the allergen-
tential antigen by a combination of activated mast cells, while the activated antigen-presenting cells
mechanisms. The initial repertoire indirectly induce new allergen-specific B cells to produce more IgE
of IgMs generated in the bone • Allergen immunotherapy can generate allergen-specific antibo-
marrow by “V(D)J” gene recombi- dies of IgG and IgA classes to compete with IgE for allergens
nation and junctional nucleotide
variation is highly diverse and is
further adapted by antigen stimu- immunoglobulin gene (Figure 2). potent molecules that cause the
lation of the B cells in the immune This changes the antibody class symptoms of allergy. The activat-
response. This results in cell prolif-
and the way it is able to engage dif- ed antigen-presenting cells stim-
eration and the formation of ger-
ferent effector cells in the immune ulate T helper 2 (Th2) cells, which
minal centers in lymphoid tissues,
response. Germinal center reac- in turn induce the production of
where they undergo two process-
tions may also occur in the target more allergen-specific antibodies
es: somatic hypermutation (SHM)
organs of allergy. in a positive feedback loop primed
and class switch recombination
by allergen.
(CSR). SHM introduces point mu- Antibodies of the IgE class are
tations in the antigen-binding central to the allergic response Antibodies of the same or cross-re-
sites, which may increase or de- (Figure 3). They are synthesized acting specificity, but another an-
crease affinity for antigen result- and secreted by IgE-expressing tibody class can compete with IgE
ing in selection of high-affinity B cells that have differentiated for antigen binding to prevent or
mutants that compete for antigen into IgE-secreting plasma cells. suppress the allergic response.
in a process called affinity matu- IgEs bind to mast cells and anti- This may occur in specific allergen
ration. CSR replaces the constant gen-presenting cells bearing the immunotherapy, which stimulates
region of the heavy-chain with one high-affinity IgE receptor, FcεRI, to a modified Th2 response, causing
of another class encoded in a tan- sensitize the cells for allergen ac- a massive up-regulation of IgG4
dem array downstream from the tivation. Allergen-activated mast and IgA2. Some of these antibod-
VDJ sequence in the expressed cells release the physiologically ies may recognize the allergen and

64 Immunoglobulin E and other antibodies in allergy

Global atlas oF allergy

Figure 1 All five antibody classes

have the same basic “immunoglobu-
lin” structure with two heavy- and two
light-chains, each with variable-re-
gions (white) containing the anti-
gen-combining site and class-specific
constant-regions shown in different
colors. The distinctive ε constant re-
gion of the IgE heavy-chain is shown in
green. Carbohydrates attached to the
protein are depicted as small purple
circles. The different constant-regions
are encoded in a tandem array in the
germ line immunoglobulin heavy-
chain gene locus on human chromosome 14, downstream from the heavy-chain variable-region of the expressed heavy-
chain gene.

Figure 2  Class switch recombination

is required to express IgE. The immu-
noglobulin heavy-chain locus contains
the rearranged variable (VDJ) region

Section A - Allergy - from genetics to mechanisms

linked to a transcriptional enhancer
(E) and a series of three elements re-
quired for expression of the complete
heavy-chain, an “intervening” exon (I),
a switch region (S) and a constant re-
gion (C). During class switch recombi-
nation the VDJ, I and proximal part of
S are recombined with the distal part
of S within another germ line gene
cassette (I, S, and C distinguished by
Greek letters corresponding to the
newly expressed antibody class). The
intervening sequence is deleted and
the ends join to form a circle. Prior
to recombination, specific cytokines
stimulate germ line gene transcrip-
tion from the I exon promoters of the
two genes that subsequently undergo
recombination. The germ line gene
transcript corresponding to the gene
to be expressed helps to instigate the
subsequent recombination. The I exon
promoter in the switch circle, now
attached to the previously expressed
gene, remains transiently active, producing a circle transcript whose sequences can be used to identify the genes that re-
combined. The new immunoglobulin gene in the shortened chromosome is expressed from the VDJ promoter, leading to
the synthesis of the immunoglobulin heavy-chain mRNA and protein. The light-chain is unchanged after heavy-chain re-
combination.

compete with IgE. It is thought KEY REFERENCES nal-centre reactions in allergic in-
that immune deviation to IgG4 flammation. Trends Immunol 2006;
1. Gould HJ, Sutton BJ. IgE in allergy 27:446-52.
and IgA2 allergen specificities and asthma today. Nat Rev Immu-
3. Matsuoka T, Shamji MH, Dur-
may contribute to the success of nol 2008; 8:205-17.
ham SR. Allergen immunotherapy
specific allergen immunotherapy 2. Gould HJ, Takhar P, Harries HE, and tolerance. Allergol Int 2013;
(Figure 4). Durham SR, Corrigan CJ. Germi- 62:403-13.

Immunoglobulin E and other antibodies in allergy 65

 Global atlas oF allergy

Figure 3  IgE binds very tightly to

mast cells and antigen-presenting
cells through its high-affinity
receptor, FcεRI. Specific allergen
crosslinking of the IgE-receptor
complex on mast cells induces cell
degranulation with the release of
mediators leading to the allergic
response and also the production
of IL-4 and IL-13 and expression of
CD40L by the antigen-presenting
cells and mast cells. These cytokines
lead to B cell proliferation and further
switching to IgE in B cells expressing
other isotypes in a positive feedback
loop, resulting the generation of even
more IgE.
Section A - Allergy - from genetics to mechanisms

Figure 4  Natural exposure to

allergens may induce allergen-
specific IgE production in sensitive
individuals by stimulation of antigen-
presenting cells in a T helper 2 (Th2)
immune response. This IgE sensitizes
effector cells (mast cells, basophils
and eosinophils) and the generation
of allergen-specific IgE by B cells.
Exposure to high-doses of allergens
through immunotherapy induces IL-
10/IL27 release from dendritic cells
leading to suppression of the Th2 by
deviation of T cell differentiation into
the T helper 1 cell and T regulatory
(Treg) cell pathways. The resultant
cytokines, IFN-γ IL-12, IL-10 and
TGF-β lead to the generation of
allergen-specific IgG4 and IgA2
antibodies that compete with IgE for
allergens.

66 Immunoglobulin E and other antibodies in allergy

Global atlas oF allergy

15 Role of superantigens
in allergic diseases
Donald Y. M. Leung 
National Jewish Health
Denver, USA

Atopic dermatitis (AD) is the most

common chronic skin disease in the Ke y m essag es
general population. It often pre-

Section A - Allergy - from genetics to mechanisms

sents during early childhood and • Staphylococcus aureus is a major trigger of atopic dermatitis and
is the prelude to development of may contribute to severity of rhinosinusitis and asthma
food allergy, asthma and allergic • S. aureus exacerbates allergic diseases by secreting virulence
rhinitis. A majority of AD patients factors such as superantigens and alpha toxin
have a systemic and skin direct- • Staphylococcal virulence factors alter host responses to
ed Th2 immune response lead- allergens and microbes
ing to allergen sensitization and • Th2 skin immune responses and filaggrin deficiency increases
the propensity of atopic skin to become colonized and infected
increased skin colonization with
with S. aureus
Staphylococcus aureus (S. aureus).
These patients also have a defect
in the terminal differentiation of
proteins such as filaggrin, and de- stimulates cytokine release from
their skin keratinocytes leading to
creased expression of antimicro- antigen-presenting cells (Figure
reduced expression of skin barrier
bial peptides needed for skin host 3). Evidence supporting a role for
defense against invading bacteria superantigens in AD include the
and viruses. Reduced barrier func- observation that most AD pa-
tion is due to a combination of gene tients make IgE antibodies direct-
mutations encoding skin barrier ed against superantigens found
proteins such as filaggrin with the on their skin and the presence of
downregulation of epithelial dif- these IgE antibodies to superan-
ferentiation protein levels induced tigens correlate with skin disease
by Th2-type cytokines and IL-22. severity. Basophils and skin mast
Loss of filaggrin has been linked to cells from patients with anti-su-
enhanced allergen penetration into perantigen IgE release histamine
the skin, increased S. aureus growth on exposure to superantigens, but
Figure 1  Child with atopic dermati- and S. aureus infection (Figure 1). not in response to superantigens
tis superinfected with superantigen Staphylococcus aureus triggers and to which they have no specific
secreting Staphylococcus aureus. maintains skin inflammation in AD IgE. Importantly, the superanti-
(Reprinted from J Allergy Clin Immu- via the production of virulence fac-
nol, 125/1, Boguniewicz M, Leung DY.
gen, staphylococcal enterotoxin B
tors, such as superantigens and al- (SEB), can induce eczematoid skin
Recent insights into atopic dermatitis pha toxin (Figure 2).
and implications for management of in- changes when applied to the skin.
fectious complications, 4-13, Copyright Superantigens are potent poly- After stimulation by SEB, T reg-
2010, with permission from Elsevier.) clonal T cell activators that also ulatory cells lose their immuno-

Role of superantigens in allergic diseases 67

 Global atlas oF allergy

reduction of skin inflammation.

AD patients with S. aureus infec-
tion should receive antibiotics as
this may reduce the severity of
their skin disease. Together, these
observations fulfill Koch’s postu-
lates and support a role for staph-
ylococcal superantigens in AD.
There is also increasing data sug-
gesting that in certain clinical sit-
uations, S. aureus may contribute
to severity of rhinosinusitis and
asthma, by augmenting the airway
inflammation and promoting pol-
yclonal local IgE formation, and
by inducing corticosteroid resist-
Figure 2  Virulence factor production by S. aureus (Reprinted from J Allergy Clin ance.
Immunol, 125/1, Schlievert PM, Strandberg KL, Lin YC, Peterson ML, Leung DYM.
KEY REFERENCES
Section A - Allergy - from genetics to mechanisms

Secreted virulence factor comparison between methicillin-resistant and methicillin-

sensitive Staphylococcus aureus, and its relevance to atopic dermatitis, 39-49, 1. Boguniewicz M, Leung DY. Recent
Copyright 2010, with permission from Elsevier.) insights into atopic dermatitis and
implications for management of
infectious complications. J Allergy
Clin Immunol 2010;125: 4-13.
2. Ong PY, Ohtake T, Brandt C, Strick-
land I, Boguniewicz M, Ganz T, et al.
Endogenous antimicrobial peptides
and skin infections in atopic derma-
titis. N Engl J Med 2002;347:1151-
1160.
3. Irvine AD, McLean WHI, Leung DY.
Filaggrin Mutations Associated
with Skin and Allergic Diseases. N
Engl J Med 2011;365:1315-1327.
4. Gittler JK, Shemer S, Suárez-
Fariñas M, Fuentes-Duculan J,
Gulewicz KJ, Wang CQF, et al. Pro-
gressive activation of TH2/TH22
cytokines and selective epidermal
proteins characterizes acute and
Figure 3  Model comparing activation of CD4+ T cells and macrophages by the chronic atopic dermatitis. J Allergy
superantigen, SEB, compared with antigenic peptide activation of the same cells.
Clin Immunol 2012; 130:1344-54.
In comparison to peptide activation, SEB causes polyclonal T cell stimulation.
(Reprinted from J Allergy Clin Immunol, 125/1, Schlievert PM, Strandberg KL, Lin YC, 5. Schlievert PM, Strandberg KL, Lin
Peterson ML, Leung DYM. Secreted virulence factor comparison between methicillin- YC, Peterson ML, Leung DYM. Se-
resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic creted virulence factor comparison
dermatitis, 39-49, Copyright 2010, with permission from Elsevier.) between methicillin-resistant and
methicillin-sensitive Staphylococ-
suppressive activity, suggesting a become corticosteroid resistant cus aureus, and its relevance to
novel mechanism by which super- and to secrete IL-31, a highly pru- atopic dermatitis. J Allergy Clin Im-
ritogenic cytokine that induces ec- munol 2010;125:39-49.
antigens could augment T-cell ac-
zema in animal models. 6. Boguniewicz M, Leung DY. The
tivation and skin inflammation in
ABC’s of managing patients with
patients with AD. Superantigens Treatment of AD patients should severe atopic dermatitis. J Allergy
also selectively induce T cells to focus on skin barrier repair with Clin Immunol 2013;132: 511-512.

68 Role of superantigens in allergic diseases

Global atlas oF allergy

Cytokines in
16 allergy
Lars K. Poulsen 
National University Hospital
Copenhagen, Denmark

Cytokines are soluble proteins or

peptides that act as the hormones Ke y m essag es
- messengers - of the immune sys-

Section A - Allergy - from genetics to mechanisms

tem and between other cells of the • Cytokines act as messengers of the immune system with other
body. They confer cell-to-cell com- cells of the body
munication which may take place • Various groups of cytokines are responsible for the sensitisation
between adjacent cells (juxtacrine) to an allergen and for eliciting the allergic inflammation.
or cells in different organs of the • There are sensing cytokines, T cell instructing cytokines, effector
body (para- or endocrine). A cy- cytokines, resolving cytokines and chemokines
• The integrated actions of the cytokines in development,
tokine signal is delivered via a re-
elicitation and eventually resolving the inflammation is called the
ceptor on the surface of a cell, and
cytokine network of allergy
since different cells may express
the same receptor, a cytokine can
have several functions (pleiotropy)
cells - followed by a number, but (CD4+) cell to develop into dif-
depending on the target cell. Also
more and similar molecules have ferent kinds of cells, each of them
a target cell may have receptors
been discovered, so instead of just equipped for different kinds of im-
for several similar cytokines al- mune response: IL-12 and γ-inter-
interleukin-1 (IL-1), we now have
lowing for redundancy. IL-1α, IL-1β and IL-1RA (= Interleu- feron will produce T helper cells
There are more than 100 de- kin 1 Receptor Antagonist). type 1 (Th1) that helps fighting
scribed cytokines and their names bacteria and viruses, IL-4 leads to
Various groups of cytokines are
are not easy to cope with, since no Th2 cells which fights large mul-
responsible for the different
unified nomenclature exists. Some ticellular parasites like worms,
phases of the allergic sensitization
are named after where they were but unfortunately also create the
(building up the allergic immune
first found and/or their function, allergic immune response. Oth-
response) and elicitation (reactions
such as thymic stromal lymphopoi- er Th-cell types such as Th17
upon exposure to an allergen):
etin (TSLP), others after the first (believed to be active in fighting
function identified, like Granulo- The sensing cytokines: IL-33, IL-25, bacterial or fungal infections, but
cyte-Macrophage Colony Stimu- TSLP. These are released from unfortunately also involved in au-
lating Factor (GM-CSF), and some the epithelial cells of the mucous toimmune diseases), and T regu-
may even have several names giv- membranes and signals to the al- latory (dampening the inflamma-
en to them by different research lergen-presenting dendritic cells tion) also exists.
groups. An attempt to unify the to take up incoming allergens and
T-cell effector cytokines in allergy
bring them to the lymph nodes.
nomenclature has been made by are the cytokines by which Th-
the word interleukin - meaning The T-cell instructing cytokines will cells exerts their action: Th2 cells
messengers between white blood instruct undifferentiated T helper release IL-4 and IL-13 which in-

Cytokines in allergy 69
 Global atlas oF allergy

Viruses Allergens
Airway epithelial cells

TSLP, IL-4
IL-25, IL-33 IL-4 IL-13

CXCL1 IL-17 Dendritic cell TH0 cell TH2 cell

CXCL8 IL-22 IL-23 B cell
TGFβ IL-4
IL-10 TGFβ IgE
TGFβ IL-12 TGF β IL-5
IL-6 IFNγ

TH17 cell

TNF
Neutrophil IFN β TH1 cell Treg cell Eosinophil TH9 cell
Section A - Allergy - from genetics to mechanisms

MMP IL-9
Neutrophil elastase
• Basic proteins
ROS
Mucus • Cysteinyl leukotrienes
• Cytokines
Mast cell
Epithelial
cells
• Histamine
• Cysteinyl leukotrienes
• Prostagladins
Blood vessel Fibroblasts Smooth muscle cells • Cytokines

Figure 1  The complex interplay of cytokines in allergic inflammation: red - sensing cytokines; green - T-cell instructing
cytokines; violet - T-cell effector cytokines; blue - Resolving cytokines; pink - Chemokines.

structs B-cells to produce the al- Chemokines is a special group of tically by the so-called biological
lergy antibody IgE, IL-5 that stim- cytokines that attract leukocytes therapeutics where cytokine ac-
ulates the bone marrow to form to the site of inflammation, and tions are antagonized.
the eosinophilic granulocyte, and the immune system uses these to
IL-9 that together with IL-13 cre- move leukocytes in the tissues, KEY REFERENCES
when they have left the blood- 1. Galli SJ, Tsai M, Piliponsky AM. The
ates the allergic inflammation e.g.
stream. development of allergic inflamma-
in the lung as is the case in asthma. tion. Nature 2008; 454:445-454
The integrated actions of the cy- 2. Poulsen LK, Hummelshoj L. Trig-
The resolving cytokines such as
tokines in development, elicita- gers of IgE class switching and
IL-10 and Transforming Growth tion and eventually resolving the allergy development. Ann Med
Factor (TGF-β) comprise a small inflammation is called the cytokine 2007;39:440-456.
but important group of cytokines network of allergy. Since several of 3. Williams CM, Rahman S, Hubeau
that down-regulates the allergic these cytokines play a profound C, Ma HL. Cytokine pathways
inflammation, restoring the home- role in allergy, many attempts are in allergic disease. Toxicol Pathol
ostasis of the immune system. being made to use this therapeu- 2012;40:205-215.

70 Cytokines in allergy
Global atlas oF allergy

Cell migration and

17 chemokines
Cristiana Stellato  Gilda Varricchi  Gianni Marone 
University of Salerno University of Naples University of Naples
Salerno, Italy Federico II, Italy Federico II, Italy

The immune system relies on a

tightly regulated migration pro- Ke y m essag es
cess for the ordered compart-

Section A - Allergy - from genetics to mechanisms

mentalization of immune cells • Cell migration in the immune system is a highly regulated,
within the lymphoid organs, for multi-step process involving adhesion molecules, chemotactic
implementation of the homeo- factors and their receptors and is necessary for the homeostatic
static immune surveillance as well immune surveillance as well as for the coordinated recruitment
as for an appropriate response to of inflammatory cells at sites of inflammation
environmental insults through • Chemokines represent a superfamily of small proteins that
regulate immune cell trafficking and the recruitment and
innate and adaptive effector re-
activation of specific leukocyte cell types to sites of inflammation
sponses. Circulating leukocytes
• Chemokines are divided in four subclasses – CC, CXC, CX3C
and tissue-dwelling immune cells
and C – and activate cell targets through class-specific seven-
proceed from hematopoietic to
transmembrane chemokine receptors
vascular compartments and into
• Dysregulation of the chemokine system plays a crucial role in
tissue sites through receptor-me-
chronic inflammatory diseases, metabolic disorders, cancer and
diated, multi-step processes in- aging
volving many classes of traffick- • Antagonism of chemokine receptors has so far shown partial
ing molecules, including adhesion success as therapeutic strategy, and is now assisted by research
molecules (selectins and integrins) toward more specific downstream regulatory pathways
with their counterligands and che- modulating the chemokine network
moattractants, either lipid-derived
or belonging to the chemokine su-
perfamily. It is the combinatorial whose first identified member, members sharing the same recep-
nature of the diverse patterns of CXCL8, was initially characterized tor (Table 1). The ensuing signal-
expression and activation of these by its potent and specific leukocyte ing involves multiple and diverse
molecules and their receptors on chemoattractant activity – hence pathways that are highly recep-
immune and structural cells, to- the name, derived from ‘chemot- tor-, cell type- and context-specif-
gether with their modulation in actic cytokines’. Chemokines are ic and produce diverse functional
response to environmental clues, divided into the CXC, CC, CX3C outcomes. Among these, the con-
as in case of inflammatory or tu- and C subfamilies based on the trol of immune cell trafficking in
morigenic settings, that ultimately number and spacing of conserved homeostasis and the regulation of
provides a high level of specificity cysteine residues. They bind to the leukocyte recruitment, phenotype
in cellular trafficking.
seven-transmembrane, G-protein and activation in innate and adap-
Chemokines constitute a su- coupled receptors that are specif- tive immune responses remains
perfamily of small polypeptides, ic for each subclass, with multiple a defining and pivotal function of

Cell migration and chemokines 71

 Global atlas oF allergy

TABLE 1
Nomenclature of Chemokine Families and Paired Receptors

Standard Chromo- Human Chemokine Standard Chromo- Human Chemokine

name some ligand receptor(s) name some ligand receptor(s)
CCR1, CCR5
CXC-chemokines CCL3L3 17q21.1 LD78β
(CD195)
CXCL1 4q21.1 GROα/MGSAα CXCR2>CXCR1 CCL4 17q12 MIP-1β CCR5 (CD195)
CXCL2 4q21.1 GROβ/MIP-2α CXCR2 CCL4L1 17q12 LAG-1 CCR5 (CD195)
CXCL3 4q21.1 GROβ/MIP-2β CXCR2 CCL4L2 17q12 CCL4L CCR5 (CD195)
CCR1, CCR3,
CXCL4 4q21.1 Platelet Factor-4 CXCR3 (CD183) CCL5 17q12 RANTES
CCR5 (CD195)
CXCL4L1 4q12-q21 PF4V1 CXCR3 (CD183) CCL6*
CCR1, CCR2,
CXCL5 4q21.1 ENA-78 CXCR2 CCL7 17q11.2 MCP-3
CCR3
CCR3, CCR5
CXCL6 4q21.1 GCP-2 CXCR1,CXCR2 CCL8 17q11.2 MCP-2
(CD195)
Section A - Allergy - from genetics to mechanisms

CXCL7 4q21.1 NAP-2 CXCR2 CCL9*

CXCL8 4q21.1 IL-8 CXCR1,CXCR2 CCL10*
CXCL9 4q21.1 MIG CXCR3 (CD183) CCL11 17q11.2 Eotaxin CCR3
CXCL10 4q21.1 IP-10 CXCR3 (CD183) CCL12*
CXCL11 4q21.1 I-TAC CXCR3 (CD183) CCL13 17q11.2 MCP-4 CCR2, CCR3
CCR1, CCR5
CXCL12 10q11.21 SDF-1α/β CXCR4 (CD184) CCL14 17q12 HCC-1
(CD195)
CXCL13 4q21.1 BCLC CXCR5 CCL15 17q12 HCC-2 CCR1, CCR3
CXCL14 5q31.1 BRAK CXCR4 (CD184) CCL16 17q12 HCC-4 CCR1, CCR2
CXCL15* CCL17 16q13 TARC CCR4
CXCL16 17p13 SR-PSOX CXCR6 CCL18 17q12 PARC Unknown
CXCL17 19q13.2 DMC Unknown CCL19 9p13.3 ELC CCR7 (CD197)
C-chemokines CCL20 2q36.3 MIP-3α, LARC CCR6
XCL1 1q24.2 Lymphotactin/α XCR1 CCL21 9p13.3 SLC CCR7 (CD197)
XCL2 1q24.2 Lymphotactin/β XCR1 CCL22 16q13 MDC CCR4
CX3C-chemokines CCL23 17q12 MPIF-1 CCR1
CX3CL1 16q13 Fractalkine CX3CR1 CCL24 7q11.23 Eotaxin-2 CCR3
CC-chemokines CCL25 19p13.3 TECK CCR9
CCL1 17q11.2 I-309 CCR3 CCL26 7q11.23 Eotaxin-3 CCR3
CCL2 17q11.2 MCP-1 CCR2 CCL27 9p13.3 CTACK CCR10
CCR1, CCR5
CCL3 17q12 MIP-1α CCL28 5p12 MEC CCR3/CCR10
(CD195)
CCR1, CCR5
CCL3L1 17q21.1 LD78β
(CD195)
*No human ortholog described
Modified from Bachelerie et al., Pharmacol. Rev. 66: 1-79, 2014, with update on Pubmed Library and Genebank.

72 Cell migration and chemokines

Global atlas oF allergy

Section A - Allergy - from genetics to mechanisms

Figure 1  . The association of CC and CXC chemokines (CCL and CXCL indicated by outer arrows, member numbers
listed in the outer gray circle) and their receptors (listed in pink circle below ) to a selection of diseases, gained from
animal models and from data obtained in human samples and in clinical trials.  Abbreviations: Sep, Sepsis; RA, Rheumatoid
arthritis; T, Transplant; IBD, Inflammatory Bowel Disease; Onc, Oncology; SLE, Systemic Lupus; MS, Multiple Sclerosis;
Ath Scl, Atherosclerosis; COPD: Chronic Obstructive Pulmonary Disease; AMD, Acute macular degeneration; NP,
Neuropathic pain; Asth, Asthma; At. Derm, Atopic dermatitis; Hep, Hepatitis; Panc, Pancreatitis; Pso, Psoriasis; GVHD,
Graft vs Host disease. (Reprinted with permission from Garin and Proudfoot, Exp. Cell. Res. 317: 602-612, 2011.)

the chemokine superfamily. The cell types, with CXC members act- while CC chemokines shape leu-
key role of chemokines in chronic ing on effector functions relevant kocyte trafficking and function in
inflammatory diseases is now firm- in diseases characterized by neu- Th2-dependent, eosinophil-rich
ly established (Figure 1). In these trophilic, Th1- and Th-17-driven inflammatory processes such as
contexts, the CXC and CC sub- responses, such as COPD, multiple allergic asthma, early-stage atopic
classes, though with overlaps, seg- sclerosis, Crohn’s disease and spe- dermatitis, eosinophilic gastroin-
regate their control over different cific phenotypes of severe asthma; testinal diseases (Figure 2). Among

Cell migration and chemokines 73

 Global atlas oF allergy

Asthma
Section A - Allergy - from genetics to mechanisms

COPD

Figure 2  Involvement of chemokines and chemokine receptors in the inflammatory response present in bronchial asthma
and COPD . In asthma, dendritic- and epithelial-derived chemokines elicited by the inhaled allergens recruit and activate
Th2 cells and eosinophils through CCR4 and CCR3, respectively, contributing to the generation of an IgE-mediated inflam-
matory response. In COPD, chemokines released from lung epithelial cells and macrophages following exposure to cigarette
smoke and/or pollutants generate a neutrophilic/monocytic-enriched infiltrate driven by Th1/Th17 cells that contributes to
the inflammatory response and determins lung structural damage. (Reprinted by permission from Macmillan Publishers Ltd: Nat
Rev Immunol, Barnes PJ, Immunology of asthma and chronic obstructive pulmonary disease, 8,183-192, copyright 2008.)

74 Cell migration and chemokines

Global atlas oF allergy

the CC chemokines, CCL2/Mono- Inhibition of leukocyte recruit- tion: present and future therapeu-
cyte Chemoattractant Protein-1 ment is a major mechanism of glu- tic targets. Nat Immunol 2005;6:
(MCP-1) is a non-redundant, po- cocorticoids’ anti-inflammatory 1182-1190.
tent regulator of monocytes, ba- action and a major goal for novel
3. Charo IF, Ransohoff RM. The many
sophils and dendritic cells and par- therapies selectively targeting
ticipates to the Th2 polarization specific recruitment pathways. roles of chemokines and chemok-
of memory T cells. The CX3C and Antagonism of chemokine-me- ine receptors in inflammation. N
the C subfamilies are represented diated functions offers major Engl J Med 2006;354:610-621.
by a single member, CX3CL1/frac- challenges, partly due to member 4. Garin A, Proudfoot AE. Chemok-
talkine, which is the only cell mem- redundancy in each subclass, but ines as targets for therapy. Exp Cell
brane-associated chemokine, and mostly to the complexity of the
Res 2011;317:602-612.
lymphotactin, respectively. control of their expression, which
spans from transcriptional to post- 5. Islam SA, Luster AD. T cell homing
Chemokines’ range of regulatory
translational and extracellular ma- to epithelial barriers in allergic dis-
competences has been widened
trix-dependent mechanisms, that ease. Nat Med 2012;18:705-715.
over the last decades, as almost
are diversely affected in specific
all cell types, including structural 6. Fan J, Heller NM, Gorospe M,
disease settings. Antagonism of
cells such as fibroblasts, endothe- Atasoy U, Stellato C. The role of
single chemokine receptors has
lial and epithelial cells, as well as post-transcriptional regulation in
so far shown only partial success

Section A - Allergy - from genetics to mechanisms

tumor cells have been found to chemokine gene expression in in-
as therapeutic strategy, and is
express regulated profiles of func-
now flanked by research toward flammation and allergy. Eur Respir J
tional chemokine receptors. By
more specific downstream regu- 2005;26:933-947.
regulating cell proliferation, differ-
latory pathways modulating the
entiation and apoptosis functions, 7. Bachelerie F, Ben-Baruch A, Bur-
chemokine network.
and – either directly or indirectly khardt AM, Combadiere C, Farber
– controlling angiogenesis and ex- JM, Graham GJ et al. International
KEY REFERENCES
tracellular matrix remodeling, the 1. Rot A, von Andrian UH. Chemok- Union of Pharmacology. LXXXIX.
chemokine system is also central ines in innate and adaptive host de- Update on the extended family of
to cancer-related inflammation, fense: basic chemokinese grammar
chemokine receptors and introduc-
angiogenesis, tumor cell survival for immune cells. Annu Rev Immunol
and invasiveness, and is critically 2004;22:891-928. ing a new nomenclature for atypi-
involved in the step-wise process 2. Luster AD, Alon R, von Andrian UH. cal chemokine receptors. Pharma-
of wound healing. Immune cell migration in inflamma- col Rev 2014;66:1-79.

Cell migration and chemokines 75

 Global atlas oF allergy

Complement-Mediated
18 Regulation of the
Allergic Response
Marsha Wills-Karp 
Johns Hopkins Bloomberg School of Public Health
Baltimore, USA

Asthma is thought to arise as a

result of aberrant T helper type 2 Ke y m essag es
(Th2)-polarized immune respons-
Section A - Allergy - from genetics to mechanisms

es to innocuous environmental al- • The phylogenetically ancient complement activation system is

lergens, however the mechanisms activated in the lungs of asthmatic individuals
driving these aberrant immune re- • Several environmental triggers of asthma including allergens, air
sponses remain elusive. As a phy- pollutants, cigarette smoke, and viruses activate the complement
logenetically ancient immune sys- system and mediate Th2-driven immune responses
tem, the complement activation • Genetic polymorphisms in the C3 and C3aR1 genes are
associated with susceptibility to the development of asthma in
system, is a sophisticated network
children and adults
of soluble and membrane-bound
• Modification of complement activation pathways may provide a
proteins. It has evolved to recog-
novel strategy for the treatment of asthma
nize “danger or pattern-associated
molecular patterns” expressed by
foreign organisms through “hard-
to directly activate complement tiate recruitment and activation of
wired” pattern recognition recep-
at the airway surface. Genetic de- various inflammatory cells asso-
tors (PRRs). Activation of these ciated with asthma pathogenesis
letion of C3 in animal models has
PRRs culminates in the generation (Figure 4).
been shown to protect against the
of C3 and the production of two
development of allergen-, pollut- In humans, segmental allergen
pro-inflammatory anaphylatoxins,
ant-, and RSV-induced asthmat- provocation resulted in a signifi-
C3a and C5a, which induce inflam-
ic responses and Th2 cytokine cant increase in C3a levels in the
mation and the membrane attack
production suggesting that C3a bronchoaveolar lavage of asth-
complex, which lyses foreign cells.
production at the airway surface matics, with no change in healthy
The anaphylatoxins C3a and C5a
serves as a common pathway for volunteers. This differential pro-
are potent pro-inflammatory me-
the induction of Th2-mediated duction of C3a between individu-
diators that bind to specific cell
inflammatory responses thereby als with asthma and those without
surface receptors and regulate
driving and/or exacerbating the asthma suggest that there may be
many processes observed in asth-
disease (Figure 1, 2, 3). The exact alterations in the genetic control
ma including leukocyte activation,
mechanisms by which C3 regu- of the production of, the activation
smooth muscle contraction, and
lates allergic responses are un- of, or the response to various com-
mucus secretion.
known, but current evidence sug- plement components that may un-
Consistent with a role for C3-C3a gests that C3a can both enhance derlie susceptibility to asthma. In-
in asthma, exposure to a variety of antigen uptake by antigen-pre- deed, associations between single
environmental triggers of asthma senting cells, thereby enhancing nucleotide polymorphisms (SNPs)
in animal models has been shown sensitization to allergens, and ini- in the C3 gene and atopic asthma

76 Complement-mediated regulation of the allergic response

Global atlas oF allergy

1.4 A B
3.0
1.2 *
2.5
1.0

Cells/ml (x103)
PC200 (µg/g)

2.0
0.8
1.5
0.6
1.0 **
0.4
0.2 0.5

0.0 0.0
PBS C3 +/+ C3 -/- IL-4 IFN-γ

Figure 1  Allergen-induced asthma is C3 dependent. A) The effect of C3 deficiency on airway hyperresponsiveness

(AHR) in anesthetized C3−/− and C3+/+ mice. AHR was assessed 24 hrs after the last challenge and is expressed as the
provocative concentration of ACh (in micrograms per gram) that increased baseline airway resistance 200% (PC200). B)
IL-4- and IFN-γ-producing cells in the lungs from C3−/− (■) and C3+/+ littermates (□) were quantitated 24 h after the last Ag
challenge. (Reproduced from Drouin SM, Corry DB, Kildsgaard J, Wetsel RA. 167:4141-4145, Copyright 2001 with permission
from the American Association of Immunologists.).
C
800
*

Section A - Allergy - from genetics to mechanisms

APTI (cm H2O * sec)
600

400

200

0
PBS wt PM wt PBS C3-/- PM C3-/-

Figure 2  Air pollution exposure-induced airway hyperresponsiveness is C3-dependent. Lung sections from PM-exposed
mice were stained with anti-C3 mAb (A) or (B) isotype control antibodies. Specific C3 staining is observed in the airway
epithelial layer. C) Airway responsiveness (APTI) to acetylcholine stimulation is significantly reduced in C3-deficient mice
after particulate matter (PM) exposure as compared to PM-exposed wildtype mice. (P < 0.05). (Reproduced from American
Journal of Respiratory Cell and Molecular Biology, the official journal of the American Thoracic Society, Walters DM, Breysse PN,
Schofield B, et al., 27, 413-418, Copyright 2002 with permission from American Thoracic Society).
A B 1000
1200 **
*

900 750
cm H2O - sec

600 500

300 250

0 0
+/+ -/- +/+ -/-
Complement C3 Mature B cells
Figure 3  Respiratory syncytial virus-induced airway hyperresponsiveness is C3-dependent. Airway hyperresponsiveness
in wildtype and C3- and B cell-deficient mice challenged with RSV 7 days after immunization with formalin-fixed RSV. (A)
B6129F2 WT (C3+/+) and C3 deficient (C3−/−), and (B) C57BL/10 (B+/+) and B10 μMT (B−/−) mice. AHR to acetylcholine
challenge is defined by the time-integrated rise in peak airway pressure. (Reproduced from Journal of Experimental Medicine,
Polack FP, Teng MN, Collins PL, et al., 196, 859-65, Copyright 2002 with permission from The Rockefeller University Press).

Complement-mediated regulation of the allergic response 77

 Global atlas oF allergy

Epithelial
Cell

Genetic
Eos
C3 SNPs C3aR
ASM
DC
C3 C3a Ag
C3aR Th2
Environment Complement
al Production Airway
Triggers and C3aR
Activation Contraction
Allergens
Viruses
Ozone
PM
Mast
ETS Cell
Figure 4  Complement activation pathways regulate Th2-mediated immune responses. Following airway exposure to a
variety of environmental triggers of asthma in genetically susceptible individuals, C3 is produced and secreted by airway
epithelial cells lining the airways. C3 is cleaved into its active form, C3a, presumably by proteases either contained in the
Section A - Allergy - from genetics to mechanisms

allergens or produced by the epithelium. C3a then binds to its receptor, C3aR1 on antigen presenting cells, enhancing
uptake of antigen by these cells. Antigen-loaded APCs then drive the differentiation of naïve T cells to Th2 cells. Th2
cytokines in turn recruit and active the effector cells of the allergic response, eosinophils and mast cells. During the
effector phase of the response, C3a can bind its receptor on these effector cells enhancing their recruitment and
activation. Growth factors and bronchoactive substances from these cells lead to increased airway smooth muscle growth
and contractile capacity.

have been reported in children of allergic diseases. Further inves- Prince GA, Exner M, Regele H, et al.
and adults. Interestingly, the fre- tigations into the mechanisms by A role for immune complexes in en-
quency of these SNPs is high, sug- which C3a modules allergic asth- hanced respiratory syncytial virus
gesting that these polymorphisms disease. J Exp Med 2002;196:859-
ma may offer novel therapeutic
865.
may have conferred evolutionary approaches for the treatment of
advantage in the past and perhaps 4. Wills-Karp M. Complement activa-
asthma.
tion pathways: a bridge between
in protection from parasitic infec-
innate and adaptive immune re-
tions. KEY REFERENCES sponses in asthma. Proc Am Thorac
1. Drouin SM, Corry DB, Kildsgaard Soc 2007;4:247-251.
Although we are in the initial stag-
J, Wetsel RA. Cutting edge: the
es of understanding the role of absence of C3 demonstrates a
5. Barnes KC, Grant AV, Baltadzhieva
complement pathways in asthma D, Zhang S, Berg T, et al., Variants in
role for complement in Th2 effec-
pathogenesis, one may postulate the gene encoding C3 are associ-
tor functions in a murine model of
that changes in the activation of ated with asthma and related phe-
pulmonary allergy. J Immunol 2001;
notypes among African Caribbean
specific complement components 167:4141-4145.
families. Genes Immun 2006;7:27-
due to differences in exposure 2. Walters DM, Breysse PN, Schofield 35.
to different environmental trig- B, Wills-Karp M. Complement Fac- 6. Hasegawa K, Tamari M, Shao C,
gers or to genetic alterations in tor 3 mediates particulate matter– Shimizu M, Takahashi N, et al. Var-
complement family genes or the induced airway hyperresponsive- iations in the C3, C3a receptor and
convergence of both of these fac- ness. Am J Respir Cell Mol Biol 2002; C5 genes affect susceptibility to
tors may play an important role in 27:413-418. bronchial asthma. Hum Genet 2004;
susceptibility to the development 3. Polack FP, Teng MN, Collins PL, 115:295-301.

78 Complement-mediated regulation of the allergic response

Global atlas oF allergy

Lipid mediators of
19 hypersensitivity and
inflammation
Marek Sanak 
Jagiellonian University Medical College
Kraków, Poland

Since the discovery that bron-

choconstriction and edema can Ke y m essag es
be mediated by cysteinyl leukot-

Section A - Allergy - from genetics to mechanisms

rienes, lipid mediators attracted • Lipid mediators regulate both the physiological status and
much attention in allergology. The inflammation in the airways
biological effect of a lipid media- • Cysteinyl leukotrienes and prostaglandin D2 are the best studied
tor is determined by its receptor inflammatory mediators of hypersensitivity and allergic disorders
affinity and intracellular signal • Other lipid mediators, like pro-inflammatory eoxins and anti-
transduction, and receptors dif- inflammatory lipoxins also participate in allergic reaction
• A class of phospholipid and ceramide mediators interact with
fer in their specificity and cellular
immune response in allergy
distribution. Lipid mediators of
inflammation are difficult to study
due to their complex metabolism,
piratory epithelium also secretes rhinosinusitis. Patients with aspi-
chemical similarities and rapid in-
15-hydroxyeicosapentaenoic acid rin-exacerbated respiratory dis-
activation. Their levels in airways
(15-HETE) to its basal surface. ease (AERD) overproduce pros-
can be measured in bronchial or
Upon stimulation with Th2 cy- taglandin D2, but this finding is
nasal lavage, induced sputum or
tokines (IL-4, IL-13), the asthmat- also present in other eosinophilic
exhaled breath condensate, while ic respiratory epithelium under- phenotypes of asthma. During an
systemic production can be as- goes mucous cell metaplasia with aspirin provocation test, bron-
sessed in urine. amplication of the production of choconstriction is mediated by a
Regulation of the airways tonus, 15-HETE. 15-HETE can be metab- further increase in the local and
secretion or inflammation involves olized to eoxins, isomers of cystei- systemic production of cysteinyl
numerous mediators (Figures 1 nyl leukotrienes. The concentra- leukotrienes, a unique feature of
and 2). Respiratory epithelium tion of eoxins (EXC4, EXD4 and this disease.
produces prostaglandin E2 (PGE2), EXE4) is increased together with
cysteinyl leukotrienes in children The integrity of the lung function
secreted to the apical surface. It
with asthma. Moreover, EXD4 and is maintained by PGE2, which in-
has been recently demonstrated
EXE4 leves correlate with bronchi- hibits inflammation at physiologi-
that excessive PGE2 can impair
al hyperreactivity . cal concentrations. PGE2 can pro-
phagocytic clearance of solid par-
mote tissue injury in high doses.
ticles by alveolar macrophages. A One of the asthma phenotypes
decreased number of carbon par- is characterized by an overpro- Other lipid mediators are released
ticles in alveolar macrophages and duction of cysteinyl leukotrienes. by activated cells only. They act
increased systemic production of These asthmatics have hypersen- as highly bioactive autacoids ca-
PGE2 metabolites were report- sitivity to non-steroidal anti-in- pable of chemoattraction of neu-
ed in children with asthma. Res- flammatory drugs and chronic trophils (12-HETE, leukotriene B4)

Lipid mediators of hypersensitivity and inflammation 79

 Global atlas oF allergy

ins are also generated from poly-

unsaturated fatty acids by reactive
oxygen species in a non-enzymatic
reaction. A separate class of lipid
mediators are phospholipids and
ceramides. Platelet-activating fac-
tor, a phosphatydylcholine ether
of alkyl-acetyl glicerol is the most
potent mediator of anaphylaxis
and bronchoconstriction. Cer-
amides are abundant constituents
of the cell membrane mediating
apoptosis. Lipid mediators can
bridge inflammation with the cel-
lular immune response in allergic
disorders.

KEY REFERENCES
1. Brugha RE, Mushtaq M, Round T,
Section A - Allergy - from genetics to mechanisms

Figure 1  Main classes of inflammatory lipid mediators in the airways are Gadhvi DH, Dundas I, Gaillard E, et
cysteinyl leukotrienes, eoxins and prostaglandins. Platelet activating factor and al. Carbon in airway macrophages
ceramides are also released during allergic reaction. from children with asthma. Thorax
2014 in press.
2. Jakieła B, Gielicz A, Plutecka H,
Hubalewska M, Mastalerz L, Bo-
chenek G, et al. Eicosanoid bio-
synthesis during mucocilliary and
mucous metaplastic differentia-
tion of bronchial epithelial cells.
Prostaglandins Other Lipid Mediat
2013;106:116-23.
3. Sachs-Olsen C, Sanak M, Lang AM,
Gielicz A, Movinckel P, Lødrup
Carlsen KC, et al. Eoxins: a new
inflammatory pathway in child-
hood asthma. J Allergy Clin Immunol
2010;126:859-867.
4. Sanak M, Gielicz A, Bochenek G,
Kaszuba M, Niżankowska-Mogil-
nicka E, Szczeklik A. Targeted eicos-
anoid lipidomics of exhaled breath
condensate provide a distinct pat-
tern in the aspirin-intolerant asth-
ma phenotype. J Allergy Clin Immu-
nol 2011;127:1141-1147.
Figure 2  Lipid mediators are produced in airways by structural and 5. Haworth O, Levy BD. Endogenous
inflammatory cells. In general, tissue infiltrating inflammatory cells produce lipid mediators in the resolution of
pro-inflammatory mediators, while structural ones produce anti-inflammatory airway inflammation. Eur Respir J
mediators. Excessive production of lipid mediators by respiratory epithelial 2007;30:980-950.
cells and alveolar macrophages also promotes inflammation. 6. Vadas P, Gold M, Perelman B, Liss
GM, Lack G, Blyth T, et al. Plate-
or eosinophils and lymphoid cells (lipoxins, resolvins, protectins) let-activating factor, PAF acetylhy-
(PGD2). Some can provide termi- and their biosynthesis requires drolase, and severe anaphylaxis. N
nation signals for inflammation cell interaction . Bioactive oxylip- Engl J Med 2008;358:28-35.

80 Lipid mediators of hypersensitivity and inflammation

Global atlas oF allergy

Lipid mediators in
20 resolution of allergic
inflammation
Evangelos Andreakos 
Academy of Athens
Athens, Greece

Persistent non-resolving inflam-

mation underlies the pathogen- Ke y m essag es
esis of allergic diseases including

Section A - Allergy - from genetics to mechanisms

rhinitis and asthma, and deter- • Non-resolving inflammation underlies the pathogenesis of
mines both the intensity of the allergic diseases
symptoms and the chronicity of • Resolution of inflammation is an active, finely orchestrated and
the disease. Yet, the mechanisms complex process
controlling resolution of inflam- • Resolution of inflammation involves anti-inflammatory, immune
mation have only recently started regulatory, cell death and lipid mediator-related mechanisms
to become elucidated. • ω3-derived specialized proresolving lipid mediators (SPMs)
such as protectins, resolvins and maresins are key mediators of
Resolution is an active and highly inflammation resolution
orchestrated process of similar • Allergic diseases are associated with defects in the generation of
complexity to the onset and pro- SPMs
gression of inflammation. It starts • Synthetic SPMs or compounds triggering their production are
early in the inflammatory re- promising therapeutics for the treatment of allergic diseases
sponse and involves the induction
of anti-inflammatory/regulatory
networks aiming at terminating genation of arachidonic acid into vate inflammatory cells, promote
pro-inflammatory signalling, and prostaglandins and leukotrienes apoptotic cell and tissue debris
biosynthetic circuits triggering the that occurs during the initiation of clearance, and repair damaged tis-
production of specialized prore- an inflammatory response is fol- sue, altogether leading to the res-
solving lipid mediators (SPMs) lowed by the generation of lipox- toration of homeostasis.
essential for return to homeosta- ins, lipids with anti-inflammatory Notably, ω3-derived SPMs also
sis. The relative balance between and proresolving properties, in possess antimicrobial function.
pro-inflammatory, anti-inflamma- a process termed ‘lipid mediator PD1 is induced by antiviral TLRs
tory and proresolving respons- class switching’. As the inflam- and exhibits potent antiviral ac-
es, influenced by environmental matory response progresses, the tivity, while several resolvins and
exposures and lifestyle factors, production of additional SPMs protectins enhance antibacterial
eventually determines whether derived from ω3 PUFAs such as defences. This has significant im-
the inflammatory response will protectins, resolvins and mares- plications for the role of lipid me-
persist or terminate. ins ensues (Figure 1). These act in diators in allergic disease exacer-
Central to the resolution of inflam- a stereospecific manner through bations, which are often triggered
mation are bioactive lipids derived G protein-coupled receptors to by infections. The biosynthesis of
from ω3 and ω6 polyunsaturated reverse vasodilation and suppress SPMs is dependent on lipoxygen-
fatty acids (PUFA). The early oxy- leukocytic cell infiltration, de-acti- ase-5 and lipoxygenase-12,15,

Lipid mediators in resolution of allergic inflammation 81

 Global atlas oF allergy

Onset Resolution
ω-6 ω-3

Lipoxins
Prostaglandins Resolvins
Leukotriennes Protectins

Termination
Initiation Inflammatory response (Time)
Return to homeostasis

Figure 1  Generation of eicosanoids and specialized proresolving lipid mediators as inflammation progresses. As the
inflammatory response proceeds, the production of additional proresolving lipids derived from ω3 PUFAs such as
protectins, resolvins and maresins ensues. These act in an orchestrated manner to terminate inflammation and ensure the
transition to homeostasis.

Airway lumen
Section A - Allergy - from genetics to mechanisms

Pollutants
Smoke
Allergen Virus INDUCERS OF PRORESOLVING
Respiratory
epithelium LIPID MEDIATORS
TLR agonists

Viruses ω3
DHA, EPA Type 2 inflammation
ω6
Lipoxins AA
Protectins
Protectins Resolvins
Resolvins Maresins
Maresins ILCs NEU Vasoconstriction
Th2 Cyto
Cell deactivation Suppression of cell influx
eI kines Antimicrobial defences
T cell apoptosis
Vasoconstriction

EOS

Chronic inflammation MAC

Increased efferocytosis
Apoptotic cell clearance
Production of IL-10
Tissue restitution
Atopy RESOLUTION

Figure 2  Proresolving activities of ω3/ω6 polyunsaturated fatty acid (PUFA)-derived bioactive lipids in respiratory
allergies. Specialized proresolving lipid mediators (SPMs) are generated in response to viral infection, Toll-like receptor
(TLR) stimulation or type 2 inflammation. SPMs act in concert to reverse vasodilation, prevent leukocytic cell infiltration,
de-activate inflammatory cells including Th2 cells and innate lymphoid cells (ILCs), upregulate macrophage efferocytic
function and antimicrobial defences, promote clearance of apoptotic cells and debris, and repair damaged tissue,
eventually restoring homeostasis. AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; EOS,
eosinophil; MAC, macrophage; NEU, neutrophil. (Adapted from Andreakos E. Asthma exacerbations: a molecular dichotomy
between antiviral and pro-inflammatory responses revealed.;EMBO Mol Med. 2012;4(12):1231-3. Reprinted with permission
under the Creative Common Attribution License or equivalent.)

82 Lipid mediators in resolution of allergic inflammation

Global atlas oF allergy

key enzymes that carry out the tients with asthma, and low PD1 ogy of asthma. Annu Rev Physiol
oxygenation of PUFAs. Substrate levels have been observed during 2009;71:489-507.
availability, temporal expression acute exacerbations. PD1 and re- 3. Levy BD, Serhan CN. Resolution
and activation of these and other solvins D1 and E1 have been fur- of acute inflammation in the lung.
key enzymes ultimately determine ther used to promote resolution of Annu Rev Physiol 2014;76:467-492.
which SPMs will be produced, allergic airway inflammation in ex-
4. Koltsida O, Karamnov S, Pyrillou
where and when. perimental mouse models. On the
K, Vickery T, Chairakaki AD, Tam-
basis of current data, SPMs can
There is emerging evidence that vakopoulos C et al. Toll-like re-
affect multiple processes during
SPMs are essential for the reso- ceptor 7 stimulates production of
an allergic response as depicted in
lution of allergic inflammation. specialized pro-resolving lipid me-
Figure 2. In conclusion, although
Lipoxin A4 (LXA4) has been found diators and promotes resolution
it its early days, the field of res-
in nasal secretions of patients with of airway inflammation. EMBO Mol
olution of inflammmation raises
allergic rhinitis or chronic rhinosi- Med 2013;5:762-775.
expectations for the application
nusitis, as well as bronchoalveolar
of SPMs or substances triggering 5. Morita M, Kuba K, Ichikawa A, Na-
lavage and exhaled breath con-
their production for the treatment kayama M, Katahira J, Iwamoto R,
densate of patients with asthma,
of allergic diseases. et al. The lipid mediator protectin
and low LXA4 levels have been
D1 inhibits influenza virus replica-
linked to the severity of the dis-
KEY REFERENCES tion and improves severe influenza.
ease. LXA4 has also has been

Section A - Allergy - from genetics to mechanisms

1. Barnig C, Cernadas M, Dutile S, Cell 2013;153:112-125.
shown to inhibit IL-13 production Liu X, Perrella MA, Kazani S et al.
by human innate lymphoid cells Lipoxin A4 regulates natural killer 6. Serhan CN, Chiang N, Van Dyke TE.
and resolve allergic inflammation cell and type 2 innate lymphoid cell Resolving inflammation: dual an-
in rodents. Similarly, protectin D1 activation in asthma. Sci Transl Med ti-inflammatory and pro-resolution
(PD1) has been detected in ex- 2013;5:174ra26. lipid mediators. Nat Rev Immunol
haled breath condensate from pa- 2. Hamid Q, Tulic M. Immunobiol- 2008;8:349-361.

Lipid mediators in resolution of allergic inflammation 83

 Global atlas oF allergy

Allergy and the

21 epithelial barriers
Stephen T. Holgate 
University of Southampton
Southampton, UK

Asthma is a disorder largely re-

stricted to the conducting airways Ke y m essag es
characterised by episodic bron-
Section A - Allergy - from genetics to mechanisms

choconstriction superimposed on • The epithelium in chronic asthma resembles a chronic wound

a background of airway hypere- with impaired barrier function
sponsiveness and is generally re- • This manifests as enhanced susceptibility to injury by viruses,
pollutants and allergens and aberrant repair to sustain
sponsive to bronchodilator drugs.
inflammation and remodelling
Airway inflammation is another
• Recapitulation of morphogenetic epithelial growth and
characteristic of asthma which, to
transcription factors suggest persistent activation of the
a variable extent, is responsive to
epithelial mesenchymal trophic unit (EMTU)
corticosteroids and often associ- • A new approach to prevention and treatment might aim to
ated with allergy. increase airway resilience rather than focusing on suppressing
This concept of allergy driving an inflammation once present
IgE, mast cell and eosinophilic in- • Inadequate epithelial tight junction assembly has been demon-
flammation in asthma has been strated in asthma, atopic dermatitis and chronic rhinosinusitis
heavily underpinned by involve-
ment of the Th2 subtype of T cells
capable of releasing an array of cy- Activation of the tion (Figure 1). We referred to this
tokines and chemokines linked to epithelial mesenchymal interaction as activation of the
the allergic cascade. trophic unit epithelial mesenchymal trophic
In addition to inflammation, the unit (EMTU) since many of the sig-
However, this simplistic approach pathology of asthma is dominat- nalling mechanisms are similar to
has not been rewarded by thera- ed by structural changes includ- those engaged in lung morphogen-
peutics targeting individual com- ing epithelial damage and mucous esis in the developing foetal lung.
ponents of the allergic cascade, metaplasia, angiogenesis, smooth
which while identifying selective muscle proliferation and angio- Enhanced susceptibility
subgroups of “responders”, has genesis. In 2000, we proposed that of the asthmatic
not provided a ubiquitous series these structural features were epithelium to injury
of treatments where “one size the consequence of the airways The airways in chronic asthma
fits all”. These less than encour- resembling a chronic wound in are more susceptible to injury as
aging findings raise the question which epithelial damage is accom- revealed by the majority of novel
whether the current Th2 model panied by aberrant production genes discovered by GWAS being
for asthma adequately explains of growth factors and mediators preferentially expressed in the
the disease in its very wide range that not only drive remodelling, epithelium. There is also strong
of manifestations. but also sustain chronic inflamma- genetic and gene expression evi-

84 Allergy and the epithelial barriers

Global atlas oF allergy

Section A - Allergy - from genetics to mechanisms

Figure 1  Schematic representation of the activated epithelial mesenchymal trophic unit (EMTU) in active asthma.
Increased susceptibility of the epithelium to environmental injury such as biologically active allergens, respiratory viruses
and pollutants together with a delayed repair response leads to the secretion of a range of growth factors, cytokines and
chemokines that both drive airway wall remodelling and sustain chronic airway inflammation. (From Holgate S.T. Arshad
SH, Roberts GC, Howarth PH et al. A new look at the pathogenesis of asthma. Clin Sci. 2009; Reprinted with permission under the
Creative Common Attribution License or equivalent.)

dence that anti-oxidant pathways explains viral exacerbations of ly for 14 days almost abolishes the
in the asthmatic airways are de- asthma, the relatively weak effect post-viral exacerbation in parallel
fective leading to enhanced tissue of corticosteroids and the mixed with maintaining biomarkers of
damage on exposure to viruses neutrophilic/eosinophilic inflam- anti-viral defence in respiratory
and pollutants. Even under basal matory profile. The primary defect secretions.
conditions, the asthmatic epithe- appears to be in the first step of
lium shows enhanced expression induction of the anti-viral protec- The asthmatic epithelium
of biomarkers of apoptosis (e.g. tive cytokines interferons (IFNs) displays impaired healing
caspases, P85 fragment of PARP) β and λ after ds viral RNA binds The epithelium also contributes
indicating loss of resilience. to microsomal TLR3 (Figure 2). At to persistence of asthma through
least part of this defect can be ac- enhancing remodelling pathways
Asthmatic airways, both in chil- counted for by the enhanced basal in the form of aberrant epithelial
dren and adults, are more vulner- production of TGFβ to reduce repair. Over expression of the epi-
able to common and usually innoc- SMAD3 phosphorylation and in- dermal growth factor (EGF) family
uous respiratory viruses such as crease nuclear inhibitory signals of receptors and their phosphoryl-
rhinoviruses (RVs) adenoviruses provided by SOCS1 and 3. Since ation in the asthmatic epithelium
and coronaviruses. When infect- exogenous IFNβ could restore de- increases in proportion to disease
ed with major or minor subclass fective anti-viral defence to asth- severity and is not accompanied by
RVs, asthmatic epithelial cells fail matic epithelium in vitro, inhaled appropriate proliferative respons-
to eliminate the virus adequately IFNβ could be a novel therapeutic es as a consequence of mobilisa-
leading to enhanced replication, for severe exacerbations. Indeed, tion of cell cycle inhibitors such as
shedding and cytotoxic cell death when administered at the first P21waf to the epithelial nuclei where
with pro-inflammatory media- sign of a common cold in severe they inhibit cell cycling. The net
tor release. Such a mechanism asthma inhaled IFNβ1α given dai- result of this is delayed epithelial

Allergy and the epithelial barriers 85

 Global atlas oF allergy

Figure 2  In
chronic asthma,
there is a defect
innate immunity at
the level of defec-
tive production of
interferons when
toll-like recep-
tors such as TLR3,
TLR5 and TLR7 be-
come activated by
viral nucleic acids
as the first step in
triggering an an-
ti-viral response.
This results in
virus survival,
replication and
eventual cytotoxic
destruction of ep-
ithelial cells with
Section A - Allergy - from genetics to mechanisms

release of inflam-
matory mediators
that contribute to
exacerbations. The
defect appears to
be in Step 1 of the
anti-viral cascade
involving defective interferon regulatory factor (IRF) 3 signalling to the interferon genes with low production of IFN induc-
tion, reduced signalling via the common IFN receptor and, therefore, reduced IRF7 amplification of the antiviral cascade in
Step 2. The IRF7 pathway itself remains intact. For this reason a small amount of exogenous IFNβ acting via the common
IFN receptor can restore a full anti-viral response as shown in the left bottom panel. It is upon this principle that inhaled
IFNb1ais being developed for the prevention/treatment of severe asthma exacerbations. (From Holgate S.T. Arshad SH, Rob-
erts GC, Howarth PH et al. A new look at the pathogenesis of asthma. Clin Sci. 2009; Reprinted with permission under the Creative
Common Attribution License or equivalent).

healing following environmental the epithelial barrier function is Is asthma a disorder of

insults and enhanced pro-fibrotic, persistently deranged in asthma epithelial sensing of the
myogenic and angiogenic growth at the level of junctional integrity. inhaled environment?
factor production such as TGFβ The defective barrier function in Such a “pro-asthmatic” epithelium
PDGFs, IGFs, FGFs and VEGFs to asthmatic epithelium persists in may have its origin in the way the
drive structural remodelling (5). differentiated epithelial cell cul- epithelium senses the inhaled en-
The epithelium of asthmatic chil- tures following repeated passage vironment, with altered sensitiv-
dren displays similar characteris- indicating an intrinsic abnormality ity being predetermined through
tics and when grown as a monolay- linked to enhanced mucous meta- altered expression of transcrip-
er and physically injured displays plasia, reduced cilia-genesis and tion factors involved in foetal lung
slower and incomplete restitution reduced innate immune respon- morphogenesis such as SPDEF
suggesting that the abnormality is siveness. Increased permeability increase secondary to FoxA2 and
intrinsic to the asthmatic epitheli- is enhanced by T cell interactions NKX2-1 (TTF-1) decrease. Path-
um irrespective of age. within the epithelium as well as way analyses have now shown
the actions of “biologically active” that in addition to regulating the
Inadequate epithelial allergens (e.g. proteases), viral in- “set point” for epithelial mucus
tight junction assembly in fection and pollutant exposure, production, the same transcrip-
asthma all of which perturb tight junction tion factors are also implicated in
There is increasing evidence that functions. orchestrating innate immune de-

86 Allergy and the epithelial barriers

Global atlas oF allergy

Section A - Allergy - from genetics to mechanisms

Figure 3  Schematic representation of the role of epithelial transcription factors involved in morphogenesis of the foetal
lung such as SPDEF, FoxA2 and TTF1 interacting with key transcription factors of the allergic cascade such as STAT6 in
driving mucous metaplasia and orchestrating both chronic Th2-type inflammation and tissue remodelling. In asthma, the
‘set’ point for responding to environmental insults is altered to reduce airway resilience and augment the chronic wound
scenario depicted in figure 1 and on the right side of the above figure. (Reproduced with permission from Holgate S.T. The
sentinel role of the airway epithelium in asthma pathogenesis. Immunol Rev 2011; 242: 205-219, with permission from Willey
Blackwell.).

fence (including IFN responses to KEY REFERENCES 937-947.

viral infection) and inflammatory 1. Holgate S.T. Stratified approaches 4. Holgate ST. Innate and adaptive
to the treatment of asthma. Br J Clin immune responses in asthma. Nat
pathways such as those leading to
Pharmacol 2013;76: 277-291. Med 2012;18: 73-83.
Th2-type allergic responses (Fig-
2. Holgate ST, Davies DE, Lackie PM, 5. Xiao C, Puddicombe SM, Field S,
ure 3). Wilson SJ, Puddicombe SM, Lordan Haywood J, Broughton-Head V,
JL. Epithelial-mesenchymal inter- Puxeddu I,et al Defective epithelial
This leads to the overall conclu-
actions in the pathogenesis of asth- barrier function in asthma. J Allergy
sion that the different asthma sub- ma. J Allergy Clin Immunol 2000;105 Clin Immunol 2011;128: 549-556.
types have their origin in the way (2 Pt 1): 193-204. 6. Maeda Y, Chen G, Xu Y, Haitchi
the airway epithelium “reads” the 3. Wark PA, Johnston SL, Bucchieri F, HM, Du L, Keiser AR, et al. Airway
environment and translates this Powell R, Puddicombe S, Laza-Stan- epithelial transcription factor NK2
ca V, et al. Asthmatic bronchial epi- homeobox 1 inhibits mucous cell
along discrete pathways to vari-
thelial cells have a deficient innate metaplasia and Th2 inflammation.
able disease manifestations and immune response to infection with Am J Respir Crit Care Med 2011;
responses to interventions. rhinovirus. J Expt Med 2005;201: 184:421-429.

Allergy and the epithelial barriers 87

 Global atlas oF allergy

22 Epithelial proteases
and allergic diseases
Ömer Kalayci 
Hacettepe University School of Medicine
Ankara, Turkey

Proteases are composed of a

group of molecules with diverse Ke y m essag es
physiological and pathological ef-
Section A - Allergy - from genetics to mechanisms

fects. The human body is equipped • Proteases are physiologically important digestive enzymes
with a variety of protease inhib- and generate peptides from precursor proteins. However,
itors that counteract and thus both proteases and protease inhibitors can be active players in
control the activity of proteases. inflammation
However, these protease inhibi- • Proteases can be endogenous and exogenous. Almost all inhalant
tors can be active participants of allergens such as pollens, mites and fungi have protease activity.
inflammation. • Proteases exert their activity through Protease Activated
Receptors, PAR 1-4, which are highly relevant in asthma and
Proteases are naturally present in other allergic diseases
all organisms. Depending on their • Proteases disrupt tight junctions between the cells, can
catalytically active site, they are penetrate into the tissue and directly activate the cells apart
termed as serine, cysteine, aspar- from the classical flow of immunological mechanisms
tic and metalloproteases. Endog-
enous proteases are produced
by inflammatory cells, most im- ical processes including allergic of goblet cells and increased mu-
portantly by mast cells (chymase, diseases (Table 1). cous production (Figure 1).
tryptase), neutrophils (cathep-
sin, elastase) and epithelial cells The action of proteases can be me- Some activities of proteases are
(thrombin). Almost all allergens in- diated through Protease Activat- PAR-independent and are ba-
cluding house dust mites, pollens, ed Receptors (PAR) 1-4. They are sically a function of exogenous
fungi and cockroach and many G protein-coupled receptors and proteases. They increase pro-in-
are present almost on all cell types. flammatory cytokine production
bacteria, such as staphylococcus
PAR-dependent action of proteas- by airway epithelial cells, activate
aureus, and viruses such as rhino-
es results in: increased release of eosinophils and increase mucus
virus and influenza have signifi-
pro-inflammatory cytokines by production.
cant protease activities.
epithelial cells, endothelial cells,
Physiologically, proteases func- inflammatory cells, keratinocytes Their highly relevant activity for
tion as digestive enzymes, gen- and fibroblasts; enhancement of allergic diseases is the effect of
erate active peptides from their IgE production; angiogenesis; in- proteases on epithelial tight junc-
precursors and drive innate im- creased cell migration, infiltration tions and adhesion molecules.
munity against multicellular or- and degranulation of inflamma- Through their ability to disrupt
ganisms such as parasites, which tory cells; proliferation and con- occludin and claudin molecules
are too large to be phagocytosed. traction of airway smooth muscle and to activate MMP9 (which ac-
They also participate in patholog- cells; proliferation and activation tivates other cellular proteases),

88 Epithelial proteases and allergic diseases

Global atlas oF allergy

TABLE 1
Proteases in inflammation proteases can penetrate through
the intracellular junctions in the
Source Protease Mode of action Actions
mucosal epithelial barrier and ep-
Exogeneous Pollens PAR dependent Disruption of tight junctions idermis. This allows the penetra-
Fungi PAR independ- Disruption of barrier function tion of the allergenic molecules
Mites ent Th-2 adjuvants into the tissues, where they can
Cockroach Secretion of pro-inflamma- exert their protease as well as im-
tory cytokines mune stimulating activities. This
Hymenoptera
Promotion of IgE synthesis recently emerging concept raises
Bacteria
the intriguing possibility that pro-
Viruses Activation of
tease activities of the allergens
epithelial cells
may be critical not only for the
keratinocytes maintenance of tissue inflamma-
inflammatory cells tion observed in allergic diseases,
airway smooth muscle but may also be important in the
Endogenous Thrombin Mostly PAR Activation of inception of allergic diseases. In
dependent addition, this initial penetration
Plasmin Endothelial cells
may be subsequently followed by
Tyrptase Epithelial cells
the stimulation of a variety of cell

Section A - Allergy - from genetics to mechanisms

Chymase Keratinocytes types without the classical IgE and
Plasmin Fibroblasts other cellular immune mechanism.
Kallikrein Airway smooth muscle
Trypsin All inflammatory cells KEY REFERENCES
1. Jacquet A. Interactions of airway
Elastase Glandular secretion
epithelium with protease allergens
Cathepsin G in the allergic response. Clin Exp Al-
lergy 2011;41:305-311.
2. Birben E, Sackesen C, Turgutoglu
N, Kalayci O. The role of SPINK5
in asthma related physiological
PAR
events in the airway epithelium.
PAR Respir Med 2012;106:349-55.
disruption of
tight junctions 3. Takai T, Shigaku I. Barrier Dys-
function Caused by Environmen-
tal Proteases in the Pathogenesis
Stimulation of of Allergic Diseases. Allergol Int
epithelium 2011;60:25-35.

PAR

mast cell
eosinophil endothelium neutrophil

exogenous protease
endogenous protease

airway smoth muscle

Figure 1  The action of proteases mediated trough Protease Activated

Receptors (PAR).

Epithelial proteases and allergic diseases 89

 Global atlas oF allergy

23 Mechanisms of immune
regulation in allergy

Willem van de Veen Mübeccel Akdis

Swiss Institute of Allergy and Asthma Research
Davos, Switzerland
Allergy is characterized by dom-
inant allergen-specific Th2 re- Ke y m essag es
sponses, and consequent IgE in-
Section A - Allergy - from genetics to mechanisms

duction. Many factors influence • Immune tolerance to allergens have been studied in individuals
the pathophysiology of allergic receiving allergen-specific immunotherapy (AIT) and high dose
diseases, including genetic sus- allergen exposure models such as beekeepers and cat owners
ceptibility, route/time/dose of • Early basophil and mast cell desensitisation is the first event of
allergen exposure, structural fea- immune tolerance to allergens
tures of the allergen and microbial • Induction of allergen-specific T regulatory (reg) cells
exposure. characterized by the expression of multiple suppressor factors;
CD25, CTLA-4, PD1, RUNX, HR2, IL-10 and TGF-beta is essential
The immunoregulatory mecha- • Induction of IL-10-producing Breg cells after high dose Ag
nisms that can mediate tolerance exposure and AIT was described, together with increased
towards allergens in humans have allergen-specific IgG4 production, which is specifically confined
been subject to intensive research to IL-10-producing Breg cells
during the last decades. These • Decreased eosinophil, mast cell and basophil migration and
mechanisms have been studied in activation in the affected tissues also occurs during allergen
allergic patients receiving aller- tolerance
gen-specific immunotherapy (AIT)
as well as in healthy individuals,
who are exposed to high-doses in the induction and maintenance pression of antigen-presentation
of allergens, such as beekeepers of tolerance towards allergens. capacity of DCs. IL-10 also sup-
and cat owners. These human in These cells produce immunoreg- presses mast cell and eosinophil
vivo models have demonstrated ulatory cytokines such as IL-10 activation, thereby interfering
that the mechanisms leading to and TGF-β. TGF-β is a pleiotropic with early and late phase allergic
peripheral tolerance to allergens cytokine that has a wide range of responses. Both Treg and Breg
include early desensitization of functions including suppression cells contribute to IgG4 produc-
mast cells and basophils, induc- of B and T cell proliferation and tion and suppression of IgE pro-
tion of T regulatory (reg) and Breg differentiation, as well as control duction. Inducible IL-10-produc-
cells, regulation of allergen-spe- of airway inflammation and air- ing B regulatory 1 (Br1) cells are
cific immunoglobulin production way remodeling. IL-10 is a key an- skewed towards the production of
and interference with migration ti-inflammatory cytokine, which anti-inflammatory IgG4 antibod-
and activation of eosinophils, mast inhibits effector T cell activation ies. These cells may play a role in
cell and basophils in the allergic directly through suppression of tolerance induction to allergens,
tissues.
co-stimulatory pathways in T as an increase in the frequency of
Treg and Breg cells play a key role cells, and indirectly through sup- IL-10-producing B cells specific for

90 Mechanisms of immune regulation in allergy

Global atlas oF allergy

Suppression of Th2 cell

homing to tissues
Endothelial cells Figure 1  Role of Treg and Breg
cells in the suppression of allergic
IgG4 production inflammation. Treg cells and their
cytokines mainly IL-10 and TGF-β
IgG4 production suppress Th2 type immune responses
TReg and control allergic diseases in
Br1 IL-10 B cell
TGF-β many ways. Black arrows show the
regulatory and suppressive effects
IL-10 of Treg cells on: B cells by inducing
IgG4 and IgA and suppressing IgE; on
Th2 cell by suppressing proliferation
and homing to tissues; on mast cells,
IL-4 basophils and eosinophils via direct
Th2 IL-13 and indirect suppressive effects;
mast cell basophil eosinophil
IL-3 and on epithelial cell activation and
IL-4 proinflammatory properties by
IL-5 direct and indirect suppression. In
IL-9 addition, Br1 cells, which produce
IL-10 suppress effector T cells and

Section A - Allergy - from genetics to mechanisms

contribute to IgG4 synthesis.
Direct and indirect suppressive effects on
mast cells, basophils and eosinophils

the bee venom allergen phospholi- regulates both Th1 and Th2-type tivation during allergen-specific
pase A2 was observed in bee ven- responses. Therefore, HR2 ap- immunotherapy by histamine re-
om allergic patients, who received pears to be a key mediator in the ceptor 2. J Allergy Clin Immunol
AIT. 2012;130:1153-1158.
suppression of Th2 responses and
induction of tolerance towards al- 4. van de Veen W, Stanic B, Yaman G,
The susceptibility of mast cells Wawrzyniak M, Söllner S, Akdis DG
and basophils to allergen-induced lergens. Intensive research in the
et al. IgG4 production is confined to
degranulation is reduced already area is essential to fully uncover human IL-10-producing regulatory
after the first injection of AIT. This the molecular pathways of aller- B cells that suppress antigen-spe-
may be the result of subclinical lev- gen tolerance. cific immune responses. J Allergy
els of degranulation of these cells Clin Immunol 2013;131:1204-
caused by allergen, leading to the KEY REFERENCES 1212.
1. Meiler F, Zumkehr J, Klunker S, 5. Akdis CA, Akdis M. Mechanisms of
increased activation thresholds
Rückert B, Akdis C.A, Akdis M. allergen-specific immunotherapy. J
observed during in vitro measure-
In vivo switch to IL-10-secreting Allergy Clin Immunol 2011;127:18-
ments. Furthermore, rapid up-reg- T regulatory cells in high dose 27.
ulation of histamine receptor allergen exposure. J Exp Med
(HR) 2 was observed in basophils 6. Radulovic S, Jacobson MR, Durham
2008;205:2887-2898. SR, Nouri-Aria KT. Grass pollen
during the first 6 hours of venom 2. O'Mahony L, Akdis M, Akdis CA. immunotherapy induces Foxp3-ex-
immunotherapy. HR2 triggering Regulation of the immune response pressing CD4+ CD25+ cells in the
could suppress FcεRI-mediated and inflammation by histamine and nasal mucosa. J Allergy Clin Immunol
basophil degranulation. Histamine histamine receptors. J Allergy Clin 2008;121:1467-1472.
can be released from mast cells Immunol 2011;12:1153-1162. 7. Akdis M, Akdis CA. Therapeutic
and basophils that are activated 3. Novak N, Mete N, Bussmann C, manipulation of immune tolerance
during AIT and can regulate T cell Maintz L, Bieber T, Akdis M et al. in allergic disease. Nat Rev Drug Dis-
responses as well. HR2 negatively Early suppression of basophil ac- cov 2009;8:645-660.

Mechanisms of immune regulation in allergy 91

 Global atlas oF allergy

Neuro-immune
24 regulation of allergic
inflammation
Harald Renz 
Philipps-University of Marburg
Marburg, Germany

The pathophysiology of asthma

is complex and heterogeneous Ke y m essag es
showing inter- as well as intra-in-
Section A - Allergy - from genetics to mechanisms

dividual variability. In addition to • Dysbalanced neurogenic responses may contribute to the

the profound dysregulation in in- pathogenesis of allergic diseases and other inflammatory
nate and adaptive immune func- diseases
tions, dysbalanced neurogenic re- • The axon reflex participates in the acute inflammatory response
sponses substantially contribute in rhinitis or asthma and is aggravated in asthmatic patients, due
to the disease (Figure 1). to a high degree of neuronal plasticity
• Increased neurotrophin levels were described in the asthmatic
Airway hyper-responsiveness is patients where they play a critical role in maintaining eosinophilia
considered a hallmark of asth- and Th2 driven inflammation, mast cell activation and enhance
ma. The contractility of airway IgE production by B cells
smooth muscle cells is controlled • There is an urgent need for the development of biomarkers
by several types of neurons in- assessing the state of neurogenic dysregulation in asthmatic
cluding sympathetic (adrenergic), patients together with the development of novel therapeutic
parasympathetic (cholinergic) and approaches aiming to re-establish the neurogenic homeostasis
non-adrenergic, non-cholinergic
(NANC) neurons. These types of
neurons are part of the complex
innervation network of the air-
ways and the lung.
Nervous
Neurons control lung function via System
the axon reflex (Figure 2). This is
best described for sensory neu-
Allergic
rons, which pick up stimulatory Neurotrophins
signals in the airways and transmit Phenotype
them via the sensory neurons to
the central nervous system (CNS). Immune
Stimuli able to excite these neu- System
rons include unspecific pollutants
such as tobacco smoke particles,
ozone and NO2 as well as signals
driven from microbes and aller-
gens. Cell damage caused by viral Figure 1  Neurotrophins contribute to bi-directional communication between
infection and replication is an im- nervous and immune system.

92 Neuro-immune regulation of allergic inflammation

Global atlas oF allergy

Trigger
Stimulus
Allergens
Virus(RSV)
Ozone
Cigarette smoke
Airway

Epithelium

Sensory
Neuropeptides
ganglion

Neuro-Inflammation

Section A - Allergy - from genetics to mechanisms

• plasma-extravasation
• bronchoconstriction
• chemotaxis
• activation of immune cells
• mast cell-degranulation
CNS

Figure 2  Neurogenic inflammation – The axon reflex.

Low-affinity High-affinity binding portant trigger of the axon reflex.

Efferent signals are sent back
NGF BDNF
NT-3 NT-4
from the cell body of the neurons
BDNF
NGF NT-4 NT-3
to the lung periphery. Within the
cell bodies, neuropeptides are
produced and stored. Afferent
firing of the neurons triggers not
Cell membrane only the production, but also the
retrograde transport of these
neuropeptides back to the site of
irritation and activation. These
locally released peptides (includ-
p75NTR
TrkA TrkB TrkC ing tachykinins, neurokinins and
others) play an important role in
p75NTR ↔ Trk Cooperation? mediating acute pro-inflammato-
ry events such as vasodilatation,
recruitment of inflammatory cells,
Figure 3  Neurotrophins and receptors.
activation of mast cells and eosin-
ophils and others. Therefore, the
axon reflex is one important exam-
ple of how neurons actively par-
ticipate in the acute inflammatory
response in rhinitis or asthma.

Neuro-immune regulation of allergic inflammation 93

 Global atlas oF allergy

TABLE 1 model of allergic airway inflam-

mation and asthma. Eur J Immunol
The family of NGF and its receptors in bronchial asthma
1998;28:3240-3251.
™™ augmentation of TH-2 inflammation (NGF, p75) 4. Braun A, Lommatzsch M, Manns-
™™ anti-apoptic signals (NGF, BDNF, p75) feldt A, Neuhaus-Steinmetz U,
Fischer A, Schnoy N, et al. Cellular
• eosinophils
sources of enhanced brain-derived
• pulmonary plasma cells neurotrophic factor production in
a mouse model of allergic inflam-
™™ acute broncho-constiction (NGF, p75)
mation. Am J Respir Cell Mol Biol
™™ neuronal control of airway hyperresponsiveness (BDNF) 1999;21:537-546.
™™ epithelial wound healing 5. Kerzel S, Päth G, Nockher WA,
Quarcoo D, Raap U, Groneberg DA,
et al. Pan-neurotrophin receptor
The axon reflex is aggravated in (observed in sputum, BAL, tissue, p75 contributes to neuronal hyper-
asthmatic patients, due to a high blood). Further mechanistic stud- reactivity and airway inflammation
degree of neuronal plasticity ob- ies carried out both in human and in a murine model of experimental
served in many chronic diseases. mice models further revealed that asthma. Am J Respir Cell Mol Biol
Section A - Allergy - from genetics to mechanisms

The development of the peripher- NGF and BDNF play a critical role 2003;28:170-178.
al neuronal network, the state of in maintaining eosinophilia and
6. Nassenstein C, Braun A, Erpen-
activation, and the differentiation Th2-driven inflammation, mast
beck VJ, Lommatzsch M, Schmidt
of neurons and various subtypes cell activation, while enhancing
S, Krug N, et al. The neurotrophins
is tightly controlled by another IgE production by B cells. There-
nerve growth factor, brain-derived
group of mediators termed neuro- fore, neurotrophins are consid-
neurotrophic factor, neurotro-
trophins (Figure 3). Neurotrophins ered major players in the overall
phin-3, and neurotrophin-4 are
belong to a family of mediators, maintenance of an already existing
survival and activation factors for
which control neuronal functions inflammatory response (Table 1).
eosinophils in patients with aller-
and exert also important effector There is an urgent need for the gic bronchial asthma. J Exp Med
mechanisms on many other cells development of better diagnostic 2003;198:455-467.
including immune cells. The pro- tools to assess the state of neu-
totype of the neurotrophin family 7. Abram M, Wegmann M, Fokuhl V,
rogenic dysregulation in asthmat-
is the nerve growth factor (NGF). Sonar S, Luger EO, Kerzel S, et al.
ic patients. The development of
The brain-derived neurotrophic Nerve growth factor and neurotro-
novel biomarkers should go hand
factor (BDNF) and other mem- phin-3 mediate survival of pulmo-
in hand with the development
bers of this family have also been nary plasma cells during the aller-
of novel therapeutic approaches
extensively studied. Neurotro- gic airway inflammation. J Immunol
aiming to re-establish neurogenic
phins signal through two different 2009;182:4705-4712.
homeostasis in this disease.
types of receptors, the pan-neu- 8. Sonar SS, Schwinge D, Kilic A,
rotrophin-receptor p75 and the KEY REFERENCES Yildirim AO, Conrad ML, Seidler K,
high-affinity neurotrophin recep- 1. Nockher WA1, Renz H. Neurotro- et al. Nerve growth factor enhanc-
tors TRKA, B and C. These recep- phins in allergic diseases: from neu- es Clara cell proliferation after lung
tors are also expressed at various ronal growth factors to intercel- injury. Eur Respir J 2010;36:105-
degrees and extend on cells of the lular signaling molecules. J Allergy 115.
innate and the adaptive immune Clin Immunol 2006;117:583-589.
9. Hahn C1, Islamian AP, Renz H,
system. 2. Nockher WA1, Renz H. Neurotro-
Nockher WA. Airway epithelial
phins and asthma: novel insight
An important step forward in bet- into neuroimmune interaction. J Al- cells produce neurotrophins and
ter understanding the neurogenic lergy Clin Immunol 2006;117:67-71. promote the survival of eosin-
component in asthma was the de- 3. Braun A, Appel E, Baruch R, Herz ophils during allergic airway in-
scription of increased neurotro- U, Botchkarev V, Paus R, et al. Role flammation. J Allergy Clin Immunol
phin levels in asthmatic patients of nerve growth factor in a mouse 2006;117:787-794.

94 Neuro-immune regulation of allergic inflammation

Global atlas oF allergy

25 United airways and

immune regulation
Claus Bachert 
University of Ghent
Ghent, Belgium

It is well established that the up-

per and lower airways are linked Ke y m essag es
together, we therefore, call them

Section A - Allergy - from genetics to mechanisms

“United Airways”. The develop- • The upper and lower airways are often diseased together
ment of asthma mostly begins • A high percentage of young children with asthma are sensitized
early in life time, and asthma man- to inhalant allergens
ifests before the age of 16 years; • There is an increased risk of developing late-onset asthma in
usually, this early-onset asthma chronic rhinosinusitis patients
is preceded by rhinitis symptoms. • These patients are often non-atopic, but express IgE to
staphylococcal enterotoxins
Over 80% of young children with
• Apart from inhalant allergens, staphylococcal enterotoxin–
asthma are allergen sensitized,
specific IgE is related to asthma
and atopy in this age group in-
creases disease morbidity. Addi-
tionally, atopy plays a critical role
often suffer from sinus disease diators and cytokines. With the
in the inception of asthma attacks
with symptoms such as nasal ob- Th2 cells being prominent, an eo-
in this age group, in particular dur-
struction, loss of smell and facial sinophilic type of inflammation is
ing viral infection. Also in later life,
pain/headache. CRS can be differ- orchestrated, which involves key
rhinitis is a powerful predictor of entiated into CRS without nasal interleukins (ILs) such as IL-4 and
asthma, and atopy significantly in- polyps (CRSsNP) and with nasal IL-5. Very similar mechanisms,
creases the risk for asthma devel- polyps (CRSwNP), based on symp- although patients with CRSwNP
opment in late-onset asthma. toms (loss of smell is typical for often are non-atopic, also prevail
A recent Europe-wide epidemio- CRSwNP, headache and facial pain in late-onset asthmatics with si-
logic study on the prevalence of are typical for CRSsNP), nasal en- nus disease. Among the group of
chronic rhinosinusitis (CRS), a dis- doscopy (presence of bilateral na- nasal polyps, especially the IL-5
ease manifesting in the nose and sal polyps) and CT scanning. From positive endotype, predominantly
paranasal sinuses, confirmed the those phenotypes, CRSwNP has showing an eosinophilic inflamma-
well-known association between a clearly increased risk of asthma tion, bears a high risk of asthma
allergic rhinitis and early-onset comorbidity in Caucasian popula- comorbidity (up to 70%). In these
asthma, but also demonstrated a tions. patients, serum total IgE often
clearly increased risk of suffering Allergic airway disease is charac- is increased, independent of the
from late-onset asthma in CRS terized by the mucosal synthesis atopic status of the patient. IgE
patients. Thus, whereas younger of IgE molecules, which arm den- antibodies to Staphylococcus au-
patients with asthma frequently dritic cells and mast cells. These reus superantigens (SE-IgE) can
complain of allergic rhinitis symp- armed cells upon contact with be detected in a large proportion
toms, older patients with asthma the allergen, release specific me- of these patients in the upper air-

United airways and immune regulation 95

Section A - Allergy - from genetics to mechanisms Global atlas oF allergy

Figure 1  The association (relative risk ratio with 95% confidence interval) of early- and late-onset asthma with nasal
allergies (early-onset) and chronic rhinosinusitis (late-onset). (Reproduced with permission from Jarvis D, Newson R, Lotvall
J,et al. Asthma in adults and its association with chronic rhinosinusitis: The GA2LEN survey in Europe. Allergy 2012;67:91-98,
with permission from Willey Blackwell)

SAE-IgE

0 1

IFNg Cases: 15 Figure 2  Classification tree for

Controls:10 comorbid asthma in patients with
0 1 5.8 (1.8 29.6) nasal polyps: SE-IgE positivity
(categorical classifying determinant)
is associated with a significantly
increased risk to suffer from co-
IL 17 Cases: 0
Controls: 14
morbid asthma. (Reprinted from J
0.12 (0.03 3) Allergy Clin Immunol, 126/5, Bachert
0 1 C, Zhang N, Holtappels G,Presence
of IL-5 protein and IgE-antibodies to
staphylococcal enterotoxins in nasal
Cases: 3 Cases: 6 polyps is associated with co-morbid
Controls:17 Controls: 4 asthma, 962-968, Copyright 2010, with
Ref. 5.1 (1.4 38)
permission from Elsevier.)

96 United airways and immune regulation

Global atlas oF allergy

1.0 Diagnostic tools in asthma should

include questions on nasal and si-
nus symptoms, blood eosinophils,
Controls
Non-severe total IgE and specific IgE abs to
0.5
inhalant allergens and SEs also in
GP-IgE Pos
SE-IgE Neg non-atopic subjects. The treat-
ment of the upper airways in these
0.0 HDM-IgE Pos patients might furthermore sup-
HDM-IgE Neg
port the management of the lower
SE-IgE Pos
GP-IgE Neg airways, and therefore should be
part of the individual therapeutic
-0.5 Severe
strategy.

KEY REFERENCES
-1.0 1. Shaaban R, Zureik M, Soussan D,
Neukirch C, Heinrich J, Sunyer J,
-1.0 -0.5 0.0 0.5 1.0
et al. Rhinitis and onset of asthma:
Figure 3  Multiple correspondence analyses factor map with 95% confidence a longitudinal population-based
ellipses situating relationships between parameters and disease severity. SE study. Lancet 2008;372:1049-

Section A - Allergy - from genetics to mechanisms

IgE is situated near severe asthma, whereas GP and HDM IgEs are situated 1057.
near non-severe asthma. (Reprinted from J Allergy Clin Immunol, 130/2, Bachert
2. Jarvis D, Newson R, Lotval J,
C,van Steen K, Zhang N,Specific IgE against Staphylococcus aureus enterotoxins: an
Hastan D, Tomassen P, Bousquet PJ,
independent risk factor for asthma, 376-381, Copyright 2012, with permission from
Bousquet J, et al. Asthma in adults
Elsevier.)
and its association with chronic rhi-
nosinusitis: The GA2LEN survey in
Europe. Allergy 2012;67:91-98.
3. Bachert C, Zhang N, Holtappels G,
De Lobel L, van Cauwenberge P,
Shixi L, et al. Presence of IL-5 pro-
tein and IgE-antibodies to staph-
ylococcal enterotoxins in nasal
polyps is associated with co-mor-
bid asthma. J Allergy Clin Immunol
2010;126:962-968.
4. Bachert C, van Steen K,Zhang N,
Holtappels G,, Cattaert T, Maus B,
Figure 4  Odds ratios for asthma presence for each of the tertiles of serum et al. Specific IgE against Staphylo-
SE-IgE in a pan-European study involving app. 3000 patients. The concentration coccus aureus enterotoxins: an in-
of SE-IgE is significantly associated with an increased risk of suffering from dependent risk factor for asthma. J
asthma (Reproduced with permission from Tomassen P, Jarvis D, Newson R, et al. Allergy Clin Immunol 2012;130:376-
Staphylococcus aureus enterotoxin specific IgE and its association with asthma in 381.
the general population: a GA²LEN. Study. Allergy 2013;68:1289-97, with permission 5. Tomassen P, Jarvis D, Newson R,
from Willey Blackwell.) Van Ree R, Forsberg R, Howarth
ways, but also with increasing se- ies are also associated with an P, et al. Staphylococcus aureus en-
verity of asthma in serum. SE-IgE increased risk of asthma in the terotoxin specific IgE and its asso-
antibodies are significantly asso- ciation with asthma in the general
general European population, ac-
ciated with severe asthma, oral population: a GA²LEN. Study. Aller-
cording to a recent epidemiolog- gy 2013;68:1289-97
corticosteroid use and hospitali- ic study investigating more than
zations within the last 12 months, 6. Fokkens WJ, Lund VJ, Mullol J,
55000 patients. Local IgE there- Bachert C, Alobid I, Baroody F et
and lung function parameters. fore needs to be recognized as an al. European Position Paper on Rhi-
As well as IgE antibodies to in- important mediator of disease of nosinusitis and Nasal Polyps 2012.
halant allergens, SE-IgE antibod- the airways. Rhinol Suppl 2012;23:1-298.

United airways and immune regulation 97

 Global atlas oF allergy

Genetics of
26 allergy
Stephan Weidinger 
University Hospital Schleswig-Holstein
Kiel, Germany

Atopic diseases (eczema, asthma,

rhinitis) affect an increasing num- Ke y m essag es
ber of individuals worldwide and
Section A - Allergy - from genetics to mechanisms

represent a major global health • Epidemiological and genetic research has provided firm evidence
problem. Epidemiological and ge- for the existence of genetic determinants of atopic diseases with
netic research has provided firm reported heritability estimates of up to 80%
evidence for the existence of ge- • Atopic diseases are complex, polygenic traits, influenced by
netic determinants of atopic dis- multiple disease genes
eases with reported heritability • Results from studies using high density association mapping
estimates of up to 80% (Figure 1). suggest that epithelial events and innate immune function are
Atopic diseases are typical com- major drivers of pathogenesis
plex, polygenic traits, which are • The detection of molecular interactions between susceptibility
thought to be influenced by mul- genes and environmental triggers over time and the elucidation
tiple disease genes. As for other of epigenetic factors as potentially underestimated source of
complex traits, the identification hidden heritability will be major tasks for the next years
of these genes is hampered by
considerable phenotype and locus
heterogeneity, incomplete pene- tary alterations of structural pro- intermediate molecular mecha-
trance and interaction with most- teins and innate immune function nisms of immune mechanisms and
ly unknown non-genetic factors, are major drivers of pathogenesis. inflammation and illustrating the
as well as by the yet incompletely With the exception of few sin- need for a more accurate classifi-
understood interrelation of these gle loci exerting large effects on cation of allergic diseases based
diseases with each other and with some phenotypes, e.g. filaggrin on their phenotypic and molecu-
intermediate traits like IgE. Only null mutations on atopic dermati- lar basis (Figure 3). Of note, the
recently, it has become possible tis (Figure 2), the majority of loci observed increase in prevalence
to systematically unravel the poly- displays rather modest effects of atopic diseases is not primar-
genic etiology of complex human when considered in isolation, and ily genetic, but rather due to the
diseases by high density associa- the despite impressive progress in dramatic changes of environmen-
tion mapping, which has allowed the field, only a small proportion tal conditions and modern health
a breakthrough in the definition of the total heritability is yet ex- hazards that trigger a genetic
of disease genes with an unprec- plained by known risk variants. It vulnerability into action. The de-
edented richness of findings and is further becoming clear that ge- tection of molecular interactions
a surprisingly high degree of re- netic risk factors overlap between between susceptibility genes and
producibility. For allergic diseases, traditional entities rather than environmental triggers over time
results from such studies suggest providing direct discriminators and the elucidation of epigenetic
that epithelial events, e.g. heredi- suggesting shared and potentially factors as potentially underesti-

98 Genetics of allergy
Global atlas oF allergy

1
MZ DZ
H: 0.82-0.96
0,8 0,86
H: 0.60-0.79
0,76
H: 0.55-0.71
H: 0.40-0.65
0,6 0,65
0,6

0,4 H: 0.30-0.40
0,34

0,2
0,21 0,19
0,16
0,13
0,08
0

Section A - Allergy - from genetics to mechanisms

Atopic
Ekzem Asthma Crohn T2D T1D
dermatitis

Figure 1  A genetic predisposition to the development of asthma, allergic rhinitis, and atopic dermatitis (AD) has been
confirmed by numerous epidemiological studies with the strongest evidence delivered by twin studies, which show a
distinctly higher concordance rate among monozygotic twins as compared to dizygotic twin pairs (for AD: 0.72-0.77 vs
0.15-0.23), and segregation analyses, which suggest that genetic factors account for more than 80% of the variance in the
susceptibility to AD.

R2447X

2282del4 3321delA Q1701X E2422X S2554X S3269X

R501X 3222del4 3702delG Q1790X Q2417X S3247X K4671X

441delA 1249insG R826X 4271delAA 6950del8 S2889X K4021X

N C

3673delC R1474X 6834del5 7945delA 11029delCA

R1140X S1695X 5757del4 S2706X R4307X Q3683X

Q1256X E1795X 7267delCA 11033del4

5360delG 6867delAG

Figure 2  The strong association of low-frequency FLG null mutations with atopic dermatitis is one of the most robust
genotype-phenotype linkages observed in complex human genetic disorders, and illustrates the importance of epithelial
barrier defects in the development of allergic disease.

Genetics of allergy 99
 Global atlas oF allergy

FLG IL2/IL21 HLA-DRB1 PRR5L CLEC16A TNFRSF6B

SLC9A4 RAD50/IL13 C11orf30 ZNF652

1 2 3 4 5 6 7 8 9 10 11 12 1314 1415 15
16 16 17 18 19 202122

Crohn‘s disease Ulc. colitis Asthma Rheum. arthritis Allergic rhinitis Multiple sclerosis Ulc. colitis
Celiac disease Type 1 diabetes Atopy Psoriasis Ulcerative colitis Type 1 diabetes Crohn‘s disease
Atopy IgE levels Vitiligo Atopy NOD2- IBD Glioma

Psoriasis ALL Asthma

Crohn‘s disease

strong correlation agonistic association

moderate correlation antagonistic association
Section A - Allergy - from genetics to mechanisms

Figure 3  The majority of established risk loci for atopic dermatitis are also implicated in the development of other
immune mediated-diseases with both agonistic and antagonistic effects.

mated source of this hidden her- Ruschendorf F, Patone G et al. A 2010;363:1211-1221.

itability will be major tasks for the common variant on chromosome 5. Paternoster L, Standl M, Chen
next years. 11q13 is associated with atopic CM, Ramasamy A, Bonnelykke
dermatitis. Nat Genet 2009;41:596- K, Duijts L et al. Meta-analysis of
601. genome-wide association stud-
KEY REFERENCES
1. Ellinghaus D, Baurecht H, Es- 3. Irvine AD, McLean WH, Leung DY. ies identifies three new risk loci
parza-Gordillo J, Rodriguez E, Filaggrin mutations associated for atopic dermatitis. Nat Genet
Matanovic A, Marenholz I, H et with skin and allergic diseases. N 2012;44:187-192.
al. High-density genotyping study Engl J Med 2011;365:1315-1327. 6. Weidinger S, Baurecht H, Naumann
identifies four new susceptibility 4. Moffatt MF, Gut IG, Demenais F, A, Novak N. Genome-wide associa-
loci for atopic dermatitis. Nat Genet Strachan DP, Bouzigon E, Heath tion studies on IgE regulation: are
2013;45:808-812. S, et al. A large-scale, consorti- genetics of IgE also genetics of at-
2. Esparza-Gordillo J, Weidinger S, um-based genomewide associa- opic disease? Curr Opin Allergy Clin
Folster-Holst R, Bauerfeind A, tion study of asthma. N Engl J Med Immunol 2010;10:408-417.

100 Genetics of allergy

Global atlas oF allergy

Epigenetics of
27 Allergy
R. Sharon Kimberly Morvarid Kari C.
Chinthrajah Vu Tavassoli Nadeau
Stanford University
Stanford, USA
Epigenetics is the study of herit-
able changes in gene activity that Ke y m essag es
are not caused by changes in the

Section A - Allergy - from genetics to mechanisms

DNA sequence (Figure 1). These • Epigenetic modifications result in changes in the expression
include modifications to the struc- of genetic material and can occur by three processes: DNA
ture supporting the DNA called methylation, histone modification or microRNA mediated changes
histones. Histone modification • Like genetics, epigenetic marks are inherited with each cell
(adding or removing acetyl groups) division and can persist through generations and may account in
determines DNA packaging and part for the increased prevalence of allergic disease
the cell’s ability to access and read • Genes in immune cells responsible for disease can be
the associated sequence. DNA can epigenetically modified by variables such as environmental
also be modified directly by adding exposures, diet, and the microbiome
a methyl group to cytosine bases, • Identical twins with discordant asthmatic status have been
which may restrict access to the shown to have different epigenetic marks on key immunologic
DNA for transcription into mRNA. genes in their genome
Finally, gene expression can be
regulated at the post-transcrip-
tional level by microRNAs, which studies, in which one twin suf- cumulative effect over multiple
can further modify mRNA tran- fered from asthma and the other generations (Figure 4). This is par-
did not. Asthmatic twins were ticularly relevant when consider-
scripts and histones to alter the
found to exhibit DNA methyla- ing the epidemiology of allergic dis-
expression of genes (Figure 2).
tion patterns that differed from ease, which seems to be amplified
Many environmental factors are their healthy counterpart. Most with subsequent generations. At
thought to regulate gene expres- notably, they had increased meth- the population level, allergic sen-
sion through these mechanisms ylation and decreased expression sitization seems to have occurred
and studies are ongoing to identify of the FOXP3 gene, which is im- in waves. The first wave was char-
specific exposures and pathways portant for the anti-inflammatory acterized by allergic rhinitis and
of effect (Figure 3). One of the function of T regulatory cells. Ad- asthma in industrialized countries
main characteristics of epigenetic ditionally, they showed decreased (US, UK, Australia), more than 50
changes is that it is passed on to function of non-allergic effector T years ago. The second wave is now
daughter cells with each cell divi- cells through methylation of the food allergy. Interestingly, devel-
sion so it may have a long lasting IFN-gamma gene. oping countries are currently just
effect on cell function. seeing the first wave. This implies
Furthermore, there is evidence
The importance of epigenetics in that some epigenetic marks can be that factors such as pollution, diet,
determining allergic phenotype transmitted from parents to chil- and lifestyle may be driving epige-
was illustrated in identical twin dren trans-generationally, with netic changes in different parts of

Epigenetics of allergy 101

 Global atlas oF allergy

ACTIVE
GENE
(Euchromatin)

DNA Histone tails Chromatin

methylation acetylation remodeling

TET DNMT HAT HDAC ATP-dependent

enzymes

Figure 1  Different epigenetic

mechanisms determine a
gene’s active vs silenced state.
DNA methylation involves
SILENCED adding a methyl group DNA
GENE base cytosine (red circle).
(Heterochromatin) This prevents gene access
to transcription factors and
promotes other epigenetic
changes. Histones, which are
Section A - Allergy - from genetics to mechanisms

large molecules that act as a scaffold for DNA strands, can be modified on
the world that are skewing people
their tails. Modification such as histone acetylation (green stars) can favour
towards an allergic phenotype. histone molecules to spread apart, allowing for an open DNA structure called
Epigenetics is an exciting and ex- euchromatin. Other histone modifications have been shown to favour a very
panding field of asthma and allergy condensed state (heterochromatin) in which DNA transcription is impossible.
research that provides new insight Chromatin remodelling is an active process that requires the intervention
into our understanding of these of various ATP-dependent enzymes. (HAT = Histone acetyltransferase;
complex syndromes, and possibly TET = Ten-eleven translocation dioxygenase; DNMT = DNA
useful biomarkers for diagnosis methyltransferase; HDAC = Histone deacetylase).
and characterization of various al-
lergic sub-phenotypes. RNA-induced silencing complex
miRNA duplex

KEY REFERENCES
1. Kohli A, Garcia MA, Miller RL, Ma-
her C, Humblet O, Hammond SK, et
al. Secondhand smoke in combina-
tion with ambient air pollution ex-
posure is associated with increased
CpG methylation and decreased ex-
pression of IFN-γ in T effector cells
and Foxp3 in T regulatory cells in
ribosome
children. Clin Epigenetics 2012;4:17.
2. Amarasekera M, Prescott SL, Palm- Blocked
protein
er DJ. Nutrition in early life, im- mRNA synthesis
mune-programming and allergies:
mRNA
the role of epigenetics. Asian Pac J degradation
Allergy Immunol 2013;31:175-182.
3. Martino D, Prescott S. Epigenetics Figure 2  MicroRNA (miRNA) is transcribed from eukaryotic DNA with RNA
and prenatal influences on asthma polymerase to form a double-stranded structure. Further processing of the
and allergic airways disease. Chest miRNA results in a structure with other proteins essential to miRNA’s function,
2011;139:640-647. shown here as the three blue geometric shapes.  This complex is called an
4. Begin P, Nadeau KC. Epigenetic RNA-induced silencing complex, or RISC.  The RISC will bind to complementary
regulation of asthma and allergic mRNA sequences and has 2 modes of action: one, it can occlude and prevent
disease. Allergy, Asthma & Clinical translation of the mRNA into functional proteins; two, it can recruit other
Immunology 2014 proteins to degrade the bound mRNA.

102 Epigenetics of allergy

Global atlas oF allergy

Environmental Exposures Constituting Prenatal

Epigenetic Changes to Immunity
Pollution Food

Folate
Tobacco
n-3 Polyunsatu-
rated Fatty Acids
Pollution
Anti-oxidants

Bacteria Figure 3  Environmental factors such as

Farming pollution, food, agriculture and microbiota
Viruses have been shown to have significant impli-

Section A - Allergy - from genetics to mechanisms

cations on early immune programming and
development. Prenatal exposure to these
Pets elements is postulated to cause epigenetic
Probiotics
changes to genes and signaling pathways
Agriculture Microbiota of fetal immunity that may have lasting
effects during the child’s life.
Trans-generational Amplification Hypothesis

Figure 4  Figure A depicts a trans-

generational model of atopic disease
predisposition that is solely based on
environmental stressors. This model
predicts that environmental pressure
directly correlates with an increase in
Figure A baseline genetic risk for disease only for
generations that lived during the changed
environment. Figure B illustrates an
epigenetic transgenerational inheritance
model wherein a change in environment
not only increases baseline risk for disease
but also induces epigenetic changes in
subsequent generations as shown in
animal models. This could lead to an
amplification of the atopic disease that
lasts up to two generations after return to
normal environment.

Figure B

Epigenetics of allergy 103

 Global atlas oF allergy

Endotypes of
28 allergic diseases
Ioana Agache  Cezmi A. Akdis 
Transylvania University Swiss Institute of Allergy and Asthma
Brasov, Romania Research, Davos, Switzerland

The heterogeneity of allergic

diseases in relation to clinically Ke y m essag es
significant outcomes, including
Section A - Allergy - from genetics to mechanisms

response to treatment, has been • The heterogeneity of allergic diseases in relation to clinically
established beyond any doubt. significant outcomes, including response to treatment, pushed
However, current guidelines ig- towards the development of the concept of phenotypes and
nore disease heterogeneity and endotypes
causal pathways, leading to unsuc- • There are several benefits of using endotypes such as stratified
cessful clinical “bulk” trials or con- treatment and better characterization of subjects in genetic and
tradictory results in epidemiologic epidemiologic studies and clinical trials for drug development
and genetic surveys. • Several endotypes can be described for asthma, rhinitis and
chronic rhinosinusitis based on the mechanisms of inflammation,
In the beginning, disease pheno- driving cause, genetic factors, tissue-related factors and
types describing clinical and mor- response to treatment
phologic characteristics as well • Translation of biomarkers into pathway-specific diagnostic
as unique responses to treatment tests is essential and should guide the design of future clinical
have been developed to address trials, incorporating both longitudinal and mechanism-tailored
the complexities of the disease. endpoints
Phenotypes are clinically rele- • Stratified treatment should be endotype-, biomarker- and
vant observable characteristics outcome-driven
in terms of presentation, triggers,
and treatment response, but do
not necessarily relate to or give derstanding of pathophysiological (Figure 2).
insights into the underlying patho- mechanisms of allergic disease.
The ideal biomarker should be
logical mechanism. For most of the
New and expensive biological pathway-specific, reproducible,
allergic diseases heterogeneous
therapies for allergic diseases are easily measurable, and affordable.
and mechanisms of the disease-re-
emerging that are highly effica- Biomarker research is increasingly
lated metabolic, inflammatory,
cious only for a selected group of shifting towards multidimensional
immunological, and remodeling
patients. The response to targeted approaches, in which the clinical
pathways have been described,
interventions in allergic disease value of a combination of various
and defined as a disease endotype.
may vary among individuals or for markers is studied. Translation of
There are several benefits of en- the same individual in relation to biomarkers into pathway-specific
dotyping in a clinical setting (Fig- outcome measures (dissociated diagnostic tests is essential and
ure 1). In addition, aligning mouse effect). Therefore, targeted treat- should guide the design of future
models to human endotypes is a ment should be both biomark- large clinical trials, incorporating
more relevant approach to the un- er-driven and outcome-driven both longitudinal and mechanism

104 Endotypes of allergic diseases

Global atlas oF allergy

In epidemiological trials: subgrouping of asthma cohorts using

endotypes may better determine the incidence, prevalence, morbidity,
mortality and health-care resources utilisation related to asthma.

In genetical studies: relating endotypes to genes may

yield more specific associations.

In drug-related trials: refining inclusion criteria using endotypes may

identify patient subgroups with particular benefit from
existing as well as new treatments. This could result in a
substantial improvement in asthma care.

It is anticipated that in the future endotype-tailored treatment

(stratified medicine) could lead to measurable improvement in the
optimization of care of individual cases and hopefully result in an
improvement in health care costs by applying specific treatments

Section A - Allergy - from genetics to mechanisms

only to those who will benefit from it.

Figure 1  Potential advantages of endotyping. (Reproduced with permission from Agache I, Akdis C, Jutel M, Virchow JC,
Untangling asthma phenotypes and endotypes. Allergy. 2012;67:835-46, with permission from Willey Blackwell.)

Response to a targeted antiasthmatic drug

Genetic and epigenetic Immune-inflammatory Remodeling phenotype Efficacy at the target site
background pathway (ASM, epithelium) of the drug formulation

inter- and intraindividual

differences in response
(dissociated effect)

biomarker outcome
driven treatmen driven treatment

Figure 2  Response to targeted treatment in asthma. (Reproduced from Agache IO. From phenotypes to endotypes to asthma
treatment. Curr Opin Allergy Clin Immunol. 2013 Jun;13:249-56.)

Endotypes of allergic diseases 105

 Global atlas oF allergy

TABLE 1 tailored endpoints. The selection

of outcome measures is difficult,
Th2 high and Th2 low asthma endotypes
as it must reflect the mechanistic
Endotype Biomarker intervention and should be rele-
vant for both the population as a
Th2 high IgE driven (atopic Total serum IgE
whole and for the particular indi-
and non-atopic) IgE on DC
Sputum total or specific IgE vidual.
While endotype-driven thera-
IL-4/IL-13 driven Serum periostin
Sputum IL-13 peutic strategies are becoming
IL-4 rc α SNPs increasingly successful in asthma,
only feeble attends were made for
IL-5/eotaxin driven Sputum/blood eosinophils other allergic diseases. In addition,
FeNO the issues related to the dissociat-
Eotaxin 2
ed effect and drug efficacy at the
PGD2 driven ? target site remain unresolved.
Aspirin intolerant Sputum/urine leukotrienes and For asthma the “Th2 high” and
prostaglandins “Th2 low” endotypes are well rec-
ognized and used to ascribe spe-
Section A - Allergy - from genetics to mechanisms

Mast cell/IL-9 driven) ?

cific treatment. Several subtypes
Eosinophilic obese Sputum IL-5 of the Th2-high and Th2-low en-
asthma Submucosal eosinophils dotypes can be described based
on the main operating molecular
Asthmatic Eosinophilic inflammation
mechanism (Table 1).
granulomatosis (Th1 Corticosteroid resistance
driven) ? Autoimmunity markers Applying the same model to al-
Innate immune TSLP
lergic and non-allergic rhinitis
response driven IL-33/ST-2 could prove as successful in pro-
moting personalized approaches,
Th2 low Neutrophilic (Th17/ Sputum neutrophilia especially for the severe forms of
IL-8/purinergic Low IgE the disease. The well recognized
inflammation driven) Low eosinophils
link between rhinitis and asthma
High reversibility
should be integrated and tackled
Paucigranulocytic No inflammation (sputum/bronchial within the framework provided by
(EMTU driven) biopsies) endotypes.
Prominent remodeling
Rhinitis endotypes can be defined
Small airways Flow, resistance, ventilation heterogeneity in relation to the background in-
disease Alveolar inflammation flammation or in terms of treat-
Microbioma Non-eosinophilic exacerbation-prone ment responsiveness. The follow-
asthma ing endotypes can be proposed
PCR evidence of infections for allergic rhinitis: eosinophilic
or Th2 (IL-4/IL-13) inflammation;
Innate IR driven BAL/sputum TNF-α steroid-responsive, anti IgE re-
Non-eosinophilic L-Arg/ADMA sponsive, anti IL-5 responsive,
obese asthma anti IL-4/IL-13 responsive. For
non-allergic rhinitis the defini-
Abbreviations:
tion of endotypes (eosinophilic or
ADMA = asymmetric dimethyl arginine; BAL = broncho-alveolar lavage; EMTU =
neutrophilic inflammation, steroid
epithelium-mesenchyme trophic unit; FeNO = fractional exhaled nitric oxide; L-Arg
= L-arginine; PCR = polymerase chain reaction; SNPs = single-nucleotide polymor-
responsive or resistant) should
phisms include the driving cause: supe-
rantigens, local IgE production,
autoantibodies. In the same line a

106 Endotypes of allergic diseases

Global atlas oF allergy

PRACTALL document described of children with cow’s milk allergy chow JC. Untangling asthma phe-
several endotypes for chronic rhi- can be distinguished by casein- notypes and endotypes. Allergy
nosinusitis (CRS) characterized and milk-specific IgE levels, milk 2012;67:835-846.
by differences in responsiveness specific basophil reactivity, and 4. Akdis CA, Bachert C, Cingi C, Dyke-
to treatment, including topical milk SPT mean wheal diameters. wicz MS, Hellings PW, Naclerio RM
intranasal corticosteroids and bi- et al. Endotypes and phenotypes of
In another study IL-25 was found
chronic rhinosinusitis: a PRACTALL
ological agents, such as anti–IL-5 highly elevated only in children document of the European Acade-
and anti-IgE mAb (Figure 2). Some with a clinical response to peanut, my of Allergy and Clinical Immu-
of the described CRS endotypes suggesting a role for IL-25 in the nology and the American Academy
were based on different biomark- pathogenesis of peanut allergy of Allergy, Asthma & Immunology.
ers linked to underlying mecha- and as a biomarker of a severe at- J Allergy Clin Immunol 2013;131:
nisms. opic phenotype. 1479-1490.
5. Wollenberg A, Seba A, Antal AS.
Atopic dermatitis (AD) is a chron- For drug allergy several pheno- Immunological and molecular tar-
ic inflammatory skin disease with types were described for the hy- gets of atopic dermatitis treat-
complex genetic and immunolog- persensivity to non-steroidal an- ment. Br J Dermatol 2014 Apr 11.
ical mechanisms. Several endo- ti-inflammatory drugs (NSAIDS): doi: 10.1111/bjd.12975. [Epub
types can be proposed according aspirin-exacerbated respiratory ahead of print]
to the inflammatory background disease, aspirin-exacerbated cuta- 6. Mu Z, Zhao Y, Liu X, Chang C, Zhang

Section A - Allergy - from genetics to mechanisms

such as Th2/IL-22/periostin high neous disease, multiple NSAID-in- J. Molecular Biology of Atopic Der-
or Th17/Th1 high or in relation to duced urticaria/angioedema, matitis. Clin Rev Allergy Immunol
the expression of fillagrin, MATT single NSAID-IgE reactions and 2014. [Epub ahead of print]
or vitamin D pathway genes muta- single NSAID T cell responses, 7. Ford LS, Bloom KA, Nowak-
tions. For the Th2 type AD serum which differ in terms of the path- Węgrzyn AH, Shreffler WG, Masi-
periostin is related to disease se- lamani M, Sampson HA. Basophil
ogenic pathways involved, as well
verity. Targeting both the inflam- reactivity, wheal size, and immuno-
as the mediators released after globulin levels distinguish degrees
matory-immune dysregulated provocation tests. of cow's milk tolerance. J Allergy
pathways or the barrier defect Clin Immunol 2013;131:180-186.
holds future promise. Several new Key References 8. Aalberse JA, van Thuijl AO, Meijer
targets such as toll-like recep- 1. Lotvall J, Akdis CA, Bacharier LB, Y, de Jager W, van der Palen-Merk-
tors, type 2 innate lymphoid cells Bjermer L, Casale TB, Custovic A us T, Sprikkelman AB et al.Plasma
and tight junction proteins are et al. Asthma endotypes: a new IL-25 is elevated in a subgroup
emerging. Promising new thera- approach to classification of dis- of patients with clinical reactiv-
peutic agents in the near future ease entities within the asthma ity to peanut. Clin Transl Allergy
syndrome. J Allergy Clin Immunol 2013;3:40.
are sphinganin, cannabinoids and
2011;127:355–360.
highly targeted monoclonal anti- 9. Ayuso P, Blanca-López N, Doña I,
2. Agache IO. From phenotypes to Torres MJ, Guéant-Rodríguez RM,
bodies.
endotypes to asthma treatment. Canto G et al. Advanced pheno-
For food allergy phenotypes Curr Opin Allergy Clin Immunol typing in hypersensitivity drug re-
prove useful for predicting severe 2013;13:249-256. actions to NSAIDs. Clin Exp Allergy
reactions. Different phenotypes 3. Agache I, Akdis C, Jutel M, Vir- 2013;43:1097-1109.

Endotypes of allergic diseases 107

 Global atlas oF allergy

Animal models of
29 allergic disease
Remo Frei Liam O’Mahony
  Swiss Institute of Allergy and Asthma Research
Davos, Switzerland

Animal models have been devel-

oped for almost all types of aller- Ke y m essag es
gic disease such as asthma, allergic
Section A - Allergy - from genetics to mechanisms

rhinitis, food allergy, anaphylax- • A wide range of animal models exist for a variety of allergic
is, atopic dermatitis and allergic diseases
conjunctivitis. These models are • Animal models are particularly useful for identifying novel
important to examine the mech- cellular and molecular immunological mechanisms of allergy
anism of the disease, the activity • No single animal model completely recreates all the aspects of an
of a variety of genes and cellular allergic response
pathways, define the role of en-
vironmental factors (such as the
microbiota), predict the safety of of the allergen with substances the features of allergy. This is very
(e.g. LPS), which stimulate the in- important to take into account
new drugs before being used in
nate immune response. Certain when choosing the correct model
clinical studies, define the patho-
protocols require the combina- to address the specific experimen-
genic pathways and suggest new
tion of allergen with an adjuvant, tal question. For example, chronic
therapeutic options. The correct
for example aluminium hydroxide exposure models are required to
animal model should reflect the
(ALOH3, Alum), which is one of the examine many of the structural
disease pathophysiology as close-
preferred adjuvants in respiratory changes associated with allergic
ly as possible and new models are allergy models. The sensitization, responses within the airways.
essential for the development of challenge and analysis parameters
new therapies. of murine allergy models are sum- Notwithstanding the limitations
marized in Figure 1. of these models, several studies
Laboratory mice do not usually
carried out in animal models have
spontaneously develop allergies Although murine models of aller- given important clues that explain
and a range of sensitization and gy provide important insights into the pathophysiological conditions
challenge protocols have been the disease mechanisms, there related to the disease status. For
developed. The number of sensiti- are some limitations that should instance, the role of Th2 type cy-
zations and challenges is decisive be considered. In addition to the tokines and T regulatory cells in
for the development of acute or genetic and physiological differ- the pathogenesis of allergy have
chronic forms of these models. The ences between humans and mice, been particularly well-studied in
nature of the allergic disease and there are also limitations due to
animal models.
inflammatory response is directly complexity of this disease. In oth-
influenced by the genetic back- er words, mice do not develop al- Human clinical studies remain the
ground of the mice, the allergen, lergy. One can replicate important gold standard for determining the
type of the sensitization and chal- components of the disease, but no clinical efficacy of new therapeu-
lenge protocol and contamination single model accurately models all tic approaches. Murine models

108 Animal models of allergic disease

Global atlas oF allergy

Sensitization

Food allergy Respiratory allergy Skin allergy

Challenge

Spleen
Colon Lymph nodes
Spleen
Serum Lung
Lymph nodes

Section A - Allergy - from genetics to mechanisms

Analyses
Bronchoalveolar
IgE lavage
Ear thickness

Lung function Differential

qPCR Histology Flow Re-
cell count
cytometry stimulation

Figure 1  Overview of the experimental steps commonly used in allergy models. Allergy mouse models typically comprise
a sensitization, a challenge, and an analyses phase. After sensitization, allergic responses are provoked, depending on
the model, by oral application (food allergy), by inhalation (respiratory allergy), or by skin contact (skin allergy) with the
allergen. The severity and mechanisms of the allergic response are determined using a variety of technologies, focused on
the relevant model organs or using functional assessments such as lung function testing or ear thickness measurements.

will continue to provide important 2008;1:213-220.

mechanistic clues, while improved 3. Lyons A, O’Mahony D, O’Brien F,
models may extend our under- MacSharry J, Sheil B, Ceddia M et
standing of the basic mechanisms al. Bacterial strain-specific induc-
for examining new therapeutic op- tion of Foxp3+ T regulatory cells is
tions. protective in murine allergy mod-
els. Clin Exp Allergy 2010;40:811-
Key References 819.
1. Fuchs B, Braun A. Improved mouse
models of allergy and allergic asth-
ma--chances beyond ovalbumin.
Curr Drug Targets 2008;9:495-502.
2. Nials AT, Uddin S. Mouse models of
allergic asthma: acute and chronic
allergen challenge. Dis Model Mech

Animal models of allergic disease 109