REVIEW

published: 21 November 2018

doi: 10.3389/fped.2018.00350

Celiac Disease: A Review of Current

Concepts in Pathogenesis,
Prevention, and Novel Therapies
Jason A. Tye-Din 1,2,3,4*, Heather J. Galipeau 5 and Daniel Agardh 6,7
1
Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia, 2 Department of Medical Biology, University
of Melbourne, Parkville, VIC, Australia, 3 Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC,
Australia, 4 Centre for Food & Allergy Research, Murdoch Children’s Research Institute, Parkville, VIC, Australia, 5 Farncombe
Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada, 6 The Diabetes and Celiac Disease
Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden, 7 Unit of Endocrinology and Gastroenterology,
Department of Pediatrics, Skåne University Hospital, Malmö, Sweden

Our understanding of celiac disease and how it develops has evolved significantly over
the last half century. Although traditionally viewed as a pediatric illness characterized by
malabsorption, it is now better seen as an immune illness with systemic manifestations
affecting all ages. Population studies reveal this global disease is common and, in many
Edited by:
countries, increasing in prevalence. These studies underscore the importance of specific
Ron Shaoul, HLA susceptibility genes and gluten consumption in disease development and suggest
Rambam Health Care Campus, Israel that other genetic and environmental factors could also play a role. The emerging data
Reviewed by: on viral and bacterial microbe-host interactions and their alterations in celiac disease
Gianfranco Meloni,
University of Sassari, Italy provides a plausible mechanism linking environmental risk and disease development.
Tudor Lucian Pop, Although the inflammatory lesion of celiac disease is complex, the strong HLA association
Iuliu Haţieganu University of Medicine
and Pharmacy, Romania
highlights a central role for pathogenic T cells responding to select gluten peptides that
*Correspondence:
have now been defined for the most common genetic form of celiac disease. What
Jason A. Tye-Din remains less understood is how loss of tolerance to gluten occurs. New insights into
[email protected] celiac disease are now providing opportunities to intervene in its development, course,
diagnosis, and treatment.
Specialty section:
This article was submitted to Keywords: celiac disease, gluten, T cells, microbiome, pathogenesis
Pediatric Gastroenterology,
Hepatology and Nutrition,
a section of the journal
Frontiers in Pediatrics
INTRODUCTION
Received: 22 August 2018 Celiac disease (CeD) is a chronic immune-mediated enteropathy precipitated by to dietary
Accepted: 29 October 2018 gluten in genetically predisposed individuals (1). Current diagnosis is based on demonstrating
Published: 21 November 2018
the enteropathy in small intestinal biopsies where histologic examination shows villous atrophy,
Citation: crypt hyperplasia and intraepithelial lymphocytosis, and the presence of circulating CeD-specific
Tye-Din JA, Galipeau HJ and
antibodies to tissue transglutaminase (tTG), deamidated gliadin peptides (DGP), and endomysium
Agardh D (2018) Celiac Disease: A
Review of Current Concepts in
(EMA). In children who have symptoms suggestive of CeD, a strongly positive tTG antibody
Pathogenesis, Prevention, and Novel (tTGA) titre and a CeD-associated HLA genotype, the diagnosis of CeD may be possible without
Therapies. Front. Pediatr. 6:350. the need for small intestinal biopsy (2). Since the 1950s when gluten was identified as the causative
doi: 10.3389/fped.2018.00350 trigger of CeD, a strict and lifelong gluten-free diet (GFD) has been the mainstay of treatment.

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Tye-Din et al. Current Concepts in Celiac Disease

While CeD is common around the globe and is rising in for consumption by most people with CeD, although adverse
prevalence in many populations, it is frequently undetected immune and clinical effects have been reported (20–22) and some
in clinical practice (3). Symptomatic and untreated disease cultivars may be more immunogenic (23). Several expert reviews
is associated with elevated morbidity and mortality and have concluded that further research into the toxicity of oats in
impaired quality of life (4–7). The clinical presentation is CeD is needed (24, 25).
broad and includes gastrointestinal upset, chronic fatigue, Why CeD develops in some people remains unanswered.
nutrient deficiencies, poor growth, and failure to thrive. Extra- Epidemiologic and prospective observational studies implicate a
intestinal manifestations are common, and while they were range of environmental factors that impact disease development.
once considered more frequent in adults than children with A role for the microbiome in the development of tolerance
CeD, recent data suggests the frequency is similar in CeD and disease pathogenesis is also emerging. Genetic and
children, although the types and rates of recovery differ (8). In immunological studies have revealed the importance of key
children, extra-intestinal manifestations include short stature, HLA and non-HLA susceptibility genes in disease development
anemia, delayed puberty, dental enamel hypoplasia, reduced and a long-lived pathogenic population of gluten-specific T
bone density, oral ulcers, liver and biliary disease, and dermatitis cells targeting certain gluten peptides (T cell epitopes). The
herpetiformis. Poor growth and anemia tend to be the most emerging story of CeD development is one where environmental
common and there is a correlation with more severe histological factors increase the risk of CeD in genetically predisposed
damage at diagnosis compared to children with a gastrointestinal individuals by shaping the immunologic context in which gluten
presentation or screen-detected cases (9). Insidious effects of is presented and shifting the balance from gluten tolerance
undiagnosed CeD in children include behavioral disturbances to reactivity, and that this may be in part mediated through
and reduced educational performance (10). microbiome-host interactions. Contemporary clinical issues of
CeD is also associated with an increased risk of autoimmune importance include expediting the detection and diagnosis of
diseases including Hashimoto’s thyroiditis, Graves’ disease and CeD, improving and quality of life and health outcomes for those
type 1 diabetes (T1D) (11–14). A large Danish population diagnosed, and developing treatments that are more effective and
study revealed the prevalence of autoimmune diseases was less burdensome than the current approach of a lifelong and
16.4% among CeD patients compared with 5.3% in the general strict GFD. This article will review current knowledge about CeD
population in 2016 (12). Approximately 5% of patients with development and pathogenesis and how this knowledge is being
CeD have T1D and ∼6% of T1D patients have CeD (15). applied to explore novel diagnostic, treatment and preventative
In Northern Sardinia, a population with a high prevalence approaches.
of CeD (16), patients with autoimmune thyroiditis had a 4-
fold greater prevalence of CeD than the general population
and while iron deficiency was present in almost half, none THE ROLE OF ENVIRONMENT IN DISEASE
had gastrointestinal symptoms (17). The co-occurrence of DEVELOPMENT
autoimmune diseases supports the concept of shared genetic and
immune pathways contributing to immune dysregulation and CeD is a global disease that has been reported in Western and
loss of self-tolerance, however it remains unclear whether CeD Eastern Europe, North America, South America, Asia, Oceania,
directly leads to other autoimmune disease and whether early and Africa (3, 26). It appears to be relatively uncommon in
diagnosis and treatment with a GFD alters this risk (18). Next southeast Asia and sub-Saharan Africa. Recent reports from
generation sequencing of the HLA region shows that extended China suggest the illness could be substantially unrecognized
class II haplotypes differ between populations (19); this may there however more biopsy-based studies are required (27). In
partially explain regional differences in the degree of association a systematic review and meta-analysis, the global seroprevalence
between CeD and autoimmune disease. The strong association and biopsy-confirmed prevalence of CeD was estimated to be
of CeD with autoimmunity, especially T1D and autoimmune 1.4% and 0.7%, respectively (3). The sero-prevalence of CeD in
thyroid disease, supports screening for these conditions in CeD the US from National Health and Nutrition Examination Surveys
patients. (NHANES) was 0.7% and, consistent with a range of population
The consumption of gluten containing foods is necessary for studies from around the globe, showed that most cases remain
CeD to develop. Gluten is the viscoelastic protein that remains undiagnosed in the community (28). Since CeD is frequently
after washing dough and is composed of alcohol-soluble gliadins undiagnosed an active case-finding approach is considered best
and alcohol-insoluble glutenins. The rheological properties of practice.
gluten allow it to impart a light and extensible texture to food The prevalence of CeD varies with sex, age, and geographic
making it highly favored in the food industry. Modern wheat location with the frequency of predisposing HLA haplotypes
gluten arises from a hexaploid genome, making it heterogeneous in the general population and per-capita wheat consumption
and more genetically complex than the human genome. Similar the two major determinants of prevalence. There is a modest
proteins rich in glutamine and proline (thus, the collective term gender bias in favor of females (29). Familial clustering in
prolamins) are found in barley and rye and termed hordeins CeD is common with 10% of first-degree relatives of a CeD
and secalins, respectively, and are also toxic in CeD. Avenin, sufferer affected. The high concordance rate for monozygotic
the prolamin component in oats, is phylogenetically distinct twins (∼80%) compared to HLA-identical siblings (∼30%) and
from wheat, barley and rye prolamin. Oats are considered safe dizygotic twins (∼10%) underscores the importance of both

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Tye-Din et al. Current Concepts in Celiac Disease

genetic factors (HLA and non-HLA genes) and the environment lower-risk HLA-DQ2.2/DQ7 haplotype (67). Larger prospective
in CeD risk (30). studies with a longer follow-up are underway and will shed light
The high prevalence of CeD observed among populations on whether gluten intake is an independent risk factor in CeD.
living in areas with a high consumption of wheat products
are highly suggestive for involvement of dietary gluten in CeD Infections
development (26). Although intake of gluten is necessary for CeD Several studies have shown that children that later develop
to develop, it does not solely explain why not all genetically- CeD are more frequently affected by infections during early
predisposed individuals consuming gluten develop CeD and why life (37, 68, 69). One limitation is that these studies are based
the disease can develop later in life despite many decades of on questionnaires filled in by parents and the type and site of
gluten intake. Significant differences in the prevalence of CeD infection is not specified. In a multicenter, prospective birth
between people of similar genetic background and wheat intake cohort study parents that reported a gastrointestinal infection 3
living in nearby regions (for example, Finland and Russian months prior to seroconversion of tTGA were at an increased
Karelia) is strong evidence that the risk of CeD is influenced risk of CeD autoimmunity later in life (38). There is also an effect
by other factors apart from genetic susceptibility and wheat of seasonality on the risk of developing CeD, hypothesized to be
consumption (31). Indeed, population studies have implicated caused by viral infections occurring during a vulnerable period
a range of environmental factors associated with CeD risk of immune development. This is supported by the association
(summarized in Table 1). Heterogeneity of study design has with frequent rotavirus infections and increased risk of CeD
yielded conflicting results in the search for triggers in CeD. We autoimmunity from longitudinal prospective studies (39) and a
have limited our review to focus on the association between CeD protective effect of rotavirus vaccination (38).
and diet, infections, antibiotic use, and delivery mode. How infections trigger CeD development remains
unexplained. Gastrointestinal infections may increase
Infant Feeding gastrointestinal permeability to increase the passage of gluten
The steep rise in CeD incidence in young children after changes across the mucosa, or elevate tTG expression that can increase
in the Swedish national infant feeding recommendation in the the generation of immunogenic gluten peptides. Molecular
mid-1980s that suggested postponing gluten introduction from 4 mimicry could possibly occur if the foreign antigen (such as
to 6 months of age hinted that timing of gluten intake influenced a virus or bacteria) shares sequence or structural similarities
CeD risk (61). However, the epidemic of CeD that occurred with gluten itself and then initiates an anti-gluten response.
in Sweden occurred simultaneously with companies raising the Several studies have shown antibodies to adenovirus (70–72)
gluten content in commercial baby formulas and was confounded and rotavirus peptides (73) circulating in CeD sera but further
by an observed protective effect of long breastfeeding duration studies are required to determine the significance of these
(62). This made it difficult to disentangle whether timing or associations with disease pathogenesis. In recent work in
amount of gluten intake in relation to weaning impacted on the mice, viral infection led to a break in oral tolerance to dietary
risk of CeD. The hypothesis that timing of first gluten exposure proteins (40). Some reoviruses can promote a proinflammatory
was associated with CeD was further supported in a study that phenotype in mouse dendritic cells (DCs) which lose their
found infants exposed to gluten either early (<4 months) or capacity to promote tolerance toward food antigens and
late (>7 months) were at an increased risk (63). Since this first cause a pathogenic T cell response instead. Reovirus infection
prospective study was published several follow-up papers from causes increased signaling by type 1 interferons and increased
larger longitudinal prospective birth cohorts summarized in two expression of the transcription factor interferon regulatory
recent systemic reviews with meta-analysis (32, 33) have not been factor 1 (IRF1) which can block the conversion of T cells into
able to confirm the previous findings that either age of gluten regulatory T cells (Tregs) and promote a proinflammatory
introduction or breast-feeding influence CeD risk. TH1 response to dietary antigens, respectively. Supporting
Although there are wide differences in gluten intake between relevance in humans, patients with CeD tended to have higher
countries (64), it is not entirely clear whether the quantity of anti-reovirus antibody titers. Importantly, reovirus infections are
gluten intake during early childhood affects the risk of CeD. A often silent or asymptomatic in humans and a large proportion
Swedish retrospective case-control study indicated that children of the population is exposed to self-limiting gastrointestinal
that later developed CeD consumed larger amounts of gluten infections during childhood. The findings provide a mechanistic
before the age of 2 years than healthy children (62). This finding explanation that links an apparently innocuous virus with the
was in line with another cross-sectional study from the same loss of tolerance to a common food antigen. More research is
group that observed a lower prevalence of CeD in a birth cohort required to unravel the significance of viral, bacterial or other
reporting a lower gluten consumption in children born after microbial host interactions or infections in the development of
(65) as compared to children born during the years of the CeD.
Swedish epidemic (66). In a nested case-control study, a high
intake of gluten amount increased the risk for CeD in Swedish Antibiotics and Delivery Mode
children (35). However, whether gluten intake contributes to CeD Early case-control studies reported a link between prior antibiotic
development is still controversial as another multicenter study use and subsequent CeD development in both adults (74) and
consisting of five other European countries found no association children (69). Similarly, children with CeD were more likely to
with CeD and gluten amount except for children carrying the have been born by cesarean section (c-section) (75). A large

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TABLE 1 | Environmental factors potentially associated with CeD development.

Risk factor Effect on CeD risk Studies (refs)

GLUTEN INGESTION
Age at gluten introduction No association Systemic review with meta-analysis (32); review (33); RCT (34).
(timing)
Amount of gluten Conflicting data A case-control study showed the amount of gluten consumed until 2 years of age increased CeD
introduction risk (35); An RCT in HLA-at risk infants with low dose of gluten (100 mg) introduced at 4–6 months
showed overall no effect on risk (36).
INFECTIONS
Infections (overall) Increased Increased risk of CeD especially with many infections (10 or more) up to 18 months of age (37).
Infections (gastrointestinal) Increased Gastrointestinal infection increased CeD risk autoimmunity by 33%. Risk was reduced in children
vaccinated against rotavirus (38).
Rotavirus Increased In Sweden rotavirus vaccination has not reduced CeD prevalence (39).
Reovirus Past infection associated Higher prevalence of reovirus antibodies in CeD patients vs. controls; Reovirus infection may impair
with CeD and possible development of oral tolerance (40).
mechanism established
Helicobacter pylori Conflicting data Inverse relationship with CeD (41–43); positive or no association with CeD (44, 45).
PERI-NATAL FACTORS
Season of birth Increased risk if born in Multiple populations assessed in different studies (38, 46–48).
summer
Elective cesarean section No association Multiple populations assessed in different studies e.g., Norwegian Mother and Child (MoBa) Cohort
Study (49), TEDDY cohort (50) and others (51).
Geographic location Possibly increased with National Health and Nutrition Examination Survey (NHANES) database; CeD more common in
northern latitude (single northern compared to southern latitudes (52). However, exceptions to the north-south gradient exist
study) e.g., high prevelance of CeD in Northern Africa (26), (53) and Sardinia (16).
Socio-economic status Increased risk with higher Unclear if due to biological effect e.g., hygiene hypothesis (31) or if due to differences in health
SES seeking behavior (54).
Maternal gluten No association TEDDY cohort; mother’s intake of gluten in late pregnancy was not associated with risk of celiac
consumption disease in offspring (55).
MEDICATIONS
Proton Pump Inhibitors (PPI) Increased Prior use of PPI strongly associated with CeD: OR 4.79; 95% CI 4.17-5.51) (56).
Antibiotics No increased risk Use of the most prescribed antibiotics during the first 4 years of life was not associated with the
development of autoimmunity for T1D or CeD (57).
Maternal iron Conflicting data Increased risk in MoBa cohort (58) but not replicated in TEDDY cohort (59).
supplementation
Vitamin D No association Maternal or neonatal vitamin D status not related to the risk of childhood CeD (60).

case-control study found that while emergency c-section was THE MICROBIOME IN CELIAC DISEASE
not associated with later CeD development, elective cesarean
delivery was (76). However, conflicting data has been reported. Microbial colonization occurs at birth and shapes the
For instance, no link between increased CeD risk and antibiotic development of the mucosal and systemic immune system
use during the first 6 months of life (68) or antibiotic use during and the intestinal barrier. These host-microbe interactions
pregnancy (77) was found. The Environmental Determinants continue throughout life, and a disruption of these interactions,
of Diabetes in the Young (TEDDY) study is a multicenter through altered bacterial composition or functions, have been
observational cohort study that aims to identify environmental hypothesized to increase the risk of a range of autoimmune
factors associated with T1D and CeD in children at HLA or inflammatory diseases such as CeD. Altered microbiota
risk followed from birth (78). It found no association between composition in patients with CeD may represent an
antibiotic use and CeD autoimmunity during the first 4 years environmental modifier of CeD development.
of life (57) or between delivery by c-section and increased CeD An early study described the presence of rod-shaped bacteria
risk (50). Similarly, large observational studies found no link in duodenal biopsies of Swedish children with CeD born
between c-section and CeD development (49, 69, 79). Finally, during the epidemic, which weren’t observed in biopsies
a large register-based study, that included children from two of control children (80), or in children born following the
independent cohorts, found that birth delivery mode was not epidemic (81). The bacteria were subsequently identified as
associated with increased risk of diagnosed CeD (51). Although Clostridium spp, Prevotella spp, and Actinomyces spp, and
the data is conflicting, the potential links between early events their presence was suggested to be a risk factor for CeD that
that can alter the microbiota composition, such as antibiotic use contributed to the increase in disease incidence in Sweden
or birth delivery mode, and later CeD implicate a role of the from 1985-1995 (81). Subsequent clinical studies have described
microbiome in disease development. differences in both fecal and duodenal microbial composition

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Tye-Din et al. Current Concepts in Celiac Disease

in children and adults with active compared with treated to children who were at low genetic risk for CeD (95, 96),
CeD, or healthy controls (82). While no specific microbial suggesting that the high-risk genotype may influence early gut
signature has been described for CeD, many groups have microbiota composition. Infants at the highest risk for CeD
described increases in the proportions of Bacteroides and had a higher prevalence of enterotoxigenic E. coli compared to
members of Proteobacteria, and decreases in Lactobacillus and those at low or intermediate risk for CeD (97). In addition,
Bifidobacterium (83, 84). In addition, CeD patients suffering in a cohort of 164 infants, those at risk for CeD had lower
from persistent symptoms were shown to have increased numbers of Bifidobacterium spp and B. longum and increased
abundance of Proteobacteria compared to those who were numbers of B. fragilis and Staphylococcus spp. The differences in
asymptomatic (85). While these studies suggest an association Bacteroides and bifidobacteria were attenuated by breastfeeding
between altered microbial composition and development of (98). At-risk children that later developed CeD were recently
CeD, studies exploring mechanisms and causality are lacking. shown to have an altered microbial trajectory that coincided with
Moreover, whether alterations in the microbial composition are immune changes. These changes were suggestive of a “premature
a cause or consequence of small intestinal inflammation has not maturation” of the gut microbiota in children who went on to
been fully elucidated. develop CeD (99). On the other hand, the fecal microbiota of
Recent studies have suggested that the microbiota from CeD at-risk infants who went on to develop CeD was similar at 9–
patients may harbor more pathogenic or pro-inflammatory 12 months to those infants that remained healthy by the age
bacteria. Reports of CeD diagnosis following Campylobacter of four (100). Whether the duodenal microbial composition
jejuni infection (86) suggest that bacterial infections could or function is altered in at-risk individuals that go on to
precede CeD development. Escherichia coli clones isolated develop CeD needs to be investigated further in larger clinical
from CeD patients expressed a higher number of virulent trials.
genes compared to those isolated from healthy controls Diet and environment also determine gut microbiota
(87). Similarly, the presence of virulent genes were higher composition (101, 102), highlighting the complexity of
in Staphylococcus spp and in Bacteroides fragilis strains delineating the influence of genotype and environment on
isolated from CeD patients compared to healthy controls shaping the microbiota. Larger clinical trials where both the
(88, 89). Importantly, strains isolated from CeD patients composition and function of the microbiota is studied in
were more pro-inflammatory in vitro and stimulated altered at-risk individuals and followed over time are needed to help
DC morphology, characteristic of DC maturation, increased understand gene-microbe interactions in CeD development.
pro-inflammatory cytokine production, and altered epithelial
barrier integrity. Similarly, Neisseria flavescens, a member of
Proteobacteria, was identified in the duodenum of active THE ROLE OF GENETICS IN DISEASE
CeD patients but not from control subjects and induced DEVELOPMENT
an inflammatory phenotype in human and murine DCs
(90). While environmental factors are important for CeD development
In contrast to the above studies, bacterial infections may a notable feature of CeD is its high heritability and strong HLA
also protect against CeD development. Some studies indicate association (103). This strong genetic association reflects the
an inverse relationship between the presence of Helicobacter central role of CD4+ T cells as the HLA molecules associated
pylori and CeD in both adults and children (41–43) whereas with CeD bind specific gluten peptides that activate T cells (104).
other studies have shown a positive or no association (44, 45). Ninety percent of Caucasian CeD patients possess the HLA-
Mechanisms underlying this association have not been elucidated DQ2.5 haplotype (encoded by the DQA1∗ 05:01 and DQB1∗ 02:01
and inconsistencies across studies may relate to differences in alleles) either in cis or trans positions, and the remaining carry
techniques used to determine H. pylori status or H. pylori either HLA-DQ8 (encoded by the DQA1∗ 03:01 and DQB1∗ 03:02
virulence. Less virulent strains may exacerbate the mucosal alleles), HLA-DQ2.2 alone (encoded by the DQB1∗ 02:02 allele)
response in CeD whereas more virulent strains may provide or HLA-DQ7 alone (encoded by the DQA1∗ 05:01 allele). Less
protection against CeD (45, 91). than 1% of CeD patients lack these HLA haplotypes (105) and
Functional differences in the microbiota could also affect their absence can be exploited in the clinical setting to assist in
metabolic processes important in CeD pathogenesis. The excluding a diagnosis of CeD.
gastrointestinal tract harbors diverse bacteria that participate A “gene-dose effect” related to the number of copies of the
in gluten metabolism in vitro and this may differ between DQB1∗ 02 allele has been reported to affect CeD risk, clinical
healthy individuals and those with CeD (92–94). As most studies phenotype and patient responses to a T cell targeted therapy.
have measured microbial composition in active or treated CeD The presumed basis for this effect is that gluten presented
compared to healthy controls it is difficult to determine whether by APCs in HLA-DQ2.5 homozygous (i.e., two copies of
functional differences are present prior to disease onset. DQB1∗ 02) individuals can induce at least a 4-fold higher T-cell
To gain insight into the potential role of microbial factors response compared with gluten presented by APCs in HLA-
in CeD development, previous studies have profiled the fecal DQ2.5 heterozygous (i.e., one copy of DQB1∗ 02) individuals
microbial composition of genetically at-risk children. High-risk (106). The CeD risk in HLA-DQ2.5 homozygous patients is ∼2.5
children were shown to harbor a different microbiota compared and 5 times that conferred by HLA-DQ2.5 heterozygosity and

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lower risk HLA groups, respectively (107). A prospective Italian T cells from intestinal tissue of CeD patients (122) (Figure 1).
study (Celiac Disease and Age at Gluten Introduction study; These pathogenic T cells have a Th1 phenotype characterized
CELIPREV) followed newborns with a family history of CeD and by production of IFN-γ and TNF-α (123) and almost all
showed the risk of CeD autoimmunity (positive CeD-serology are HLA-DQ2- and/or DQ8-restricted (122, 124, 125). Gluten
panel) at 10 years of age was far higher among children who were peptides that have been post-translationally modified by the
HLA-DQ2.5 homozygous (or who had two copies of DQB1∗ 02 enzyme tTG in a process called deamidation can effectively
than among those who were HLA-DQ2.5 heterozygous or HLA- activate these T cells (126, 127). Deamidation converts specific
DQ8 (38 vs. 19%, P = 0.001), as was the risk of overt CeD (26 glutamine residues to glutamate and this modification enhances
vs. 16%, P = 0.05) (34). In this cohort, 80% of those in whom the gluten peptide’s binding affinity to disease-associated HLA
CeD developed did so during the first 3 years of life. In the dimers (128–130). Deamidation is crucial in converting poorly
TEDDY study following 6403 US and European genetically at immunogenic wild-type gluten peptides to highly immunogenic
risk children at for CeD, the risks of CeD autoimmunity and antigens for CD4+ T cells. The structural requirements
confirmed CeD by age 5 were 11 and 3%, respectively in the that generate effective binding of gluten peptides to HLA-
heterozygous children and 26 and 11%, respectively, in those who DQ2 or DQ8 and T cells via the T cell receptor (TCR)
were homozygous (108). have been further elucidated in structural studies (131, 132)
In addition, HLA-DQ2.5 homozygosity has been associated and assessment of the biased use of TCR genes (133,
with a more severe CeD phenotype with earlier disease onset, 134).
greater villous atrophy, diarrhea, and lower hemoglobin at Studies of T cells isolated from the intestine of CeD patients,
presentation, and a slower rate of villous healing on a GFD (109), or from their blood after short-term oral gluten challenge, have
plus a higher rate of refractory (non-responsive) CeD (110). In been used to define the gluten peptides (specifically, the T cell
a recent clinical trial of an immunotherapy targeting gluten- epitopes) immunogenic in CeD. Most studies have focused on
specific CD4+ T cells, CeD subjects who were HLA-DQ2.5 the 90% of CeD patients who are HLA-DQ2.5 and a range of
homozygous were more likely to experience gastrointestinal immunodominant T cell epitopes have been defined (135). Less
symptoms following systemic administration compared to those is known about the nature of the T cell response to gluten
who were heterozygous (111). in CeD patients without HLA-DQ2.5. The most immunogenic
The contribution of non-HLA genes to CeD risk susceptibility gluten epitopes for CeD patients with HLA-DQ2.5 after wheat
is much less strong (OR <1.5) than the HLA-associated ingestion reside in α-gliadin and ω-gliadin (136). Much of the
haplotypes (OR >5) but collectively are significant. More than 70 field has focused on the immunogenicity of T cell epitopes
candidate genes in over 40 non-HLA loci have been implicated in in α-gliadin, specifically those encompassed within a protease
CeD heritability (112–117). These loci encode proteins involved resistant 33mer (137). However, gluten challenge studies show
in a range of immune pathways affecting T and B cell activation, that the most immunogenic peptides induced by gluten ingestion
chemokine receptor activity and cell migration, cytokine binding, depends on whether wheat, rye or barley is ingested, and that
thymic differentiation of CD4+ and CD8+ T cells, stress a sequence from ω-gliadin (encompassing the T cell epitopes
pathways and innate immunity. Only one gene has been shown DQ2.5-glia-ω1 and DQ2.5-glia-ω2) is dominant irrespective
to be gut specific (RGS1), underscoring the systemic nature of which grain is consumed (136). Despite the multitude of
of immune dysregulation in CeD (114). To date there is no immunogenic peptides, just three peptides from wheat and
evidence to implicate specific alleles encoding gastrointestinal barley appear to recapitulate most of the response to gluten in
proteases or tTG. Mirroring the frequent disease co-occurrence, CeD patients with HLA-DQ2.5. Interestingly, after oat ingestion,
there is substantial overlap between genetic risk factors for CeD about 8% of CeD patients have detectable T cells specific for
and those of autoimmune diseases such as rheumatoid arthritis, avenin peptides that share close sequence homology with barley
multiple sclerosis and T1D (112, 115, 118, 119). Furthermore, hordein, suggesting that cross-reactive T cells may mediate
despite a much weaker clinical association with CeD, there is immune responses following oats ingestion in some CeD patients
overlap of genetic risk loci for inflammatory bowel disease such (21).
as Crohn’s disease (18, 120). Intriguingly, 90% of the identified While early work suggested T cells from children with CeD
risk loci map to non-coding regions such as promoter regions, displayed a different pattern of reactivity to gluten compared to
enhancers or non-coding RNA genes, suggesting that regulation adults (138), more recent studies show gluten-specific T cells in
of gene expression rather than changes at the protein-coding blood induced by oral wheat challenge (139), or expanded from
level are more important for CeD susceptibility and development the small intestine during active disease (140), share the same
(121). specificity for deamidated, immunodominant T cell epitopes
across all ages. The same gluten-specific T cell clonotypes persist
in patients’ blood and intestinal tissue up to several decades
A KEY ROLE FOR T CELLS IN and share the same TCR gene use motifs in CeD patients
PATHOGENESIS from Norway, Finland and Australia (134, 139, 141, 142). Their
stability over such long periods of time may be maintained by
The role of CD4+ helper T cells in CeD was confirmed ongoing gluten exposure as inadvertent gluten intake is common
with the isolation of pro-inflammatory gluten-specific CD4+ in CeD even when a strict gluten-free diet is attempted (143, 144).

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FIGURE 1 | Key steps in CeD pathogenesis. Gluten peptides containing T-cell epitopes resist gastrointestinal degradation. tTG catalyses the deamidation of gluten
peptides, which can then bind more efficiently to the disease-relevant HLA-DQ molecules on APCs. Activated gluten-specific CD4+ T cells secrete a variety of
pro-inflammatory cytokines such as IFN-γ and IL-21 that contribute to the intestinal lesion and promote activation of IELs and stimulate B-cell responses. Activated
IELs transform into cytolytic NK-like cells that mediate destruction of enterocytes expressing stress signals. IL-15 renders effector T cells resistant to the suppressive
effects of Tregs and, in the lamina propria, endows mucosal DCs with inflammatory properties promoting pro-inflammatory responses and preventing Treg
differentiation.

ANTIBODIES AND B CELLS IN CELIAC of CeD-associated HLA types as well as gluten. This supports the
DISEASE idea that tTG-specific B cells internalize tTG in complex with
gluten peptides and present gluten-derived peptides to gluten-
Measurement of tTGA is a useful screening test for CeD as specific T cells, effectively amplifying the T cell response. These
the titer reflects disease activity caused by gluten, however a T cells then provide the required “help” to the B cell, resulting in
direct role in disease pathogenesis is less clear. As tTGA are production of tTGA and DGP antibodies (149, 150).
anti-angiogenic they may contribute to some extra-intestinal In active CeD, a large number of plasma cells can be
manifestations of CeD (145). As tTGA are detectable in intestinal found in the intestinal lesion and tTG-specific plasma cells
tissue prior to the typical enteropathy of CeD and predict made up a large proportion of them (5–25%) (151). There
future disease onset, antibody production is likely to occur early is much that still needs to be understood about how these
in disease development (146). However, approximately 50% of antibody producing cells are selected and mature. tTG can form
children with positive CeD serology normalize their levels despite covalently linked multimers with itself that readily bind gluten
ongoing gluten exposure, suggesting that gluten immunity that peptides and can be taken up by tTG-specific BCR transduced
leads to a pathogenic response is not necessarily fixed once it cells and activate gluten-specific T cells with increased capacity
has commenced (147). Supporting this concept is the observation compared to tTG monomers (152). Immunoglobulin expressed
that almost 20% of adults with CeD diagnosed during childhood on B cells could act as substrates for tTG, in particular
who elect to resume gluten intake have no evidence of active IgD, resulting in BCR/tTG cross-linking (153). As B cell
disease (148). epitopes are in close proximity to immunodominant T cell
Production of tTGA appears reliant on T cells, as antibody epitopes (154) and react to a higher degree to deamidated
formation to tTG and DGP is strictly dependent on the presence peptides (155) future work needs to examine the B cell

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Tye-Din et al. Current Concepts in Celiac Disease

and T cell interaction during the gluten-specific immune co-stimulatory molecule. The effect is to ‘license’ cytotoxic IELs
response. with the ability to kill intestinal epithelial cells expressing the
stress-induced MIC molecules. Adaptive immunity to gluten and
epithelial stress where cytotoxic IELs have acquired an activated
THE DEVELOPMENT OF INTESTINAL NK cell phenotype may both be required for villous atrophy to
VILLOUS ATROPHY develop in CeD (169).
The causes of epithelial stress that trigger IEL activation
The events that culminate in the histological changes of CeD
and transformation in CeD are not known. Some hypothesize
are incompletely understood. Gluten T cell epitopes cluster in
it is driven by gluten itself or other stimuli such as those
regions of high proline making them resistant to the effect
resulting from a microbe-host interaction (Figure 2). The innate
of gastrointestinal proteases (156). These peptides may pass
immune system is a pre-programmed form of host defense
across the epithelium via transcellular (157–159) and paracellular
that responds rapidly to stimuli. Responses are triggered when
(receptor or antibody mediated) pathways (160). Increased
pattern recognition receptors, for example, toll-like receptors
epithelial permeability, a feature of active CeD, may be mediated
on macrophages, bind molecules with conserved structures. An
by a direct effect of gliadin acting via the chemokine receptor
innate immune stimulatory effect of a gliadin sequence (A-gliadin
CXCR3 in intestinal epithelial cells on tight junctions (160).
p31-43) has been reported, but this work has not been replicated
DCs are presumed to play a major role in presentation of
(170). No other gluten peptides activating innate immunity in
gluten peptides to CD4+ T cells (161), however little is known
humans have been defined. Gliadin may function as a stress signal
about their identity, where this presentation occurs, and the
for the activation of MICA expression only in the initial stages
extent to which this role is undertaken by gluten-specific B
of disease and decline to baseline levels once the inflammatory
cells. Activated CD4+ T cells produce large amounts of IFN-
lesion is established. In contrast to the critical role of HLA-
γ, that may induce cytotoxicity of intraepithelial lymphocytes
restricted, gluten-specific CD4+ T cells in CeD pathogenesis, the
(IELs), as well as IL-21, which plays a role in T-cell-dependent
relative contribution of innate immunity to disease has not been
B cell responses (162). IL-17 producing CD4+ T cells have been
established in genetic or functional studies and further research
reported in untreated CeD (163) but their role and that of IL-
in this area is required.
17A production in CeD pathogenesis is less clear (162, 164).
IL-15 and IFN-α feature prominently in the inflamed tissue in
CeD patients (165, 166). IELs are believed to play an important HOW DOES LOSS OF TOLERANCE TO
effector role in mediating destruction of enterocytes in CeD in GLUTEN DEVELOP?
a TCR-independent manner. When activated by stress signals
on intestinal epithelial cells such as HLA-E and MIC-A (167), Although gluten consumption is common in the Western diet
IELs express high levels of NK activating receptors such as most individuals who possess HLA susceptibility for CeD develop
NKG2D and CD94/NKG2C and adopt a cytolytic phenotype immunologic tolerance to it as they do for other food proteins.
capable of destroying enterocytes (168). IL-15 plays a key role Why a small percentage fail to develop or lose tolerance to
by upregulating the activating NKG2D receptor and acting as a gluten remains unresolved. Tregs are an important immune

FIGURE 2 | Potential role of microbes and environmental triggers in CeD pathogenesis. Microbes that include both commensals and opportunistic pathogens may
contribute to the development of CeD by influencing gluten peptide digestion, intestinal barrier function, epithelial cell stress, or IEL activation/upregulation through
IL-15 regulation. Pathogenic bacteria, viruses, and non-gluten components of wheat, such as amylase-trypsin inhibitors (ATIs), may also induce DC maturation and
proinflammatory cytokine production, modulating the induction of CD4+ T-cell responses.

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Tye-Din et al. Current Concepts in Celiac Disease

component contributing to intestinal homeostasis and when models have played a limited role in the development or pre-
functioning normally inhibit pathogenic responses to dietary clinical testing of new therapies (183) and have more often
antigens and help maintain oral tolerance. This role suggests been used to investigate specific mechanisms related to disease
they may be important in CeD, however identifying and studying pathogenesis (184). The transfer of gluten-specific T cells into
this cell population has been limited by the technical challenge immunodeficient mice have been used to study the role of CD4+
of identifying a population of cells truly gluten-specific and T cells in mediating tissue damage (185, 186). Transgenic mouse
functionally suppressive in vivo. These challenges have meant models have also been used to investigate specific cytokines
that studies of Treg function in CeD have been conflicting, or genetic components in CeD pathogenesis. For example,
with some indicating reduced suppressive function (171–173) mice over expressing IL-15 in the lamina propria (165) or in
and some showing it is retained (174, 175). Further studies that the epithelium (180) have shed light on the role of innate
definitively isolate true gluten-specific Tregs and assess their mediators in the development of the intestinal lesion in CeD.
function in CeD are needed. Mice that express human HLA-DQ2 or -DQ8 develop gluten-
Interestingly, the immunosuppressive cytokines IL-10 and specific T cells and some innate immune activation following
TGF-β can be detected in high amounts in the CeD intestinal sensitization to gliadin with an adjuvant. However, they do not
lesion but appear insufficient to counter active disease (176, 177). progress to full blown gluten-induced enteropathy (183, 187–
The high levels of pro-inflammatory cytokines such as IFN-γ and 189), emphasizing the importance of additional genetic, immune,
IL-15 may render this anti-inflammatory response inadequate or environmental factors in triggering tissue destruction in CeD.
(178, 179). IL-15 is a pleiotropic cytokine that may promote This lack of spontaneous loss of tolerance to gluten in transgenic
inflammation through several pathways, including driving the mouse models can be taken advantage of and utilized to better
accumulation of cytotoxic IELs in the CeD lesion, interfering understand environmental factors that participate in the loss of
with the suppressive activity of Tregs (175), impairing TGF-β tolerance to gluten. For example, the mechanisms through which
signaling (176), or allowing activation of disease-specific CD4+ T microbes contribute to CeD development can be studied by
cells (180). IL-15 also drives the expansion of aberrant IEL clones manipulating the microbiota composition or exposing transgenic
that can lead to the development of enteropathy-associated T cell mouse models to certain bacteria.
lymphoma. The multiple pro-inflammatory effects of IL-15 make In mice expressing human HLA-DQ8 the composition of
it a rational target for therapeutic blockade, and clinical trials of the gut microbiota was found to influence the degree of
anti-IL-15 biologic agents are underway in refractory CeD (181). gluten-induced immunopathology (190). Mice harboring a
Additional insights into molecular pathways altered in loss of limited microbiota devoid of Proteobacteria and opportunistic
tolerance may be gained by study of gene expression profiles in pathogens were protected from gluten-induced pathology and
CeD patients. Analysis of blood-derived non-gluten stimulated immune responses. However, this protective effect was lost when
CD4+ T cells in CeD showed significant upregulation of the these mice were supplemented with an enteroadherent strain of
IFN-γ gene and reduced expression of a network of BACH2 E. coli that was isolated from a CeD patient. Similarly, treatment
regulated genes (182). BACH2 is a transcription factor that plays of specific pathogen free mice with vancomycin increased
an important immunoregulatory role in inhibiting T effector cell Proteobacteria levels, including Escherichia, and led to more
development and promoting development of Tregs. Advances severe gluten-induced pathology. While the mechanisms remain
in techniques such as RNAseq now affords the opportunity elusive, the results provide a proof-of-concept that microbes
to analyze multiple transcriptional and phenotypic features of could alter how a host responds to gluten and could therefore be
antigen-specific effector T cells and Tregs to provide insights at targeted as a prophylactic approach.
the single cell level into these heterogeneous populations. Gnotobiotic mice, or mice colonized with known microbes,
The findings on Treg numbers in the CeD lesion suggest that provide a model where the impact of specific bacteria on gluten-
the defect in tolerance is not simply due to defects in numbers or mediated responses in vivo can be studied in a controlled
recruitment of suppressive cells, but that the pro-inflammatory environment. Studies of mice colonized with bacteria isolated
environment characteristic of CeD overcomes the tolerogenic from the duodenum of CeD patients or from healthy controls
milieu that normally maintains balance and inhibits abnormal have shown that bacteria participate in gluten metabolism in
immune responses. However, further studies on disease-relevant vivo (94). Interestingly, the immunogenicity of the end products
Tregs from the small intestine of CeD patients that assess antigen- generated by bacterially-mediated gluten digestion differed
specificity, function in vivo and the factors that impact their depending on the type of bacteria. Following human protease
function are required. digestion, elastase from Pseudomonas aeruginosa generated
highly immunogenic gluten peptides that could strongly activate
gluten-specific T cells from human CeD patients. These peptides
were better able to translocate the epithelial barrier, potentially
FROM PATHOGENESIS TO CLINICAL facilitating immune cell-peptide interactions. Conversely, gluten
CARE peptides produced following digestion by human proteases or
by elastase from P. aeruginosa were detoxified or degraded by
Insights From Animal Models Lactobacillus spp, a core member of a healthy microbiome.
Modeling CeD has been a challenge as no single animal model The continued use of gnotobiotic models will be critical for
that encompasses all elements of disease exists. As a result, mouse understanding how microbes or pathogens may interact with the

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Tye-Din et al. Current Concepts in Celiac Disease

host and/or gluten to contribute to CeD pathogenesis (Figure 2). targeted approach for microbiota-modulating preventative
Importantly, these models can also be used to test microbiota- strategies.
targeted therapies for CeD.
Improving the Diagnosis of Celiac Disease
While villous atrophy remains the cornerstone of CeD diagnosis
Can Celiac Disease Be Prevented? there is the growing realization that this “gold-standard” has
Population studies have provided important insights into limitations. For example, results are affected by the number
environmental factors associated with CeD but are unable to of samples collected and how the biopsies are oriented and
establish true causality or mechanism. If factors that impact reported (192–195). Ultra-short CeD where villous atrophy
CeD risk can be identified and modified, then prevention of is present only in the duodenal bulb and “mild enteropathy
CeD may be possible. Randomized controlled trials (RCTs) do CeD” where villous atrophy is absent in the setting of positive
allow a controlled assessment of how a factor impacts CeD CeD serology both present diagnostic challenges and highlight
risk and several have now been undertaken or are underway potential shortcomings of histology (196, 197). Improvement in
in genetically at-risk infants or children (Table 2). The results the quality of serological testing for CeD and the requirement
have sometimes differed from assumptions made in population for specific HLA genotypes for CeD to develop has meant
studies, underscoring the importance of running well designed that a serogenetic approach to CeD diagnosis is appealing and
and controlled intervention studies and undertaking research to may be sufficient for diagnosis in the right clinical situations
examine mechanism. (2, 198). As expeditious treatment of CeD may avoid or reduce
Two independent RCTs assessed whether low amounts of the risk of many CeD-associated complications such as impaired
gluten can prevent genetically at-risk children from developing bone density and stunted growth in children, improving early
CeD. The idea of a “window of opportunity” during which gluten diagnosis remains a clinical and research priority.
could be introduced in small amounts to induce tolerance was In recent years the high rate of community adoption of
based on previous experience from the Swedish epidemic and the GFD, including in children (199), has compounded the
supported by a prospective study showing infants exposed to challenge of CeD diagnosis as the accuracy of current serological
gluten either early (<4 months) or late (>7 months) were at and histological approaches depend on active gluten intake.
an increased CeD risk (63). The optimal window was proposed In order to make a CeD diagnosis reintroduction of dietary
between 4 and 6 months, preferably during ongoing breast- gluten, generally for several weeks to months, is recommended
feeding (191). In the multicenter PreventCD study, almost prior to testing but patients are often reluctant to undertake
1,000 genetically at-risk children with at least one first-degree this and for those that do many fail to tolerate it. As the
relative with CeD were randomized to a double-blind, placebo- serologic and histologic response to gluten challenge is highly
controlled dietary-intervention to receive 100 mg of gluten daily heterogeneous the optimal duration of gluten challenge required
or placebo from 16 to 24 weeks of age (36). Neither breast- for definitive diagnosis of CeD remains uncertain (200–202).
feeding nor the introduction of small quantities of gluten at Immune diagnostics that measure the gluten-specific immune
16–24 weeks of age reduced the risk of CeD by 3 years of age response target a fundamental component of CeD and may
in this group of high-risk children (36). Published in the same overcome the limitations of current diagnostics. The use of
journal, the CELIPREV group randomised over 800 newborns tetramers (203) or cytokine release assays (204) to identify
who had a first-degree relative with CeD to have dietary gluten gluten-specific T cells induced in blood after short-term oral
introduced at either 6 or 12 months (34). The results from the gluten challenge is highly sensitive and specific for CeD (205).
CELIPREV study concorded with the results from the PreventCD Diagnostics that are accurate with limited or even no gluten
study, showing that neither the delayed introduction of gluten exposure such as tetramer-based detection of gluten-specfic T
nor breast-feeding modified the risk of CeD among at-risk cells (206) are particularly appealing to clinicians and patients as
infants (34). Although CeD was not prevented by delaying they may avoid the need for prolonged gluten challenge prior to
the introduction of gluten, it was associated with a delayed testing with serology and histology. Large multi-center validation
onset of disease (34). Since these two RCTs were published, studies to confirm the accuracy of assessing disease-specific T
other clinical trials have been performed or are currently being cells as a CeD diagnostic are required, and if successful, may force
conducted. a re-think of how CeD should be classified. Arguably, CeD may
Another potential approach to CeD prevention is be better defined by the HLA-linked, T cell mediated systemic
through modification of the host-microbe interactions in response to gluten rather than histologic changes in the proximal
at-risk individuals. Trials to assess the impact of probiotic small intestine or circulating antibodies that indirectly reflect
supplementation in preventing CeD in genetically at-risk disease activity.
children are underway (Table 2). If successful, they would
support the idea that altered function of the microbiome is a Improving the Treatment of Celiac Disease
major event underpinning the development of CeD, and that While adherence to a strict and lifelong GFD still remains the
preventing dysregulated host-microbe interactions may be single proven and available treatment for CeD, it is for many
of prophylactic benefit. Furthermore, a better understanding patients complicated, onerous, and expensive. In adults with
of the mechanisms through which microbes contribute to CeD, daily consumption of as little as 50 mg of gluten, equivalent
CeD development can provide further rationale and a more to that contained in 1/100th of a slice of standard wheat bread,

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Tye-Din et al. Current Concepts in Celiac Disease

TABLE 2 | Prospective trials in infants/children looking at factors impacting celiac disease development.

Study Design Finding Reference or clinical

trials identifier

Prevent Coeliac Disease International double-blind placebo Neither breast-feeding nor introduction of small (36)
Study (PreventCD) controlled RCT: 100 mg of gluten daily or quantities of gluten at 16–24 weeks of age reduced
placebo from 16 to 24 weeks of age the risk of celiac disease by 3 years of age in this
group of high-risk children
Celiac Prevention Study Multicenter RCT: Compare introduction of Neither the delayed introduction of gluten nor (26)
(CELIPREV) gluten at 6 vs. 12 months breast-feeding modified the risk of celiac disease
among at-risk infants
Celiac Disease Prevention Double-blind RCT: Probiotic (Lactobacillus) Completed NCT03176095
With Probiotics Study (CiPP) vs. placebo in infants/children aged 2 to
12 years
PreCiSe study RCT: Probiotic vs. placebo vs. GFD from In progress NCT03562221
before age of 4 months for 3 years

over three months can damage the small intestine (207). A safe a promising tool for evaluating and selecting patients for CeD
gluten “dose” threshold relevant to children with CeD has not clinical trials where controlling for inadvertent gluten exposure is
been assessed in a controlled trial. Several longitudinal studies important, such as therapies designed to prevent symptoms due
in adults with CeD indicate that failure to achieve mucosal to inadvertent gluten exposure (215).
healing is common even in those appearing to maintain good Insight into the molecular mechanisms underpinning CeD
dietary adherence over many years (208–213). While healing pathogenesis provide several opportunities for novel therapeutics
is considered to be more complete and faster in children with development and a range of pharmaceuticals are currently
CeD treated with a GFD one study showed 19% had persistent being assessed in pre-clinical and clinical trials (Table 3). These
disease activity after 12 months on a GFD (214). Assuming can be broadly classified into luminal approaches that aim to
enough time has elapsed on the GFD, persistent mucosal quantitatively reduce the load of gluten available to trigger the
activity may be driven by ongoing, potentially intermittent, immune response and qualitative approaches that aim to induce
gluten exposure (143), such as that inadvertently consumed in gluten tolerance. A third category, not discussed in this review,
contaminated meals when eating out (144). The challenge in encompass immunomodulators (e.g., budesonide, azathioprine),
maintaining adequately strict gluten exclusion and persistent biologics (e.g., anti-IL-15, anti-CD52), and chemotherapy (e.g.,
disease activity is a major driver for research into new therapeutic cladribine) used to treat refractory CeD (219).
approaches. While several therapies are under development Quantitative approaches include the use of (i) endopeptidase
it is notable that none of them have yet been evaluated in enzymes (glutenases) derived from plants, bacteria or fungi
children. that have a gluten degrading effect, such as latiglutenase
Clinical trials of novel therapies for CeD have increased (ALV003) (220, 221) and AN-PEP (222) (ii) agents to
substantially in recent years but compared to other illnesses such reduce paracellular passage of gluten i.e., larazotide acetate,
as inflammatory bowel disease the field is still in its infancy. No an intestinal tight junction regulator that may enhance
therapeutic approach for CeD has yet completed Phase 3 clinical barrier function (223–225), and (iii) compounds that bind
trials. An understanding of the optimal goals of treatment and gluten in the gut lumen to reduce absorption, such as the
the methods to assess efficacy are an evolving area and have polymer BL-7010 (226). Supplements to the GFD which
been shaped by the requirements of regulatory bodies such as the render small amounts of dietary gluten harmless could
FDA. Symptom improvement is now regarded as a key outcome substantially improve the quality of life of patients by allowing
measure and this has driven interest in validating patient them to dine out with less fear of adverse effects resulting
reported outcome measures (215) and understanding the basis from contamination by small amounts of gluten. Enzymatic
for gluten-induced symptoms in CeD. A standardized approach approaches could also be applied during the baking process
to reporting small intestinal histology based on quantitative to reduce gluten immunogenicity (227). Genetic modification
assessment of morphology (villus height, crypt depth and their of wheat with a variety of targeted techniques such as RNA
ratio) and inflammation (density of intraepithelial lymphocytes) interference (228) and CRISPR (229) can reduce gluten T cell
is now commonly employed in CeD clinical trials (192). epitope content and immunogenicity however clinical feeding
Confirming adequate dietary gluten exclusion during studies is trials are awaited. The recent publication of the first fully
a major challenge as symptom records, serology, histology, and annotated reference wheat genome is an important advance
dietary history are indirect measures of GFD adherence (216). that may help guide targeted approaches (230). Use of protease
New technology based on the detection of urinary or fecal gluten inhibitors, such as elafin, which is decreased in the mucosa of
immunogenic peptides (GIPs) derived from the 33mer peptide patients with active CeD has been proposed as it has barrier
in wheat α-gliadin provides objective evidence of dietary gluten enhancing and anti-inflammatory effects in gluten-sensitive mice
exposure (217, 218). In addition to a role in the clinic, it may be (231).

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TABLE 3 | Experimental therapies for celiac disease in pre-clinical or clinical placebo (111, 234). The recall immune response to gluten
development. was modified in people with CeD receiving Nexvax2. A
Approach Proposed mechanism Phase of
phase 2 clinical trial of infection with the hookworm Necator
development Americanus combined with a micro-gluten challenge in 12
CeD patients showed immune modifying effects and clinical
LUMINAL protection against gluten (235) and a larger controlled study is
Endopeptidases e.g., Enzymatic degradation of gluten Phase 2 underway.
latiglutenase, An-PEP
Tight junction modulators Reduce paracellular passage of Phase 2
e.g., larazotide acetate gluten across mucosa
CONCLUSION AND FUTURE
(AT-1001) PERSPECTIVES
Transglutaminase inhibitors Inhibit conversion of gluten to more Phase 2
e.g., ZED 1227 immunogenic form Our view of CeD has evolved from a gastrointestinal illness to
Gluten binding agents e.g., Sequester gluten in the intestinal Phase 1 an immune disease characterized by the presence of specific
BL-7010 lumen HLA genes, CD4+ T cells responding to specific gluten
HLA-DQ2 blockers Prevent activation of gluten-specific Pre-clinical peptides, circulating antibodies to tTG and systemic clinical
T cells manifestations. Aside from the fact it is driven by an exogenous,
Non-toxic gluten Modified or selectively bred cereals Pre-clinical dietary antigen, the genetic and immunologic basis for CeD
devoid of toxicity
overlaps with that of traditional autoimmune diseases. While
Inhibition of inflammatory Anti-inflammatory effects and Pre-clinical
proteases e.g., elafin improved barrier function
HLA susceptibility and wheat consumption and are major
determinants of disease development it is apparent that non-
TOLEROGENIC
HLA genes and a range of environmental factors are important
Peptide-based therapeutic Epitope-specific targeting of Phase 2
vaccine (Nexvax2) gluten-specific CD4+ T cells for disease development. Prospective studies have established
Hookworm (Necator Immunoregulatory effect of Phase 2 that the timing of gluten introduction and breastfeeding do not
americanus) hookworm combined with low-dose impact the development of CeD. More results from multicenter,
gluten exposure prospective longitudinal studies are needed to understand the
Nanoparticle therapy Nanoparticle encapsulating gliadin Phase 1 long-term effects of a high amount of gluten intake and to
(TIMP-GLIA) delivered intravenously identify if other environmental exposures might trigger the
disease.
Furthermore, although in vitro and in vivo studies suggests
there are host-microbe or gluten-microbe interactions that
A phase 2 RCT of latiglutenase taken orally showed it
promote gluten-specific immune responses, larger clinical trials
could attenuate small intestinal mucosal injury in CeD patients
where both the composition and function of the microbiota
induced by 2 g of ingested gluten (221). In symptomatic CeD
is studied in at-risk individuals and followed over time are
patients following a GFD, latiglutenase reduced symptoms in the
needed to help understand gene-microbe interactions in CeD
subgroup who were seropositive (232), suggesting that gluten
development. These kinds of studies may provide insight into
exposure was necessary in order to demonstrate a positive effect
the microbial events leading to CeD development that could be
of the enzyme. In a Phase 2 trial larazotide acetate was shown to
targeted as preventative or therapeutic strategies.
reduce symptoms in CeD patients on a GFD better than a GFD
Finally, understanding how tolerance to gluten is lost in CeD
alone, but only at the lowest dose of 0.5 mg (225). More studies
is a fundamental question that needs more study. Insights into
are required to establish the efficacy of these approaches and how
disease relevant pathways may come from analysis of the genome
they can be safely used by patients. A controlled gluten challenge
and gene expression in CeD, and epigenetic studies are needed
will be an important component of the study design in order to
to examine the impact of environment on gene expression and
demonstrate efficacy and establish the amount of ingested gluten
disease development. While novel therapies for CeD have not
patients can be protected from.
yet been tested in children, emerging studies on the role of
Qualitative approaches aim to establish durable immune
environmental factors and the microbiome and how they might
tolerance to gluten. One way this might be achieved is by
targeting the long-lived population of gluten-specific T cells and impact gluten immunity and tolerance may one day make disease
deleting or rendering them functionally unresponsive (anergic) prevention possible. For now, as primary prevention of CeD is
and inducing suppressive Tregs (233). As the target T cell a highly attractive, but as yet unrealized goal, the focus must be
population is stable in established CeD (139, 140, 142), it is on driving expeditious diagnosis and treatment in symptomatic
anticipated these approaches will apply similarly to children children and adults.
as they do in adults with CeD. Phase 1 studies of Nexvax2,
a therapeutic vaccine composed of three gluten peptides AUTHOR CONTRIBUTIONS
encompassing immunodominant HLA-DQ2.5-restricted T cell
epitopes, initially caused gastrointestinal symptoms similar to JT-D wrote the first draft of the manuscript. DA and HG wrote
those triggered by gluten, however after later administration sections of the manuscript. All authors contributed to manuscript
of Nexvax2 symptoms were no different from those after revision, read, and approved the submitted version.

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Tye-Din et al. Current Concepts in Celiac Disease

REFERENCES 20. Lundin KE, Nilsen EM, Scott HG, Loberg EM, Gjoen A, Bratlie J, et al.
Oats induced villous atrophy in coeliac disease. Gut (2003) 52:1649–52.
1. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al. The doi: 10.1136/gut.52.11.1649
Oslo definitions for coeliac disease and related terms. Gut (2013) 62:43–52. 21. Hardy MY, Tye-Din JA, Stewart JA, Schmitz F, Dudek NL, Hanchapola I, et al.
doi: 10.1136/gutjnl-2011-301346 Ingestion of oats and barley in patients with celiac disease mobilizes cross-
2. Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, reactive T cells activated by avenin peptides and immuno-dominant hordein
et al. European society for pediatric gastroenterology, hepatology, nutrition peptides. J Autoimmun. (2015) 56:56–65. doi: 10.1016/j.jaut.2014.10.003
guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 22. Arentz-Hansen H, Fleckenstein B, Molberg O, Scott H, Koning F, Jung G,
(2012) 54:136–60. doi: 10.1097/MPG.0b013e31821a23d0 et al. The molecular basis for oat intolerance in patients with celiac disease.
3. Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. PLoS Med. (2004) 1:e1. doi: 10.1371/journal.pmed.0010001
Global prevalence of celiac disease: systematic review and meta-analysis. 23. Comino I, Real A, de Lorenzo L, Cornell H, Lopez-Casado MA, Barro
Clin Gastroenterol Hepatol. (2018) 16:823–36.e2. doi: 10.1016/j.cgh.2017. F, et al. Diversity in oat potential immunogenicity: basis for the selection
06.037 of oat varieties with no toxicity in coeliac disease. Gut (2011) 60:915–22.
4. Rubio-Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann doi: 10.1136/gut.2010.225268
F, et al. Increased prevalence and mortality in undiagnosed celiac 24. Pinto-Sanchez MI, Causada-Calo N, Bercik P, Ford AC, Murray JA,
disease. Gastroenterology (2009) 137:88–93. doi: 10.1053/j.gastro.2009. Armstrong D, et al. Safety of adding oats to a gluten-free diet for
03.059 patients with celiac disease: systematic review and meta-analysis of
5. Kaukinen K, Peraaho M, Lindfors K, Partanen J, Woolley N, Pikkarainen clinical and observational studies. Gastroenterology (2017) 153:395–409 e3.
P, et al. Persistent small bowel mucosal villous atrophy without symptoms doi: 10.1053/j.gastro.2017.04.009
in coeliac disease. Aliment Pharmacol Therapeut. (2007) 25:1237–45. 25. Ciacci C, Ciclitira P, Hadjivassiliou M, Kaukinen K, Ludvigsson JF, McGough
doi: 10.1111/j.1365-2036.2007.03311.x N, et al. The gluten-free diet and its current application in coeliac disease
6. Godfrey JD, Brantner TL, Brinjikji W, Christensen KN, Brogan DL, and dermatitis herpetiformis. U Eur Gastroenterol J. (2015) 3:121–35.
Van Dyke CT, et al. Morbidity and mortality among older individuals doi: 10.1177/2050640614559263
with undiagnosed celiac disease. Gastroenterology (2010) 139:763–9. 26. Lionetti E, Gatti S, Pulvirenti A, Catassi C. Celiac disease from a
doi: 10.1053/j.gastro.2010.05.041 global perspective. Best Pract Res Clin Gastroenterol. (2015) 29:365–79.
7. Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, doi: 10.1016/j.bpg.2015.05.004
Absan H, et al. Characteristics of adult celiac disease in the USA: 27. Yuan J, Zhou C, Gao J, Li J, Yu F, Lu J, et al. Prevalence of celiac
results of a national survey. Am J Gastroenterol. (2001) 96:126–31. disease autoimmunity among adolescents and young adults in China. Clin
doi: 10.1111/j.1572-0241.2001.03462.x Gastroenterol Hepatol. (2017) 15:1572–9 e1. doi: 10.1016/j.cgh.2017.04.025
8. Jericho H, Guandalini S. Extra-intestinal manifestation of celiac disease in 28. Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The
children. Nutrients (2018) 10:755. doi: 10.3390/nu10060755 prevalence of celiac disease in the United States. Am J Gastroenterol. (2012)
9. Nurminen S, Kivela L, Huhtala H, Kaukinen K, Kurppa K. Extraintestinal 107:1538–44; quiz 1537:1545. doi: 10.1038/ajg.2012.219
manifestations were common in children with coeliac disease and were more 29. Jansson-Knodell CL, King KS, Larson JJ, Van Dyke CT, Murray JA,
prevalent in patients with more severe clinical and histological presentation. Rubio-Tapia A. gender-based differences in a population-based cohort with
Acta Paediatr. (2018). 107:1–7. doi: 10.1111/apa.14324 celiac disease: more alike than unalike. Dig Dis Sci. (2018) 63:184–92.
10. Smith LB, Lynch KF, Kurppa K, Koletzko S, Krischer J, Liu E, et al. doi: 10.1007/s10620-017-4835-0
Psychological manifestations of celiac disease autoimmunity in young 30. Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M, et al. The first
children. Pediatrics (2017) 139:e20162848. doi: 10.1542/peds.2016-2848 large population based twin study of coeliac disease. Gut (2002) 50:624–8.
11. Hagopian W, Lee HS, Liu E, Rewers M, She JX, Ziegler AG, et al. Co- doi: 10.1136/gut.50.5.624
occurrence of type 1 diabetes and celiac disease autoimmunity. Pediatrics 31. Kondrashova A, Mustalahti K, Kaukinen K, Viskari H, Volodicheva
(2017) 140:e20171305. doi: 10.1542/peds.2017-1305 V, Haapala AM, et al. Lower economic status and inferior hygienic
12. Canova C, Pitter G, Ludvigsson JF, Romor P, Zanier L, Zanotti R, environment may protect against celiac disease. Ann Med. (2008) 40:223–31.
et al. Celiac disease and risk of autoimmune disorders: a population- doi: 10.1080/07853890701678689
based matched birth cohort study. J Pediatr. (2016) 174:146–52 e1. 32. Szajewska H, Shamir R, Chmielewska A, Piescik-Lech M, Auricchio R,
doi: 10.1016/j.jpeds.2016.02.058 Ivarsson A, et al. Systematic review with meta-analysis: early infant feeding
13. Assa A, Frenkel-Nir Y, Tzur D, Katz LH, Shamir R. Large population and coeliac disease–update 2015. Aliment Pharmacol Ther. (2015) 41:1038–
study shows that adolescents with celiac disease have an increased risk of 54. doi: 10.1111/apt.13163
multiple autoimmune and nonautoimmune comorbidities. Acta Paediatr. 33. Chmielewska A, Piescik-Lech M, Szajewska H, Shamir R. Primary prevention
(2017) 106:967–72. doi: 10.1111/apa.13808 of celiac disease: environmental factors with a focus on early nutrition. Ann
14. Stordal K, Bakken IJ, Suren P, Stene LC. Epidemiology of coeliac disease Nutr Metabo. (2015) 67 (Suppl. 2):43–50. doi: 10.1159/000440992
and comorbidity in Norwegian children. J Pediatr Gastroenterol Nutr. (2013) 34. Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A, Tonutti E, Amarri
57:467–71. doi: 10.1097/MPG.0b013e3182a455dd S, et al. Weaning and Risk CD. introduction of gluten, HLA status, and
15. Elfstrom P, Sundstrom J, Ludvigsson JF. Systematic review with meta- the risk of celiac disease in children. N Engl J Med. (2014) 371:1295–303.
analysis: associations between coeliac disease and type 1 diabetes. Aliment doi: 10.1056/NEJMoa1400697
Pharmacol Ther. (2014) 40:1123–32. doi: 10.1111/apt.12973 35. Andren Aronsson C, Lee HS, Koletzko S, Uusitalo U, Yang J, Virtanen SM,
16. Meloni G, Dore A, Fanciulli G, Tanda F, Bottazzo GF. Subclinical coeliac et al. Effects of gluten intake on risk of celiac disease: a case-control study
disease in schoolchildren from northern Sardinia. Lancet (1999) 353:37. on a swedish birth cohort. Clin Gastroenterol Hepatol. (2016) 14:403–9 e3.
doi: 10.1016/S0140-6736(05)74871-6 doi: 10.1016/j.cgh.2015.09.030
17. Meloni GF, Tomasi PA, Bertoncelli A, Fanciulli G, Delitala G, Meloni 36. Vriezinga SL, Auricchio R, Bravi E, Castillejo G, Chmielewska A,
T. Prevalence of silent celiac disease in patients with autoimmune Crespo Escobar P, et al. Randomized feeding intervention in infants
thyroiditis from Northern Sardinia. J Endocrinol Invest. (2001) 24:298–302. at high risk for celiac disease. N Engl J Med. (2014) 371:1304–15.
doi: 10.1007/BF03343864 doi: 10.1056/NEJMoa1404172
18. Lundin KE, Wijmenga C. Coeliac disease and autoimmune disease-genetic 37. Marild K, Kahrs CR, Tapia G, Stene LC, Stordal K. Infections and
overlap and screening. Nat Rev Gastroenterol Hepatol. (2015) 12:507–15. risk of celiac disease in childhood: a prospective nationwide cohort
doi: 10.1038/nrgastro.2015.136 study. Am J Gastroenterol. (2015) 110:1475–84. doi: 10.1038/ajg.20
19. Alshiekh S, Zhao LP, Lernmark A, Geraghty DE, Naluai AT, Agardh D. 15.287
Different DRB1∗ 03:01-DQB1∗ 02:01 haplotypes confer different risk for 38. Kemppainen KM, Lynch KF, Liu E, Lonnrot M, Simell V, Briese T,
celiac disease. HLA (2017) 90:95–101. doi: 10.1111/tan.13065 et al. Factors that increase risk of celiac disease autoimmunity after a

Frontiers in Pediatrics | www.frontiersin.org 13 November 2018 | Volume 6 | Article 350

Tye-Din et al. Current Concepts in Celiac Disease

gastrointestinal infection in early life. Clin Gastroenterol Hepatol. (2017) 57. Kemppainen KM, Vehik K, Lynch KF, Larsson HE, Canepa RJ, Simell
15:694–702 e5. doi: 10.1016/j.cgh.2016.10.033 V, et al. Environmental determinants of diabetes in the young study:
39. Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, et al. association between early-life antibiotic use and the risk of islet
Rotavirus infection frequency and risk of celiac disease autoimmunity in or celiac disease autoimmunity. JAMA Pediatr. (2017) 171:1217–25.
early childhood: a longitudinal study. Am J Gastroenterol. (2006) 101:2333– doi: 10.1001/jamapediatrics.2017.2905
40. doi: 10.1111/j.1572-0241.2006.00741.x 58. Stordal K, Haugen M, Brantsaeter AL, Lundin KE, Stene LC. Association
40. Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, between maternal iron supplementation during pregnancy and risk of celiac
Mayassi T, et al. Reovirus infection triggers inflammatory responses to disease in children. Clin Gastroenterol Hepatol. (2014) 12:624–31 e1-2.
dietary antigens and development of celiac disease. Science (2017) 356:44–50. doi: 10.1016/j.cgh.2013.09.061
doi: 10.1126/science.aah5298 59. Yang J, Tamura RN, Aronsson CA, Uusitalo UM, Lernmark A, Rewers
41. Lebwohl B, Blaser MJ, Ludvigsson JF, Green PH, Rundle A, Sonnenberg A, M, et al. Environmental determinants of diabetes in the young study:
et al. Decreased risk of celiac disease in patients with Helicobacter pylori maternal use of dietary supplements during pregnancy is not associated
colonization. Am J Epidemiol. (2013) 178:1721–30. doi: 10.1093/aje/kwt234 with coeliac disease in the offspring: the environmental determinants of
42. Ciacci C, Squillante A, Rendina D, Limauro S, Bencivenga C, diabetes in the young (TEDDY) study. Br J Nutr. (2017) 117:466–72.
Labanca F, et al. Helicobacter pylori infection and peptic disease doi: 10.1017/S0007114517000332
in coeliac disease. Eur J Gastroenterol Hepatol. (2000) 12:1283–7. 60. Marild K, Tapia G, Haugen M, Dahl SR, Cohen AS, Lundqvist M, et al.
doi: 10.1097/00042737-200012120-00004 Maternal and neonatal vitamin D status, genotype and childhood celiac
43. Narang M, Puri AS, Sachdeva S, Singh J, Kumar A, Saran RK. Celiac disease disease. PLoS ONE (2017) 12:e0179080. doi: 10.1371/journal.pone.0179080
and Helicobacter pylori infection in children: is there any association? J 61. Ivarsson A, Persson LA, Nystrom L, Ascher H, Cavell B, Danielsson L,
Gastroenterol Hepatol. (2017) 32:1178–82. doi: 10.1111/jgh.13654 et al. Epidemic of coeliac disease in Swedish children. Acta Paediatr. (2000)
44. Dore MP, Salis R, Loria MF, Villanacci V, Bassotti G, Pes GM. Helicobacter 89:165–71. doi: 10.1111/j.1651-2227.2000.tb01210.x
pylori infection and occurrence of celiac disease in subjects HLA- 62. Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding
DQ2/DQ8 positive: a prospective study. Helicobacter (2018) 23:e12465. protects against celiac disease. Am J Clin Nutr. (2002) 75:914–21.
doi: 10.1111/hel.12465 doi: 10.1093/ajcn/75.5.914
45. Konturek PC, Karczewska E, Dieterich W, Hahn EG, Schuppan D. Increased 63. Norris JM, Barriga K, Hoffenberg EJ, Taki I, Miao D, Haas JE, et al. Risk
prevalence of Helicobacter pylori infection in patients with celiac disease. Am of celiac disease autoimmunity and timing of gluten introduction in the
J Gastroenterol. (2000) 95:3682–3. doi: 10.1111/j.1572-0241.2000.03421.x diet of infants at increased risk of disease. JAMA (2005) 293:2343–51.
46. Lebwohl B, Green PH, Murray JA, Ludvigsson JF. Season of birth in a doi: 10.1001/jama.293.19.2343
nationwide cohort of coeliac disease patients. Arch Dis Child. (2013) 98:48– 64. Aronsson CA, Lee HS, Liu E, Uusitalo U, Hummel S, Yang J, et al. Age at
51. doi: 10.1136/archdischild-2012-302360 gluten introduction and risk of celiac disease. Pediatrics (2015) 135:239–45.
47. Assa A, Waisbourd-Zinman O, Daher S, Shamir R. Birth month doi: 10.1542/peds.2014-1787
as a risk factor for the diagnosis of celiac disease later in life: a 65. Ivarsson A, Myleus A, Norstrom F, van der Pals M, Rosen A, Hogberg
population-based study. J Pediatr Gastroenterol Nutr. (2018) 67:367–70. L, Danielsson L, et al. Prevalence of childhood celiac disease and changes
doi: 10.1097/MPG.0000000000002001 in infant feeding. Pediatrics (2013) 131:e687–94. doi: 10.1542/peds.201
48. Ivarsson A, Hernell O, Nystrom L, Persson LA. Children born in the summer 2-1015
have increased risk for coeliac disease. J Epidemiol Community Health (2003) 66. Myleus A, Ivarsson A, Webb C, Danielsson L, Hernell O, Hogberg
57:36–9. doi: 10.1136/jech.57.1.36 L, et al. Celiac disease revealed in 3% of Swedish 12-year-olds born
49. Emilsson L, Magnus MC, Stordal K. Perinatal risk factors for development during an epidemic. J Pediatr Gastroenterol Nutr. (2009) 49:170–6.
of celiac disease in children, based on the prospective Norwegian Mother doi: 10.1097/MPG.0b013e31818c52cc
and Child Cohort Study. Clin Gastroenterol Hepatol. (2015) 13:921–7. 67. Crespo-Escobar P, Mearin ML, Hervas D, Auricchio R, Castillejo G,
doi: 10.1016/j.cgh.2014.10.012 Gyimesi J, et al. The role of gluten consumption at an early age in
50. Koletzko S, Lee HS, Beyerlein A, Aronsson CA, Hummel M, Liu celiac disease development: a further analysis of the prospective PreventCD
E, et al. Cesarean section on the risk of celiac disease in the cohort study. Am J Clin Nutr. (2017) 105:890–6. doi: 10.3945/ajcn.116.1
offspring: the teddy study. J Pediatr Gastroenterol Nutri. (2018) 66:417–24. 44352
doi: 10.1097/MPG.0000000000001682 68. Myleus A, Hernell O, Gothefors L, Hammarstrom ML, Persson LA,
51. Dydensborg Sander S, Hansen AV, Stordal K A. -Andersen MN, Murray Stenlund H, et al. Early infections are associated with increased risk for
JA, Husby S. Mode of delivery is not associated with celiac disease. Clin celiac disease: an incident case-referent study. BMC Pediatr. (2012) 12:194.
Epidemiol. (2018) 10:323–32. doi: 10.2147/CLEP.S152168 doi: 10.1186/1471-2431-12-194
52. Unalp-Arida A, Ruhl CE, Choung RS, Brantner TL, Murray JA. Lower 69. Canova C, Zabeo V, Pitter G, Romor P, Baldovin T, Zanotti R, et al.
prevalence of celiac disease and gluten-related disorders in persons living in Association of maternal education, early infections, antibiotic use with celiac
Southern vs Northern Latitudes of the United States. Gastroenterology (2017) disease: a population-based birth cohort study in northeastern Italy. Am J
152:1922–32.e2. doi: 10.1053/j.gastro.2017.02.012 Epidemiol. (2014) 180:76–85. doi: 10.1093/aje/kwu101
53. Teresi S, Crapisi M, Vallejo MD, Castellaneta SP, Francavilla R, Iacono 70. Kagnoff MF, Paterson YJ, Kumar PJ, Kasarda DD, Carbone FR, Unsworth
G, et al. Celiac disease seropositivity in Saharawi children: a follow- DJ, et al. Evidence for the role of a human intestinal adenovirus
up and family study. J Pediatr Gastroenterol Nutr. (2010) 50:506–9. in the pathogenesis of coeliac disease. Gut (1987) 28:995–1001.
doi: 10.1097/MPG.0b013e3181bab30c doi: 10.1136/gut.28.8.995
54. Roy A, Mehra S, Kelly CP, Tariq S, Pallav K, Dennis M, et al. The association 71. Lahdeaho ML, Parkkonen P, Reunala T, Maki M, Lehtinen M. Antibodies
between socioeconomic status and the symptoms at diagnosis of celiac to E1b protein-derived peptides of enteric adenovirus type 40 are
disease: a retrospective cohort study. Therap Adv Gastroenterol. (2016) associated with celiac disease and dermatitis herpetiformis. Clin Immunol
9:495–502. doi: 10.1177/1756283X16637532 Immunopathol. (1993) 69:300–5. doi: 10.1006/clin.1993.1184
55. Uusitalo U, Lee HS, Aronsson CA, Yang J, Virtanen SM, Norris J, et al. 72. Lahdeaho ML, Lehtinen M, Rissa HR, Hyoty H, Reunala T, Maki M.
Environmental determinants of the diabetes in the young study: gluten Antipeptide antibodies to adenovirus E1b protein indicate enhanced risk of
consumption during late pregnancy and risk of celiac disease in the celiac disease and dermatitis herpetiformis. Int Arch Allergy Immunol. (1993)
offspring: the TEDDY birth cohort. Am J Clin Nutr. (2015) 102:1216–21. 101:272–6. doi: 10.1159/000236457
doi: 10.3945/ajcn.115.119370 73. Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S, et al. In celiac
56. Lebwohl B, Spechler SJ, Wang TC, Green PH, Ludvigsson JF. Use of proton disease, a subset of autoantibodies against transglutaminase binds toll-like
pump inhibitors and subsequent risk of celiac disease. Dig Liver Dis. (2014) receptor 4 and induces activation of monocytes. PLoS Med (2006) 3:e358.
46:36–40. doi: 10.1016/j.dld.2013.08.128 doi: 10.1371/journal.pmed.0030358

Frontiers in Pediatrics | www.frontiersin.org 14 November 2018 | Volume 6 | Article 350

Tye-Din et al. Current Concepts in Celiac Disease

74. Marild K, Ye W, Lebwohl B, Green PH, Blaser MJ, Card T, et al. Antibiotic coeliac disease patients and first-degree relatives. Br J Nutr. (2015) 114:1157–
exposure and the development of coeliac disease: a nationwide case-control 67. doi: 10.1017/S0007114515002767
study. BMC Gastroenterol. (2013) 13:109. doi: 10.1186/1471-230X-13-109 94. Caminero A, Galipeau HJ, McCarville JL, Johnston CW, Bernier SP,
75. Decker E, Engelmann G, Findeisen A, Gerner P, Laass M, Ney D, Russell AK, et al. Duodenal bacteria from patients with celiac disease and
et al. Cesarean delivery is associated with celiac disease but not healthy subjects distinctly affect gluten breakdown and immunogenicity.
inflammatory bowel disease in children. Pediatrics (2010) 125:e1433–40. Gastroenterology (2016) 151:670–83. doi: 10.1053/j.gastro.2016.06.041
doi: 10.1542/peds.2009-2260 95. Olivares M, Neef A, Castillejo G, Palma GD, Varea V, Capilla A, et al. The
76. Marild K, Stephansson O, Montgomery S, Murray JA, Ludvigsson HLA-DQ2 genotype selects for early intestinal microbiota composition in
JF. Pregnancy outcome and risk of celiac disease in offspring: a infants at high risk of developing coeliac disease. Gut (2015) 64:406–17.
nationwide case-control study. Gastroenterology (2012) 142:39–45 e3. doi: 10.1136/gutjnl-2014-306931
doi: 10.1053/j.gastro.2011.09.047 96. Sellitto M, Bai G, Serena G, Fricke WF, Sturgeon C, Gajer P, et al. Proof of
77. Marild K, Ludvigsson J, Sanz Y, Ludvigsson JF. Antibiotic exposure in concept of microbiome-metabolome analysis and delayed gluten exposure
pregnancy and risk of coeliac disease in offspring: a cohort study. BMC on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE
Gastroenterol. (2014) 14:75. doi: 10.1186/1471-230X-14-75 (2012) 7:e33387. doi: 10.1371/journal.pone.0033387
78. Agardh D, Lee HS, Kurppa K, Simell V, Aronsson CA, Jorneus O, et al. 97. Olivares M, Benitez-Paez A, de Palma G, Capilla A, Nova E, Castillejo G, et al.
Clinical features of celiac disease: a prospective birth cohort. Pediatrics (2015) Increased prevalence of pathogenic bacteria in the gut microbiota of infants
135:627–34. doi: 10.1542/peds.2014-3675 at risk of developing celiac disease: the proficel study. Gut Microbes (2018)
79. Sevelsted A, Stokholm J, Bonnelykke K, Bisgaard H. Cesarean 9:1–8. doi: 10.1080/19490976.2018.1451276
section and chronic immune disorders. Pediatrics (2015) 135:e92–8. 98. Palma GD, Capilla A, Nova E, Castillejo G, Varea V, Pozo T, et al. Influence of
doi: 10.1542/peds.2014-0596 milk-feeding type and genetic risk of developing coeliac disease on intestinal
80. Forsberg G, Fahlgren A, Horstedt P, Hammarstrom S, Hernell O, microbiota of infants: the PROFICEL study. PLoS ONE (2012) 7:e30791.
Hammarstrom ML. Presence of bacteria and innate immunity of intestinal doi: 10.1371/journal.pone.0030791
epithelium in childhood celiac disease.. Am J Gastroenterol. (2004) 99:894– 99. Olivares M, Walker AW, Capilla A, Benítez-Páez A, Palau F, Parkhill J, et al.
904. doi: 10.1111/j.1572-0241.2004.04157.x Gut microbiota trajectory in early life may predict development of celiac
81. Ou G, Hedberg M, Hörstedt P, Baranov V, Forsberg G, Drobni M, et al. disease. Microbiome (2018) 6:36. doi: 10.1186/s40168-018-0415-6
Proximal small intestinal microbiota and identification of rod-shaped 100. Rintala A, Riikonen I, Toivonen A, Pietilä S, Munukka E, Pursiheimo JP,
bacteria associated with childhood celiac disease. Am J Gastroenterol. (2009) et al. Early fecal microbiota composition in children who later develop
104:3058–67. doi: 10.1038/ajg.2009.524 celiac disease and associated autoimmunity. Scand J Gastroenterol. (2018)
82. Verdu EF, Galipeau HJ, Jabri B. Novel players in coeliac disease pathogenesis: 53:403–9. doi: 10.1080/00365521.2018.1444788
role of the gut microbiota. Nat Rev Gastroenterol Hepatol. (2015) 12:497–506. 101. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D,
doi: 10.1038/nrgastro.2015.90 et al. Environment dominates over host genetics in shaping human gut
83. Sanchez E, Donat E, Ribes-Koninckx C, Fernandez-Murga ML, Sanz Y. microbiota. Nature (2018) 555:210–5. doi: 10.1038/nature25973
Duodenal-mucosal bacteria associated with celiac disease in children. Appl 102. Carmody RN, Gerber GK, Luevano JM, Gatti DM, Somes L, Svenson KL,
Environ Microbiol. (2013) 79:5472–9. doi: 10.1128/AEM.00869-13 et al. Diet dominates host genotype in shaping the murine gut microbiota.
84. Pozo-Rubio T, Olivares M, Nova E, De Palma G, M2ujico JR, Ferrer MD, Cell Host Microbe. (2015) 17:72–84. doi: 10.1016/j.chom.2014.11.010
et al. Immune development and intestinal microbiota in celiac disease. Clin 103. Kuja-Halkola R, Lebwohl B, Halfvarson J, Wijmenga C, Magnusson
Dev Immunol. (2012) 2012:654143. doi: 10.1155/2012/654143 PK, Ludvigsson JF. Heritability of non-HLA genetics in coeliac disease:
85. Wacklin P, Laurikka P, Lindfors K, Collin P, Salmi T, Lahdeaho ML, a population-based study in 107 000 twins. Gut (2016) 65:1793–8.
et al. Altered duodenal microbiota composition in celiac disease patients doi: 10.1136/gutjnl-2016-311713
suffering from persistent symptoms on a long-term gluten-free diet. Am J 104. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for
Gastroenterol. (2014) 109:1933–41. doi: 10.1038/ajg.2014.355 a primary association of celiac disease to a particular HLA-DQ alpha/beta
86. Verdu EF, Mauro M, Bourgeois J, Armstrong D. Clinical onset of heterodimer. J Exp Med. (1989) 169:345–50. doi: 10.1084/jem.169.1.345
celiac disease after an episode of Campylobacter jejuni enteritis. Can J 105. Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, et al. HLA
Gastroenterol. (2007) 21:453–5. doi: 10.1155/2007/169591 types in celiac disease patients not carrying the DQA1∗ 05-DQB1∗ 02 (DQ2)
87. Sanchez E, Nadal I, Donat E, Ribes-Koninckx C, Calabuig M, Sanz heterodimer: results from the European genetics cluster on celiac disease.
Y. Reduced diversity and increased virulence-gene carriage in intestinal Human Immunol. (2003) 64:469–77. doi: 10.1016/S0198-8859(03)00027-2
enterobacteria of coeliac children. BMC Gastroenterol. (2008) 8:50. 106. Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, et al.
doi: 10.1186/1471-230X-8-50 The HLA-DQ2 gene dose effect in celiac disease is directly related to the
88. Sanchez E, Ribes-Koninckx C, Calabuig M, Sanz Y. Intestinal Staphylococcus magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad
spp. and virulent features associated with coeliac disease. J Clin Pathol. (2012) Sci USA. (2003) 100:12390–5. doi: 10.1073/pnas.2135229100
65:830–4. doi: 10.1136/jclinpath-2012-200759 107. Liu E, Lee HS, Aronsson CA, Hagopian WA, Koletzko S, Rewers MJ, et al.
89. Sanchez E, Laparra JM, Sanz Y. Discerning the role of Bacteroides fragilis Risk of pediatric celiac disease according to HLA haplotype and country. N
in celiac disease pathogenesis. Appl Environ Microbiol. (2012) 78:6507–15. Engl J Med. (2014) 371:42–9. doi: 10.1056/NEJMoa1313977
doi: 10.1128/AEM.00563-12 108. Liu E, Lee HS, Agardh D. Risk of celiac disease according to HLA haplotype
90. D’Argenio V, Casaburi G, Precone V, Pagliuca C, Colicchio R, Sarnataro and country. N Engl J Med. (2014) 371:1074. doi: 10.1056/NEJMc1409252
D, et al. Metagenomics reveals dysbiosis and a potentially pathogenic n. 109. Karinen H, Karkkainen P, Pihlajamaki J, Janatuinen E, Heikkinen M,
flavescens strain in duodenum of adult celiac patients. Am J Gastroenterol. Julkunen R, et al. Gene dose effect of the DQB1∗ 0201 allele contributes
(2016) 111:879–90. doi: 10.1038/ajg.2016.95 to severity of coeliac disease. Scand J Gastroenterol. (2006) 41:191–9.
91. Aydogdu S, Cakir M, Yuksekkaya HA, Tumgor G, Baran M, Arikan C, doi: 10.1080/00365520500206277
et al. Helicobacter pylori infection in children with celiac disease. Scand J 110. Al-Toma A, Goerres MS, Meijer JW, Pena AS, Crusius JB, Mulder CJ.
Gastroenterol. (2008) 43:1088–93. doi: 10.1080/00365520802101846 Human leukocyte antigen-DQ2 homozygosity and the development of
92. Caminero A, Herrán AR, Nistal E, Pérez-Andrés J, Vaquero L, Vivas refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin
S et al. Diversity of the cultivable human gut microbiome involved Gastroenterol Hepatol. (2006) 4:315–9. doi: 10.1016/j.cgh.2005.12.011
in gluten metabolism: isolation of microorganisms with potential 111. Goel G, King T, Daveson AJ, Andrews JM, Krishnarajah J, Krause R,
interest for coeliac disease. FEMS Microbiol Ecol. (2014) 88:309–19. et al. Epitope-specific immunotherapy targeting CD4-positive T cells
doi: 10.1111/1574-6941.12295 in coeliac disease: two randomised, double-blind, placebo-controlled
93. Caminero A, Nistal E, Herrán AR, Pérez-Andrés J, Ferrero MA, Vaquero phase 1 studies. Lancet Gastroenterol Hepatol. (2017) 2:479–93.
Ayala L et al. Differences in gluten metabolism among healthy volunteers, doi: 10.1016/S2468-1253(17)30110-3

Frontiers in Pediatrics | www.frontiersin.org 15 November 2018 | Volume 6 | Article 350

Tye-Din et al. Current Concepts in Celiac Disease

112. Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, et al. 130. Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L,
Multiple common variants for celiac disease influencing immune gene et al. Tissue transglutaminase selectively modifies gliadin peptides that are
expression. Nat Genet. (2010) 42:295–302. doi: 10.1038/ng.543 recognized by gut-derived T cells in celiac disease. Nat Med. (1998) 4:713–7.
113. van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye doi: 10.1038/nm0698-713
M, et al. A genome-wide association study for celiac disease identifies risk 131. Kim CY, Quarsten H, Bergseng E, Khosla C, Sollid LM. Structural basis for
variants in the region harboring IL2 and IL21. Nat Genet. (2007) 39:827–9. HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc
doi: 10.1038/ng2058 Nat Acad Sci USA. (2004) 101:4175–9. doi: 10.1073/pnas.0306885101
114. Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, 132. Henderson KN, Tye-Din JA, Reid HH, Chen Z, Borg NA, Beissbarth
et al. Newly identified genetic risk variants for celiac disease related to the T, et al. A structural and immunological basis for the role of human
immune response. Nat Genet. (2008) 40:395–402. doi: 10.1038/ng.102 leukocyte antigen DQ8 in celiac disease. Immunity (2007) 27:23–34.
115. Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, et al. doi: 10.1016/j.immuni.2007.05.015
Dense genotyping identifies and localizes multiple common and rare 133. Broughton SE, Petersen J, Theodossis A, Scally SW, Loh KL, Thompson A,
variant association signals in celiac disease. Nat Genet. (2011) 43:1193–201. et al. Biased T cell receptor usage directed against human leukocyte antigen
doi: 10.1038/ng.998 DQ8-restricted gliadin peptides is associated with celiac disease. Immunity
116. Gutierrez-Achury J, Zhernakova A, Pulit SL, Trynka G, Hunt KA, Romanos (2012) 37:611–21. doi: 10.1016/j.immuni.2012.07.013
J, et al. Fine mapping in the MHC region accounts for 18% additional genetic 134. Qiao SW, Raki M, Gunnarsen KS, Loset GA, Lundin KE, Sandlie I, et al.
risk for celiac disease. Nat Genet. (2015) 47:577–8. doi: 10.1038/ng.3268 Posttranslational modification of gluten shapes TCR usage in celiac disease.
117. Sharma A, Liu X, Hadley D, Hagopian W, Liu E, Chen WM, et al. J Immunol. (2011) 187:3064–71. doi: 10.4049/jimmunol.1101526
Identification of Non-HLA genes associated with celiac disease and country- 135. Sollid LM, Qiao SW, Anderson RP, Gianfrani C, Koning F.
specific differences in a large, international pediatric cohort. PLoS ONE Nomenclature and listing of celiac disease relevant gluten T-cell epitopes
(2016) 11:e0152476. doi: 10.1371/journal.pone.0152476 restricted by HLA-DQ molecules. Immunogenetics (2012) 64:455–60.
118. Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, et al. doi: 10.1007/s00251-012-0599-z
Shared and distinct genetic variants in type 1 diabetes and celiac disease. N 136. Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA,
Engl J Med. (2008) 359:2767–77. doi: 10.1056/NEJMoa0807917 Tatham A, et al. Comprehensive, quantitative mapping of T cell
119. Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L, epitopes in gluten in celiac disease. Sci Trans Med. (2010) 2:1–14.
et al. Meta-analysis of genome-wide association studies in celiac disease and doi: 10.1126/scitranslmed.3001012
rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 137. Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, et al. Structural
(2011) 7:e1002004. doi: 10.1371/journal.pgen.1002004 basis for gluten intolerance in celiac sprue. Science (2002) 297:2275–9.
120. Festen EA, Goyette P, Green T, Boucher G, Beauchamp C, Trynka G, et al. A doi: 10.1126/science.1074129
meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, 138. Vader W, Kooy Y, Van Veelen P, De Ru A, Harris D, Benckhuijsen W,
TAGAP, and PUS10 as shared risk loci for Crohn’s disease and celiac disease. et al. The gluten response in children with celiac disease is directed toward
PLoS Genet. (2011) 7:e1001283. doi: 10.1371/journal.pgen.1001283 multiple gliadin and glutenin peptides. Gastroenterology (2002) 122:1729–37.
121. Castellanos-Rubio A, Fernandez-Jimenez N, Kratchmarov R, Luo X, Bhagat doi: 10.1053/gast.2002.33606
G, Green PH, et al. A long noncoding RNA associated with susceptibility to 139. Hardy MY, Girardin A, Pizzey C, Cameron DJ, Watson KA, Picascia S,
celiac disease. Science (2016) 352:91–5. doi: 10.1126/science.aad0467 et al. Consistency in polyclonal T-cell responses to gluten between children
122. Lundin KE, Scott H, Hansen T, Paulsen G, Halstensen TS, Fausa O, and adults with celiac disease. Gastroenterology (2015) 149:1541–52 e2.
et al. Gliadin-specific, HLA-DQ(alpha 1∗ 0501,beta 1∗ 0201) restricted T cells doi: 10.1053/j.gastro.2015.07.013
isolated from the small intestinal mucosa of celiac disease patients. J Exp 140. Raki M, Dahal-Koirala S, Yu H, Korponay-Szabo IR, Gyimesi J, Castillejo
Med. (1993) 178:187–96. doi: 10.1084/jem.178.1.187 G, et al. Similar responses of intestinal T cells from untreated children and
123. Nilsen EM, Lundin KE, Krajci P, Scott H, Sollid LM, Brandtzaeg P. Gluten adults with celiac disease to deamidated gluten epitopes. Gastroenterology
specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines (2017) 153:787–98 e4. doi: 10.1053/j.gastro.2017.05.016
with Th1 or Th0 profile dominated by interferon gamma. Gut (1995) 141. Yohannes DA, Freitag TL, de Kauwe A, Kaukinen K, Kurppa K, Wacklin P,
37:766–76. doi: 10.1136/gut.37.6.766 et al. Deep sequencing of blood and gut T-cell receptor beta-chains reveals
124. Molberg O, Kett K, Scott H, Thorsby E, Sollid LM, Lundin KE. Gliadin gluten-induced immune signatures in celiac disease. Sci Rep. (2017) 7:17977.
specific, HLA DQ2-restricted T cells are commonly found in small intestinal doi: 10.1038/s41598-017-18137-9
biopsies from coeliac disease patients, but not from controls. Scand J 142. Risnes LF, Christophersen A, Dahal-Koirala S, Neumann RS, Sandve GK,
Immunol. (1997) 46:103–8. Sarna VK, et al. Disease-driving CD4+ T cell clonotypes persist for decades
125. Lundin KE, Scott H, Fausa O, Thorsby E, Sollid LM. T cells from the in celiac disease. J Clin Invest. (2018) 128:2642–50. doi: 10.1172/JCI98819
small intestinal mucosa of a DR4, DQ7/DR4, DQ8 celiac disease patient 143. Syage JA, Kelly CP, Dickason MA, Ramirez AC, Leon F, Dominguez R,
preferentially recognize gliadin when presented by DQ8. Human Immunol. et al. Determination of gluten consumption in celiac disease patients on
(1994) 41:285–91. doi: 10.1016/0198-8859(94)90047-7 a gluten-free diet. Am J Clin Nutr. (2018) 107:201–7. doi: 10.1093/ajcn/
126. Fleckenstein B, Molberg O, Qiao SW, Schmid DG, von der Mulbe F, nqx049
Elgstoen K, et al. Gliadin T cell epitope selection by tissue transglutaminase 144. Halmos EP, Di Bella CA, Webster R, Deng M, Tye-Din JA. Gluten in “gluten-
in celiac disease. role of enzyme specificity and pH influence on the free” food from food outlets in Melbourne: a cross-sectional study. Med J
transamidation versus deamidation process. J Biol Chem. (2002) 277:34109– Aust. (2018) 209:42–3. doi: 10.5694/mja17.00883
16. doi: 10.1074/jbc.M204521200 145. Di Simone N, Silano M, Castellani R, Di Nicuolo F, D’Alessio MC, Franceschi
127. Vader LW, de Ru AY. van der Wal, Kooy YM, Benckhuijsen W, F, et al. Anti-tissue transglutaminase antibodies from celiac patients are
Mearin ML, Drijfhout JW, et al. Specificity of tissue transglutaminase responsible for trophoblast damage via apoptosis in vitro. Am J Gastroenterol.
explains cereal toxicity in celiac disease. J Exp Med. (2002) 195:643–9. (2010) 105:2254–61. doi: 10.1038/ajg.2010.233
doi: 10.1084/jem.20012028 146. Salmi TT, Collin P, Jarvinen O, Haimila K, Partanen J, Laurila K, et al.
128. Quarsten H, Molberg O, Fugger L, McAdam SN, Sollid LM. HLA binding Immunoglobulin a autoantibodies against transglutaminase 2 in the small
and T cell recognition of a tissue transglutaminase-modified gliadin intestinal mucosa predict forthcoming coeliac disease. Aliment Pharmacol
epitope. Eur J Immunol. (1999) 29:2506–14. doi: 10.1002/(SICI)1521- Ther. (2006) 24:541–52. doi: 10.1111/j.1365-2036.2006.02997.x
4141(199908)29:08<2506::AID-IMMU2506>3.0.CO;2-9 147. Simell S, Kupila A, Hoppu S, Hekkala A, Simell T, Stahlberg MR, et al. Natural
129. van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, history of transglutaminase autoantibodies and mucosal changes in children
et al. Selective deamidation by tissue transglutaminase strongly enhances carrying HLA-conferred celiac disease susceptibility. Scand J Gastroenterol.
gliadin-specific T cell reactivity. J Immunol. (1998) 161:1585–8. (2005) 40:1182–91. doi: 10.1080/00365520510024034

Frontiers in Pediatrics | www.frontiersin.org 16 November 2018 | Volume 6 | Article 350

Tye-Din et al. Current Concepts in Celiac Disease

148. Matysiak-Budnik T, Malamut G, de Serre NP, Grosdidier E, Seguier S, 167. Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-
Brousse N, et al. Long-term follow-up of 61 coeliac patients diagnosed in Fourt I, Verkarre V, et al. IL-15 triggers an antiapoptotic pathway in
childhood: evolution toward latency is possible on a normal diet. Gut (2007) human intraepithelial lymphocytes that is a potential new target in celiac
56:1379–86. doi: 10.1136/gut.2006.100511 disease-associated inflammation and lymphomagenesis. J Clin Invest. (2010)
149. Sollid LM, Molberg O, McAdam S, Lundin KE. Autoantibodies in coeliac 120:2131–43. doi: 10.1172/JCI41344
disease: tissue transglutaminase–guilt by association? Gut (1997) 41:851–2. 168. Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, et al.
doi: 10.1136/gut.41.6.851 Coordinated induction by IL15 of a TCR-independent NKG2D signaling
150. Koning F. Celiac disease: caught between a rock and a hard place. pathway converts CTL into lymphokine-activated killer cells in celiac disease.
Gastroenterology (2005) 129:1294–301. doi: 10.1053/j.gastro.2005.07.030 Immunity (2004) 21:357–66. doi: 10.1016/j.immuni.2004.06.020
151. Di Niro R, Snir O, Kaukinen K, Yaari G, Lundin KE, Gupta NT, et al. 169. Setty M, Discepolo V, Abadie V, Kamhawi S, Mayassi T, Kent A, et al.
Responsive population dynamics and wide seeding into the duodenal lamina Distinct and synergistic contributions of epithelial stress and adaptive
propria of transglutaminase-2-specific plasma cells in celiac disease. Mucosal immunity to functions of intraepithelial killer cells and active celiac disease.
Immunol. (2016) 9:254–64. doi: 10.1038/mi.2015.57 Gastroenterology (2015) 149:681–91 e10. doi: 10.1053/j.gastro.2015.05.013
152. Stamnaes J, Iversen R, du Pre MF, Chen X, Sollid LM. Enhanced 170. Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S,
B-cell receptor recognition of the autoantigen transglutaminase 2 by et al. Association between innate response to gliadin and activation
efficient catalytic self-multimerization. PLoS ONE (2015) 10:e0134922. of pathogenic T cells in coeliac disease. Lancet (2003) 362:30–7.
doi: 10.1371/journal.pone.0134922 doi: 10.1016/S0140-6736(03)13803-2
153. Iversen RM, Fleur du PreM, Di Niro R, Sollid LM. Igs as substrates 171. Hmida NB, Ben Ahmed M, Moussa A, Rejeb MB, Said Y, Kourda N, et al.
for transglutaminase 2: implications for autoantibody production in celiac Impaired control of effector T cells by regulatory T cells: a clue to loss of oral
disease. J Immunol. (2015) 195:5159–68. doi: 10.4049/jimmunol.1501363 tolerance and autoimmunity in celiac disease? Am J Gastroenterol. (2012)
154. Stamnaes J, Sollid LM. Celiac disease: autoimmunity in response to food 107:604–11. doi: 10.1038/ajg.2011.397
antigen. Semin Immunol. (2015) 27:343–52. doi: 10.1016/j.smim.2015.11.001 172. Granzotto M, dal Bo S, Quaglia S, Tommasini A, Piscianz E, Valencic E, et al.
155. Steinsbo O, Henry Dunand CJ, Huang M, Mesin L, Salgado-Ferrer M, Regulatory T-cell function is impaired in celiac disease. Dig Dis Sci. (2009)
Lundin KE, et al. Restricted VH/VL usage and limited mutations in gluten- 54:1513–9. doi: 10.1007/s10620-008-0501-x
specific IgA of coeliac disease lesion plasma cells. Nat Commun. (2014) 173. Cook L, Munier CML, Seddiki N, van Bockel D, Ontiveros N, Hardy MY,
5:4041. doi: 10.1038/ncomms5041 et al. Circulating gluten-specific FOXP3(+)CD39(+) regulatory T cells have
156. Arentz-Hansen H, McAdam SN, Molberg O, Fleckenstein B, Lundin KE, impaired suppressive function in patients with celiac disease. J Allergy Clin
Jorgensen TJ, et al. Celiac lesion T cells recognize epitopes that cluster in Immunol. (2017) 140:1592–603 e8. doi: 10.1016/j.jaci.2017.02.015
regions of gliadins rich in proline residues. Gastroenterology (2002) 123:803– 174. Frisullo G, Nociti V, Iorio R, Patanella AK, Marti A, Assunta B, et al.
9. doi: 10.1053/gast.2002.35381 Increased CD4+CD25+Foxp3+ T cells in peripheral blood of celiac disease
157. Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, Lebreton C, Menard S, patients: correlation with dietary treatment. Hum Immunol. (2009) 70:430–5.
Candalh C, et al. Secretory IgA mediates retrotranscytosis of intact gliadin doi: 10.1016/j.humimm.2009.04.006
peptides via the transferrin receptor in celiac disease. J Exp Med. (2008) 175. Zanzi D, Stefanile R, Santagata S, Iaffaldano L, Iaquinto G, Giardullo N,
205:143–54. doi: 10.1084/jem.20071204 et al. IL-15 interferes with suppressive activity of intestinal regulatory T
158. Lebreton C, Menard S, Abed J, Moura IC, Coppo R, Dugave C, cells expanded in Celiac disease. Am J Gastroenterol. (2011) 106:1308–17.
et al. Interactions among secretory immunoglobulin A, CD71, doi: 10.1038/ajg.2011.80
and transglutaminase-2 affect permeability of intestinal epithelial 176. Benahmed M, Meresse B, Arnulf B, Barbe U, Mention JJ, Verkarre V,
cells to gliadin peptides. Gastroenterology (2012) 143:698–707.e4. et al. Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in
doi: 10.1053/j.gastro.2012.05.051 the loss of immune homeostasis in celiac disease. Gastroenterology (2007)
159. Rauhavirta T, Qiao SW, Jiang Z, Myrsky E, Loponen J, Korponay-Szabo 132:994–1008. doi: 10.1053/j.gastro.2006.12.025
IR, et al. Epithelial transport and deamidation of gliadin peptides: a role 177. Forsberg G, Hernell O, Melgar S, Israelsson A, Hammarstrom S,
for coeliac disease patient immunoglobulin A. Clin Exp Immunol. (2011) Hammarstrom ML. Paradoxical coexpression of proinflammatory and
164:127–36. doi: 10.1111/j.1365-2249.2010.04317.x down-regulatory cytokines in intestinal T cells in childhood celiac disease.
160. Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, et al. Gliadin Gastroenterology (2002) 123:667–78. doi: 10.1053/gast.2002.35355
induces an increase in intestinal permeability and zonulin release by binding 178. Di Sabatino A, Ciccocioppo R, Cupelli F, Cinque B, Millimaggi D, Clarkson
to the chemokine receptor CXCR3. Gastroenterology (2008) 135:194–204 e3. MM, et al. Epithelium derived interleukin 15 regulates intraepithelial
doi: 10.1053/j.gastro.2008.03.023 lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac
161. Beitnes AC, Raki M, Brottveit M, Lundin KE, Jahnsen FL, Sollid LM. disease. Gut (2006) 55:469–77. doi: 10.1136/gut.2005.068684
Rapid accumulation of CD14+CD11c+ dendritic cells in gut mucosa of 179. Maiuri L, Ciacci C, Vacca L, Ricciardelli I, Auricchio S, Quaratino
celiac disease after in vivo gluten challenge. PLoS ONE (2012) 7:e33556. S, et al. IL-15 drives the specific migration of CD94+ and TCR-
doi: 10.1371/journal.pone.0033556 gammadelta+ intraepithelial lymphocytes in organ cultures of treated celiac
162. Bodd M, Raki M, Tollefsen S, Fallang LE, Bergseng E, Lundin KE, et al. HLA- patients. Am J Gastroenterol. (2001) 96:150–6. doi: 10.1111/j.1572-0241.2001.
DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. 03437.x
Mucosal Immunol. (2010) 3:594–601. doi: 10.1038/mi.2010.36 180. Korneychuk N, Ramiro-Puig E, Ettersperger J, Schulthess J, Montcuquet N,
163. Monteleone I, Sarra MG, Del Vecchio Blanco G, Paoluzi OA, Franze E, Fina Kiyono H, et al. Interleukin 15 and CD4(+) T cells cooperate to promote
D, et al. Characterization of IL-17A-producing cells in celiac disease mucosa. small intestinal enteropathy in response to dietary antigen. Gastroenterology
J Immunol. (2010) 184:2211–8. doi: 10.4049/jimmunol.0901919 (2014) 146:1017–27. doi: 10.1053/j.gastro.2013.12.023
164. Fernandez S, Molina IJ, Romero P, Gonzalez R, Pena J, Sanchez F, 181. Vicari AP, Schoepfer AM, Meresse B, Goffin L, Leger O, Josserand
et al. Characterization of gliadin-specific Th17 cells from the mucosa S, et al. Discovery and characterization of a novel humanized anti-
of celiac disease patients. Am J Gastroenterol. (2011) 106:528–38. IL-15 antibody and its relevance for the treatment of refractory
doi: 10.1038/ajg.2010.465 celiac disease and eosinophilic esophagitis. MAbs (2017) 9:927–44.
165. DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, et al. Co- doi: 10.1080/19420862.2017.1332553
adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to 182. Quinn EM, Coleman C, Molloy B, Dominguez Castro P, Cormican P,
dietary antigens. Nature (2011) 471:220–4. doi: 10.1038/nature09849 Trimble V, et al. Transcriptome Analysis of CD4+ T Cells in coeliac disease
166. Monteleone G, Pender SL, Alstead E, Hauer AC, Lionetti P, McKenzie reveals imprint of BACH2 and IFNgamma regulation. PLoS ONE (2015)
C, et al. Role of interferon alpha in promoting T helper cell type 1 10:e0140049. doi: 10.1371/journal.pone.0140049
responses in the small intestine in coeliac disease. Gut (2001) 48:425–9. 183. de Kauwe AL, Chen Z, Anderson RP, Keech CL, Price JD, Wijburg O,
doi: 10.1136/gut.48.3.425 et al. Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic

Frontiers in Pediatrics | www.frontiersin.org 17 November 2018 | Volume 6 | Article 350

Tye-Din et al. Current Concepts in Celiac Disease

mice expressing specific anti-gliadin CD4+ T cells. J Immunol. (2009) patients than biopsy after 14-day gluten challenge. Gut (2018) 67:1606–13.
182:7440–50. doi: 10.4049/jimmunol.0900233 doi: 10.1136/gutjnl-2017-314461
184. Korneychuk N, Meresse B, Cerf-Bensussan N. Lessons from 202. Bruins MJ. The clinical response to gluten challenge: a review of the
rodent models in celiac disease. Mucosal Immunol. (2015) 8:18–28. literature. Nutrients (2013) 5:4614–41. doi: 10.3390/nu5114614
doi: 10.1038/mi.2014.102 203. Raki M, Fallang LE, Brottveit M, Bergseng E, Quarsten H, Lundin KE, et al.
185. Freitag TL, Loponen J, Messing M, Zevallos V, Andersson LC, Sontag- Tetramer visualization of gut-homing gluten-specific T cells in the peripheral
Strohm T, et al. Testing safety of germinated rye sourdough in a celiac blood of celiac disease patients. Proc Natl Acad Sci USA. (2007) 104:2831–6.
disease model based on the adoptive transfer of prolamin-primed memory doi: 10.1073/pnas.0608610104
T cells into lymphopenic mice. Am J Physiol. (2014) 306:G526–34. 204. Ontiveros N, Tye-Din JA, Hardy MY, Anderson RP. Ex-vivo whole blood
doi: 10.1152/ajpgi.00136.2013 secretion of interferon (IFN)-gamma and IFN-gamma-inducible protein-
186. Freitag TL, Rietdijk S, Junker Y, Popov Y, Bhan AK, Kelly CP, et al. 10 measured by enzyme-linked immunosorbent assay are as sensitive as
Gliadin-primed CD4+CD45RBlowCD25- T cells drive gluten-dependent IFN-gamma enzyme-linked immunospot for the detection of gluten-reactive
small intestinal damage after adoptive transfer into lymphopenic mice. Gut T cells in human leucocyte antigen (HLA)-DQ2.5(+) -associated coeliac
(2009) 58:1597–605. doi: 10.1136/gut.2009.186361 disease. Clin Exp Immunol. (2014) 175:305–15. doi: 10.1111/cei.12232
187. Black KE, Murray JA, David CS. HLA-DQ determines the response 205. Picascia S, Mandile R, Auricchio R, Troncone R, Gianfrani C. Gliadin-
to exogenous wheat proteins: a model of gluten sensitivity in Specific T-cells mobilized in the peripheral blood of coeliac patients by short
transgenic knockout mice. J Immunol. (2002) 169:5595–600. oral gluten challenge: clinical applications. Nutrients (2015) 7:10020–31.
doi: 10.4049/jimmunol.169.10.5595 doi: 10.3390/nu7125515
188. Galipeau HJ, Rulli NE, Jury J, Huang X, Araya R, Murray JA, et al. 206. Sarna VK, Lundin KE A, Morkrid L, Qiao SW, Sollid LM, Christophersen A.
Sensitization to gliadin induces moderate enteropathy and insulitis HLA-DQ-gluten tetramer blood test accurately identifies patients with and
in nonobese diabetic-DQ8 mice. J Immunol. (2011) 187:4338–46. without celiac disease in absence of gluten consumption. Gastroenterology
doi: 10.4049/jimmunol.1100854 (2018) 154:886–96 e6. doi: 10.1053/j.gastro.2017.11.006
189. Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, et al. 207. Catassi C, Fabiani E, Iacono G, D’Agate C, Francavilla R, Biagi F, et al. A
Gliadin-dependent neuromuscular and epithelial secretory responses in prospective, double-blind, placebo-controlled trial to establish a safe gluten
gluten-sensitive HLA-DQ8 transgenic mice. Am J Physiol. (2008) 294:G217– threshold for patients with celiac disease. Am J Clin Nutr. (2007) 85:160–6.
25. doi: 10.1152/ajpgi.00225.2007 doi: 10.1093/ajcn/85.1.160
190. Galipeau HJ, McCarville JL, Huebener S, Litwin O, Meisel M, 208. Bardella MT, Velio P, Cesana BM, Prampolini L, Casella G, Di Bella C,
Jabri B, et al. Intestinal microbiota modulates gluten-induced et al. Coeliac disease: a histological follow-up study. Histopathology (2007)
immunopathology in humanized mice. Am J Pathol. (2015) 185:2969–82. 50:465–71. doi: 10.1111/j.1365-2559.2007.02621.x
doi: 10.1016/j.ajpath.2015.07.018 209. Newnham ED, Shepherd SJ, Strauss BJ, Hosking P, Gibson PR. Adherence
191. Silano M, Agostoni C, Sanz Y, Guandalini S. Infant feeding and risk of to the gluten-free diet can achieve the therapeutic goals in almost all
developing celiac disease: a systematic review. BMJ Open (2016) 6:e009163. patients with coeliac disease: a 5-year longitudinal study from diagnosis. J
doi: 10.1136/bmjopen-2015-009163 Gastroenterol Hepatol. (2016) 31:342–9. doi: 10.1111/jgh.13060
192. Taavela J, Koskinen O, Huhtala H, Lahdeaho ML, Popp A, Laurila 210. Rubio-Tapia A, Rahim MW, See JA, Lahr BD, Wu TT, Murray JA.
K, et al. Validation of morphometric analyses of small-intestinal Mucosal recovery and mortality in adults with celiac disease after
biopsy readouts in celiac disease. PLoS ONE (2013) 8:e76163. treatment with a gluten-free diet. Am J Gastroenterol. (2010) 105:1412–20.
doi: 10.1371/journal.pone.0076163 doi: 10.1038/ajg.2010.10
193. Arguelles-Grande C, Tennyson CA, Lewis SK, Green PH, Bhagat G. 211. Wahab PJ, Meijer JW, Mulder CJ. Histologic follow-up of people with celiac
Variability in small bowel histopathology reporting between different disease on a gluten-free diet: slow and incomplete recovery. Am J Clin Pathol.
pathology practice settings: impact on the diagnosis of coeliac disease. J Clin (2002) 118:459–63. doi: 10.1309/EVXT-851X-WHLC-RLX9
Pathol. (2012) 65:242–7. doi: 10.1136/jclinpath-2011-200372 212. Lanzini A, Lanzarotto F, Villanacci V, Mora A, Bertolazzi S, Turini
194. Corazza GR, Villanacci V, Zambelli C, Milione M, Luinetti O, Vindigni D, et al. Complete recovery of intestinal mucosa occurs very rarely in
C, et al. Comparison of the interobserver reproducibility with different adult coeliac patients despite adherence to gluten-free diet. Aliment
histologic criteria used in celiac disease. Clin Gastroenterol Hepatol. (2007) Pharmacol Ther. (2009) 29:1299–308. doi: 10.1111/j.1365-2036.2009.
5:838–43. doi: 10.1016/j.cgh.2007.03.019 03992.x
195. Villanacci V, Ceppa P, Tavani E, Vindigni C, Volta U. Coeliac disease: 213. Lebwohl B, Murray JA, Rubio-Tapia A, Green PH, Ludvigsson JF. Predictors
the histology report. Dig Liver Dis. (2011) 43 (Suppl. 4):S385–95. of persistent villous atrophy in coeliac disease: a population-based study.
doi: 10.1016/S1590-8658(11)60594-X Aliment Pharmacol Ther. (2014) 39:488–95. doi: 10.1111/apt.12621
196. Kurppa K, Collin P, Viljamaa M, Haimila K, Saavalainen P, Partanen 214. Leonard MM, Weir DC, DeGroote M, Mitchell PD, Singh P, Silvester JA,
J, et al. Diagnosing mild enteropathy celiac disease: a randomized, et al. Value of IgA tTG in predicting mucosal recovery in children with celiac
controlled clinical study. Gastroenterology (2009) 136:816–23. disease on a gluten-free diet. J Pediatr Gastroenterol Nutr. (2017) 64:286–291.
doi: 10.1053/j.gastro.2008.11.040 doi: 10.1097/MPG.0000000000001460
197. Mooney PD, Kurien M, Evans KE, Rosario E, Cross SS, Vergani P, 215. Ludvigsson JF, Ciacci C, Green PH, Kaukinen K, Korponay-Szabo IR,
et al. Clinical and immunologic features of ultra-short celiac disease. Kurppa K, et al. Outcome measures in coeliac disease trials: the tampere
Gastroenterology (2016) 150:1125–34. doi: 10.1053/j.gastro.2016.01.029 recommendations. Gut (2018) 67:1410–24. doi: 10.1136/gutjnl-2017-314853
198. Anderson RP, Henry MJ, Taylor R, Duncan EL, Danoy P, Costa MJ, et al. 216. Moreno ML, Rodriguez-Herrera A, Sousa C, Comino I. Biomarkers to
A novel serogenetic approach determines the community prevalence of monitor gluten-free diet compliance in celiac patients. Nutrients (2017) 9:46.
celiac disease and informs improved diagnostic pathways. BMC Med. (2013) doi: 10.3390/nu9010046
11:1–13. doi: 10.1186/1741-7015-11-188 217. Comino I, Fernandez-Banares F, Esteve M, Ortigosa L, Castillejo G,
199. Tanpowpong P, Ingham TR, Lampshire PK, Kirchberg FF, Epton MJ, Crane Fambuena B, et al. Fecal gluten peptides reveal limitations of serological
J, et al. Coeliac disease and gluten avoidance in New Zealand children. Arch tests and food questionnaires for monitoring gluten-free diet in celiac
Dis Child. (2012) 97:12–6. doi: 10.1136/archdischild-2011-300248 disease patients. Am J Gastroenterol. (2016) 111:1456–65. doi: 10.1038/ajg.20
200. Leffler D, Schuppan D, Pallav K, Najarian R, Goldsmith JD, Hansen J, 16.439
et al. Kinetics of the histological, serological and symptomatic responses 218. Moreno ML, Cebolla A, Munoz-Suano A, Carrillo-Carrion C, Comino
to gluten challenge in adults with coeliac disease. Gut (2013) 62:996–1004. I, Pizarro A, et al. Detection of gluten immunogenic peptides in the
doi: 10.1136/gutjnl-2012-302196 urine of patients with coeliac disease reveals transgressions in the
201. Sarna VK, Skodje GI, Reims HM, Risnes LF, Dahal-Koirala S, Sollid LM, gluten-free diet and incomplete mucosal healing. Gut (2017) 66:250–7.
et al. HLA-DQ:gluten tetramer test in blood gives better detection of coeliac doi: 10.1136/gutjnl-2015-310148

Frontiers in Pediatrics | www.frontiersin.org 18 November 2018 | Volume 6 | Article 350

Tye-Din et al. Current Concepts in Celiac Disease

219. Kurada S, Yadav A, Leffler DA. Current and novel therapeutic strategies 230. Juhász A, Belova T, Florides C, Maulis C, Fischer I, Gell G, et al. Genome
in celiac disease. Expert Rev Clin Pharmacol. (2016) 9:1211–23. mapping of seed borne allergens and immune-responsive proteins in wheat.
doi: 10.1080/17512433.2016.1200463 Sci Adv. (2018) 4:eaar8602. doi: 10.1126/sciadv.aar8602
220. Tye-Din JA, Anderson RP, Ffrench RA, Brown GJ, Hodsman P, Siegel M, 231. Galipeau HJ, Wiepjes M, Motta JP, Schulz JD, Jury J, Natividad JM, et al.
et al. The effects of ALV003 pre-digestion of gluten on immune response Novel role of the serine protease inhibitor elafin in gluten-related disorders.
and symptoms in celiac disease in vivo. Clin Immunol. (2010) 134:289–95. Am J Gastroenterol. (2014) 109:748–56. doi: 10.1038/ajg.2014.48
doi: 10.1016/j.clim.2009.11.001 232. Syage JA, Murray JA, Green PH R, Khosla C. Latiglutenase improves
221. Lahdeaho ML, Kaukinen K, Laurila K, Vuotikka P, Koivurova OP, Karja- symptoms in seropositive celiac disease patients while on a gluten-free diet.
Lahdensuu T, et al. Glutenase ALV003 attenuates gluten-induced mucosal Dig Dis Sci. (2017) 62:2428–32. doi: 10.1007/s10620-017-4687-7
injury in patients with celiac disease. Gastroenterology (2014) 146:1649–58. 233. Anderson RP, Jabri B. Vaccine against autoimmune disease: antigen-
doi: 10.1053/j.gastro.2014.02.031 specific immunotherapy. Curr Opin Immunol. (2013) 25:410–7.
222. Tack GJ, van de Water JM, Bruins MJ, Kooy-Winkelaar EM, van Bergen doi: 10.1016/j.coi.2013.02.004
J, Bonnet P, Vreugdenhil AC, et al. Consumption of gluten with gluten- 234. Daveson AJM, Ee HC, Andrews JM, King T, Goldstein KE, Dzuris JL, et al.
degrading enzyme by celiac patients: a pilot-study. World J Gastroenterol. Epitope-specific immunotherapy targeting CD4-Positive T Cells in celiac
(2013) 19:5837–47. doi: 10.3748/wjg.v19.i35.5837 disease: safety, pharmacokinetics, and effects on intestinal histology and
223. Kelly CP, Green PH, Murray JA, Dimarino A, Colatrella A, Leffler plasma cytokines with escalating dose regimens of nexvax2 in a randomized,
DA, et al. Larazotide acetate celiac disease study: larazotide acetate in double-blind, placebo-controlled phase 1 study. EBioMedicine (2017) 26:78–
patients with coeliac disease undergoing a gluten challenge: a randomised 90. doi: 10.1016/j.ebiom.2017.11.018
placebo-controlled study. Aliment Pharmacol Ther. (2013) 37:252–62. 235. Croese J, Giacomin P, Navarro S, Clouston A, McCann L, Dougall A,
doi: 10.1111/apt.12147 et al. Experimental hookworm infection and gluten microchallenge promote
224. Leffler DA, Kelly CP, Abdallah HZ, Colatrella AM, Harris LA, Leon F, tolerance in celiac disease. J Allergy Clini Immunol. (2015) 135:508–16.
et al. A randomized, double-blind study of larazotide acetate to prevent doi: 10.1016/j.jaci.2014.07.022
the activation of celiac disease during gluten challenge. Am J Gastroenterol.
(2012) 107:1554–62. doi: 10.1038/ajg.2012.211 Conflict of Interest Statement: JT-D has served as a consultant and scientific
225. Leffler DA, Kelly CP, Green PH, Fedorak RN, DiMarino A, Perrow W, et al. advisory board member for ImmusanT Inc., USA, and owns shares in Nexpep Pty
Larazotide acetate for persistent symptoms of celiac disease despite a gluten- Ltd and is a co-inventor of patents pertaining to the use of gluten peptides in CeD
free diet: a randomized controlled trial. Gastroenterology (2015) 148:1311–9 therapeutics, diagnostics and nontoxic gluten. Nexpep Pty. Ltd. and ImmusanT
e6. doi: 10.1053/j.gastro.2015.02.008 Inc. were formed to develop novel diagnostics and treatments for CeD. DA has
226. McCarville JL, Nisemblat Y, Galipeau HJ, Jury J, Tabakman R, Cohen A, served as principal investigator for probiotic studies in collaboration with Probi
et al. BL-7010 demonstrates specific binding to gliadin and reduces gluten- AB, Lund, Sweden, and is the co-inventor of patents pertaining to the use of L.
associated pathology in a chronic mouse model of gliadin sensitivity. PLoS plantarum (strain HEAL9) and L. paracasei (strain 8700:2) in CeD.
ONE (2014) 9:e109972. doi: 10.1371/journal.pone.0109972
227. Gianfrani C, Siciliano RA, Facchiano AM, Camarca A, Mazzeo MF, The remaining authors declare that the research was conducted in the absence of
Costantini S, et al. Transamidation of wheat flour inhibits the response any commercial or financial relationships that could be construed as a potential
to gliadin of intestinal T cells in celiac disease. Gastroenterology (2007) conflict of interest.
133:780–9. doi: 10.1053/j.gastro.2007.06.023
228. Gil-Humanes J, Piston F, Tollefsen S, Sollid LM, Barro F. Effective Copyright © 2018 Tye-Din, Galipeau and Agardh. This is an open-access article
shutdown in the expression of celiac disease-related wheat gliadin T-cell distributed under the terms of the Creative Commons Attribution License (CC BY).
epitopes by RNA interference. Proc Natl Acad Sci USA. (2010) 107:17023–8. The use, distribution or reproduction in other forums is permitted, provided the
doi: 10.1073/pnas.1007773107 original author(s) and the copyright owner(s) are credited and that the original
229. Sanchez-Leon S, Gil-Humanes J, Ozuna CV, Gimenez MJ, Sousa C, Voytas publication in this journal is cited, in accordance with accepted academic practice.
DF, et al. Low-gluten, nontransgenic wheat engineered with CRISPR/Cas9. No use, distribution or reproduction is permitted which does not comply with these
Plant Biotechnol J. (2018) 16:902–10. doi: 10.1111/pbi.12837 terms.

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