EFFECTOR MECHANISM OF HUMORAL

IMMUNITY
CHAPTER 13
OUTLINE CHAPTER 13
• OVERVIEW
• NEUTRALIZATION OF MICROBES AND
MICROBIAL TOXINS
• ANTIBODY-MEDIATED OPSONIZATION AND
PHAGOCYTOSIS
• THE COMPLEMENT SYSTEM
• NEONATAL IMMUNITY
• Humoral immunity is mediated by secreted antibodies, and its physiologic function is
defense against extracellular microbes and microbial toxins
• Humoral immunity is the form of immunity that can be transferred from immunized to
naive individuals with serum.
• The types of microorganisms that are combated by humoral immunity are extracellular
bacteria, fungi, and even obligate intracellular microbes such as viruses, which are
targets of antibodies before they infect cells or when they are released from infected cells
OVERVIEW OF HUMORAL IMMUNITY
The main functions of antibodies are to neutralize and
eliminate infectious microbes and microbial toxins

antibody-mediated elimination of antigens involves a number of

effector mechanisms and requires the participation of
various cellular and humoral components of the immune system,
including phagocytes and complement proteins.
Antibodies are produced by plasma cells in secondary lymphoid organs and
bone marrow, and antibodies perform their effector functions at sites distant
from their production.
• Antibodies produced in the lymph nodes, spleen, and bone marrow may
enter the blood and then circulate throughout the body
• Antibodies produced in mucosa-associated lymphoid tissues are transported
across epithelial barriers into the lumens of mucosal organs, such as the
intestine and the airways, where these secreted antibodies block the entry of
ingested and inhaled microbes
• Antibodies are also actively transported across the placenta into the circulation
of the developing fetus.
• Occasionally, antibodies may be produced in peripheral non-lymphoid tissues, at
sites of infection or chronic inflammation
• In cell-mediated immunity, activated T lymphocytes are able to migrate to
peripheral sites of infection and inflammation, but they are not transported into
mucosal secretions or across the placenta
The antibodies that mediate protective immunity may be derived from
short-lived or long-lived antibody-producing plasma cells
• 1st exposure to antigen activation of naive B lymphocytes
(differentiation)
Antibody-secreting plasma cell & memory cell
• Subsequent exposure to the same antigens activation of memory B cells and
larger and more rapid antibody response
• Plasma cells generated early in an immune response or from marginal zone B cells or B-1
cells in T-independent immune responses tend to be shortlived. In contrast, class-
switched, high-affinity antibodysecreting plasma cells, which are produced in germinal
centers during T-dependent responses to protein antigens, migrate to the bone marrow
and persist at this site, where they continue to produce antibodies for years after the
antigen is eliminated.
Many of the effector functions of antibodies are mediated by the heavy chain constant
regions of Ig molecules, and different Ig heavy chain isotypes serve distinct effector
functions
Although many effector functions of antibodies are mediated by the Ig
heavy chain constant regions, all these functions are triggered by the
binding of antigens to the variable regions
• The binding of antibodies to a multivalent antigen, such as a polysaccharide
or a repeated epitope on a microbial surface, brings the Fc regions of
antibodies close together, and this clustering of antibody molecules leads to
complement activation and allows the antibodies to bind to and activate Fc
receptors on phagocytes
• The requirement for antigen binding ensures that antibodies activate various
effector mechanisms only when they are needed, that is, when the antibodies
encounter and specifically bind antigens, not when the antibodies are
circulating in an antigen-free form
NEUTRALIZATION OF MICROBES AND MICROBIAL
TOXINS
ANTIBODY-MEDIATED OPSONIZATION AND
PHAGOCYTOSIS
• Mononuclear phagocytes and neutrophils ingest microbes as a prelude to intracellular
killing and degradation. These phagocytes express a variety of surface receptors that
directly bind microbes and ingest them, even without antibodies, providing one
mechanism of innate immunity
• The efficiency of this process is markedly enhanced if the phagocyte can bind the particle
with high affinity. Mononuclear phagocytes and neutrophils express receptors for the Fc
portions of IgG antibodies that specifically bind antibody-coated particles
• Leukocyte Fc Receptors
Leukocytes express Fc receptors that bind to the constant regions of antibodies, and thereby
promote the phagocytosis of Ig-coated particles and deliver signals that regulate the activities
of the leukocytes; other Fc receptors mediate the transport of antibodies to various sites
Fcγ receptors have been classified into three groups, I, II and III, based on their affinities for
heavy chains of different IgG subclasses. Different Fc receptors are also expressed on different
cell type
Role of Fcγ Receptors in Phagocytosis and Activation of Phagocytes
Binding of Fc receptors on phagocytes to multivalent antibody-coated particles leads to
engulfment of the particles and the activation of phagocytes
Antibody-Dependent Cell-Mediated Cytotoxicity
Natural killer (NK) cells and other leukocytes bind to antibody-coated cells by Fc receptors
and destroy these cells
Antibody-Mediated Clearance of Helminths
• Antibodies, eosinophils, and mast cells function together to mediate the
killing and expulsion of some helminthic parasites.
• Helminths (worms) are too large to be engulfed by phagocytes, and their
integuments are relatively resistant to the microbicidal products of
neutrophils and macrophages
THE COMPLEMENT SYSTEM
The complement system consists of serum and cell surface proteins that interact with one
another and with other molecules of the immune system in a highly regulated manner to
generate products that function to eliminate microbes.
• The complement system is activated by microbes and by antibodies that are attached to
microbes and other antigens
• Activation of complement involves the sequential proteolysis of proteins to generate
enzyme complexes with proteolytic activity
• The products of complement activation become covalently attached to microbial cell
surfaces, to antibodies bound to microbes and to other antigens, and to apoptotic bodies
• Complement activation is inhibited by regulatory proteins that are present on normal host
cells and absent from microbes
PATHWAYS OF COMPLEMENT ACTIVATION
There are three major pathways of complement activation: the classical pathway,
which is activated by certain isotypes of antibodies bound to antigens; the
alternative pathway, which is activated on microbial cell surfaces in the absence
of antibody; and the lectin pathway, which is activated by a plasma lectin that
binds to mannose residues on microbes
THE ALTERNATIVE PATHWAY

• The alternative pathway of

complement activation
results in the proteolysis of
C3 and the stable
attachment of its
breakdown product C3b to
microbial surfaces, without
a role for antibody
THE CLASSICAL PATHWAY
• The classical pathway is initiated
by binding of the complement
protein C1 to the CH2 domains
of IgG or the CH3 domains of
IgM molecules that have bound
antigen
• Only antibodies bound to
antigens, and not free circulating
antibodies, can initiate classical
pathway activation
THE LECTIN PATHWAY
The lectin pathway of complement activation is triggered in the absence of antibody by the
binding of microbial polysaccharides to circulating lectins, such as plasma mannose (or
mannan)–binding lectin (MBL), or to ficolins
LATE STEPS OF COMPLEMENT ACTIVATION
C5 convertases generated by the alternative, classical, or lectin pathway initiate activation of
the late components of the complement system, which culminates in formation of the cytocidal
membrane attack complex (MAC)
RECEPTORS FOR COMPLEMENT PROTEINS
REGULATION OF COMPLEMENT ACTIVATION
 The proteolytic activity of C1r and C1s is inhibited by a plasma protein called
C1 inhibitor (C1 INH).
 Assembly of the
components of C3 and
C5 convertases is
inhibited by the binding
of regulatory proteins to
C3b and C4b deposited
on cell surfaces
• Cell-associated C3b
is proteolytically
degraded by a
plasma serine
protease called
Factor I, which is
active only in the
presence of
regulatory proteins
• Formation of the MAC is inhibited by a membrane protein called CD59.
FUNCTIONS OF COMPLEMENT
The principal effector functions of the complement system in innate immunity and adaptive
humoral immunity are to promote phagocytosis of microbes on which complement is activated,
to stimulate inflammation, and to induce the lysis of these microbes.
 Opsonization and Phagocytosis
 Stimulation of Inflammatory Responses
 Complement-Mediated Cytolysis
 Other Functions of the Complement System
• Opsonization and Phagocytosis
• Stimulation of Inflammatory Responses
• Complement-Mediated Cytolysis
• Other Functions of the Complement System
 By binding to antigen-antibody complexes, complement proteins promote the
solubilization of these complexes and their clearance by phagocytes
 The C3d protein generated from C3 binds to CR2 on B cells and facilitates B cell
activation and the initiation of humoral immune responses
COMPLEMENT DEFICIENCIES
• Genetic deficiencies in classical pathway components, including C1q, C1r, C4, C2, and
C3, have been described; C2 deficiency is the most common human complement
deficiency
• Deficiencies in components of the alternative pathway, including properdin and Factor D,
result in increased susceptibility to infection with pyogenic bacteria.
• Deficiencies in the terminal complement components, including C5, C6, C7, C8, and C9,
have also been described.
• Deficiencies in complement regulatory proteins are associated with abnormal
complement activation and a variety of related clinical abnormalities
• Deficiencies in complement receptors include the absence of CR3 and CR4, both
resulting from rare mutations in the β chain (CD18) that is shared by the CD11CD18
family of integrin molecules
PATHOLOGIC EFFECTS OF THE COMPLEMENT SYSTEM

Even when it is properly regulated and appropriately activated, the complement

system can cause significant tissue damage. Some of the pathologic effects
associated with bacterial infections may be due to complementmediated acute
inflammatory responses to infectious organisms. In some situations, complement
activation is associated with intravascular thrombosis and can lead to ischemic
injury to tissues
NEONATAL IMMUNITY
• Neonatal mammals are protected from infection by maternally produced antibodies
transported across the placenta into the fetal circulation and by antibodies in ingested
milk transported across the gut epithelium of newborns by a specialized process known
as transcytosis.