Page 249 - Clinical Immunology_ Principles and Practice ( PDFDrive )

230 Part two Host Defense Mechanisms and Inflammation

factors. One critical set of these effector mechanisms is encom- The other major system by which antibodies mediate effector
passed by the classical pathway of complement activation functions is cellular. The specific molecules with which cells
21
(Chapters 3, 21). The human antibody isotypes vary considerably recognize antibodies are called Fc receptors (FcR). In humans,
in their intrinsic ability to activate this pathway. The consensus there are several Fc receptors for IgG (FcγRI, FcγRIIa, FcγRIIb,
view is that IgM, IgG1, and IgG3 isotypes are effective activators. FcγRIIIa, FcγRIIIb), as well as other Fc receptors for IgA, IgE
Although some sources state that IgG2, IgG4, and IgA are weak (FcεRI, FcεRII), and IgM (Fig. 15.5). We describe selected features
or nonactivators of the classical complement pathway, evidence of Fc receptors that illuminate the principles by which they
suggests that when epitope density is high, IgG2 can also activate function.
19
the classical pathway effectively. Instead of attempting to decide Some receptors (FcγRI, FcεRI) have relatively high intrinsic
which subclass is absolutely superior, it is more useful to recognize affinities for antibody molecules and can, therefore, bind sig-
that complement-fixing ability may not be determined solely by nificant fractions of monomeric Ig at physiological concentrations.
the subclass of an IgG antibody. For example, the high-affinity receptor for IgE (FcεRI) binds
10
- 1
One obvious source for the isotype-related variation in IgE with an intrinsic affinity of approximately 1 × 10 M .
complement activating ability is variation in affinity for C1q Therefore single IgE molecules can bind to mast cells or basophils
(IgG3 > IgG1 > IgG2 > IgG4), the portion of the first component through cell surface FcεRI before interacting with allergen
in the classical pathway that physically contacts the C H 2 domains (antigen). In contrast, FcγRII and FcγRIII have relatively weak
of antibodies. The intrinsic affinity of the C1q globular heads intrinsic affinities for IgG Fc regions. Consequently, multivalent
for Fc regions of any isotype is relatively low, which may account, forms of IgG, such as are found in complexes of antibody and
in part, for the observation that two or more IgG molecules in multivalent antigens (immune complexes), are much more readily
proximity are required for activation of the classical pathway bound to these FcR. Thus for both the complement-dependent
beginning with C1. Thus in the activation of the classical pathway, and the FcR-dependent effector function pathways, multivalency
the functional affinity of C1q for antibody Fc regions is a crucial of Fc regions (functional affinity) plays a critical role.
parameter. Several types of functional consequences can follow ligation
IgG subclass–associated differences in some measures of of FcR by antibody–antigen complexes. These include activation
+
complement activation have been found, under some experimental and metabolic alteration of the FcR cells, phagocytosis of
conditions, to depend on quantitative differences in steps of the antibody-coated particulate antigens, antibody-dependent cellular
cascade subsequent to the binding of C1q to antibody. Although cytotoxicity (ADCC), and release of mediators that promote
there have been speculations regarding the role of segmental inflammation. The end result of Fc binding depends not only
flexibility in complement activation, there is no simple correlation on the receptor but also on the cell on which it is expressed and
between this physical property and activity in fixing the classical on costimulation, if any, of additional receptors on that cell. As
complement pathway. 20 an example, the most studied FcR are those that bind IgG, and
It is generally agreed that IgA does not activate the classical these receptors are expressed on many hematopoietic and even
pathway; however, its ability to activate the alternative complement nonhematopoietic cells. Within the three classes of receptors (I,
pathway has been controversial. Studies with recombinant IgA II, and III), the latter two FcR exist in two isoforms (A and B).
molecules have suggested that neither IgA1 nor IgA2 activates Of interest to the regulation of the immune response, the B
either complement pathway. However, aberrantly glycosylated isoform for FcγRII transmits an inhibitory signal, and the A
IgA and polymeric IgA may activate the lectin pathway and/or isoform transmits an activating signal.
the alternative pathway, and this activation has been postulated CD89 has been identified in humans as a receptor for IgA,
to be associated with IgA nephropathy. and it is expressed on myeloid cells including polymorphonuclear
Antibody-mediated activation of the classical complement neutrophils (PMNs), monocytes, and a population of dendritic
22
pathway has a variety of potential consequences, including creation cells (DCs). Signaling through CD89 involves an ancillary
of additional sites for attachment to a foreign particle, thereby chain that transmits an activating signal. However, not all CD89
facilitating ingestion (opsonization), elaboration of substances molecules associate with this chain, in which case, bound IgA is
22
that mediate leukocyte chemotaxis, additional metabolic changes endocytosed and recycled back to the surface of the cell. Interest-
involved in the destruction of pathogens by leukocytes, and ingly, Fc binding to CD89 may be more potent at mediating
changes in vascular permeability (Chapter 21). In this process, antibody-dependent cellular cytotoxicity than Fc binding to one
it is the antibody that provides the specificity, whereas the of the FcγR. Recent data have suggested another possible function
other molecules function without specificity for the epitopes that depends on the interaction between antibody (IgA) and a
involved. cell-surface receptor able to bind to polymeric Igs (pIgR). Transport
of IgA–antigen complexes across epithelial surfaces by pIgR may
Receptors for Fc Regions represent a form of antibody-facilitated antigen excretion. 23

KEY CoNCEPtS ANTIBODIES AS SURROGATE LIGANDS
Antibody Effector Systems The notion that one molecule can mimic a second molecule, in
• Multivalence of Fc regions is often important in activating antibody one respect or another, is of extraordinarily broad applicability
effector functions. and profound biological significance. At least three types of
• The occurrence and magnitude of effector function activation varies mimicry can be distinguished, and each type can be regarded
with antibody isotype. as a continuous (as opposed to discrete) variable. First, one
24
• Effector mechanisms are inherently nonspecific with respect to antigen. can conceive of limited structural mimicry of one molecule by
• Antibody Fc regions provide the mechanistic link between antigen-
specific V domains and antigen nonspecific effector mechanisms. another. By chance, two otherwise different molecules could
have regions that happen to contain the same or similar (in key