Many of the effector functions of antibodies are mediated by the Fc portions of the molecules; Ig classes and subclasses that differ in these Fc regions perform distinct functions. We have mentioned previously that the effector functions of antibodies require the binding of heavy-chain C regions, which make up the Fc portions, to other cells and plasma proteins. For example, IgG coats microbes and targets them for phagocytosis by neutrophils and macrophages. This occurs because the IgG molecule is able to simultaneously bind through its Fab region to the microbe and through its Fc region to IgG heavy chain–specific Fc receptors that are expressed on neutrophils and macrophages. IgE binds to mast cells and triggers their degranulation because mast cells express IgE-specific Fc receptors. Another Fc-dependent effector mechanism of humoral immunity is activation of the classical pathway of the complement system. The system generates inflammatory mediators and promotes microbial phagocytosis and lysis. It is initiated by the binding of a complement protein called C1q to the Fc portions of antigen-complexed IgG or IgM. The Fc receptor– and complement-binding sites of antibodies are found within the heavy-chain C domains of the different antibody classes (see Fig. 1).
Fig1. Structure of an antibody molecule. (A) Schematic diagram of a secreted immunoglobulin G (IgG) molecule. The antigen-binding sites are formed by the juxtaposition of VL and VH domains. The heavy-chain C regions end in tail pieces. The locations of complement- and Fc receptor–binding sites within the heavy chain constant regions are approximations. (B) Schematic diagram of a membrane-bound IgM molecule on the surface of a B lymphocyte. The IgM molecule has one more CH domain than IgG has, and the membrane form of the antibody has C-terminal transmembrane and cytoplasmic portions that anchor the molecule in the plasma membrane. (C) Structure of a human IgG molecule as revealed by x-ray crystallography. In this ribbon diagram of a secreted IgG molecule, the identical heavy chains are colored blue and red so that they can be easily visualized, although they are identical, and the light chains are colored green; carbohydrates are shown in gray. (Courtesy Dr. Alex McPherson, University of California, Irvine.)
The effector functions of antibodies are initiated only by Ig molecules that have bound antigens and not by free Ig. The reason that only antibodies with bound antigens activate effector mechanisms is that two or more adjacent antibody Fc portions are needed to bind to and trigger various effector systems, such as complement proteins and Fc receptors of phagocytes. This requirement for adjacent antibody molecules ensures that the effector functions are targeted specifically toward eliminating antigens that are recognized by the antibody and that circulating free antibodies do not, inappropriately and dangerously, trigger effector responses.
Changes in the classes of antibodies during humoral immune responses influence how the responses work to eradicate anti gens. After stimulation by an antigen, a single clone of B cells may generate progeny that each produce antibodies of different classes that nevertheless possess identical V domains and therefore identical antigen specificity. Naive B cells simultaneously produce IgM and IgD that function as membrane receptors for antigens. When these B cells are activated by foreign antigens, typically of microbial origin, they may undergo a process called class (or isotype) switching, in which the type of CH region, and therefore the antibody class, produced by the B cell changes, but the V regions and the specificity do not (see Fig. 1B). As a result of class switching, different progeny of the original IgM- and IgD-expressing naive B cell may produce antibodies of classes that are best able to eliminate the antigen. For example, the antibody response to many bacteria and viruses in the blood is dominated by IgG antibodies, but the same microbes in mucosal tissues (intestines and airways) elicit much more IgA, which is efficiently secreted into the lumens of these organs. Switching to the IgG isotype also prolongs the effectiveness of humoral immune responses because of the long half-life of IgG antibodies.
Fig2. Changes in antibody structure during humoral immune responses. The illustration depicts the changes in the structure of antibodies that may be produced by the progeny of activated B cells (one clone) and the related changes in function. (A) During affinity maturation, mutations in the V region (indicated by yellow dots) lead to changes in fine specificity without changes in C region–dependent effector functions. (B) In class switching, the C regions change (indicated by color change from purple to green, yellow, or blue) without changes in the antigen-binding V region. Class switching is seen in membrane-bound and secreted antibodies. (C) Activated B cells may shift production from largely membrane-bound antibodies containing transmembrane and cytoplasmic regions to secreted antibodies. Secreted antibodies may or may not show V gene mutations (i.e., secretion of antibodies occurs before and after affinity maturation). We will discuss the molecular basis for these changes in Chapter 12. Ig, Immunoglobulin.
The heavy-chain C regions of antibodies also determine the tissue distribution of antibody molecules. As we mentioned earlier, after B cells are activated, they gradually lose expression of the membrane-bound antibody and express more of it as a secreted protein (Fig. 1C). IgA can be secreted efficiently across mucosal epithelia and is the major class of antibody in mucosal secretions and milk. Neonates are protected from infections by IgG antibodies they acquire from their mothers through the placenta during gestation. This transfer of maternal IgG is mediated by the FcRn, which we described earlier as the receptor responsible for the long half-life of IgG antibodies.
