Features Related to Effector Functions

Many of the effector functions of immunoglobulins are mediated by the Fc portions of the molecules, and antibody isotypes 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 neutro-phils and macrophages. This occurs because the antigen-complexed IgG molecule is able to bind, through its Fc region, to y heavy chain-specific Fc receptors (FcRs) that are expressed on neutrophils and macrophages. In contrast, IgE binds to mast cells and triggers their degranulation because mast cells express IgE-specific FcRs. Another Fc-dependent effector mechanism of humoral immunity

Original antibody

Changes in antibody structure

Affinity maturation (somatic mutations in variable region)

Change from membrane to secreted form

Isotype switching

Functional significance: Antigen Effector recognition functions

Increased affinity

No change

No change

Change from B cell receptor function to effector function

No change

Each isotype serves a different set of effector functions

FIGURE 5-15 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. During affinity maturation, mutations in the V region (indicated by red dots) lead to changes in fine specificity without changes in C region-dependent effector functions. 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). In isotype switching, the C regions change (indicated by color change from purple to green or yellow) without changes in the antigen-binding V region. Isotype switching is seen in membrane-bound and secreted antibodies. The molecular basis for these changes is discussed in Chapter 11.

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 FcR- and complement-binding sites of antibodies are found within the heavy chain C domains of the different isotypes (see Fig. 5-1). The structure and functions of FcRs and complement proteins are discussed in detail in Chapter 12.

The effector functions of antibodies are initiated only by 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 FcRs of phagocytes (see Chapter 12). 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 wastefully, and inappropriately, trigger effector responses.

Changes in the isotypes of antibodies during humoral immune responses influence how and where the responses work to eradicate antigen. After stimulation by an antigen, a single clone of B cells may produce antibodies with different isotypes that nevertheless possess identical V domains and therefore identical antigen specificity. Naive B cells, for example, 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 isotype (or class) switching in which the type of CH region, and therefore the antibody isotype, produced by the B cell changes, but the V regions and the specificity do not (see Fig. 5-15). As a result of isotype switching, different progeny of the original IgM- and IgD-expressing B cell may produce isotypes and subtypes that are best able to eliminate the antigen. For example, the antibody response to many bacteria and viruses is dominated by IgG antibodies, which promote phagocytosis of the microbes, and the response to helminths consists mainly of IgE, which aids in the destruction of the parasites. Switching to the IgG isotype also prolongs the effectiveness of humoral immune responses because of the long half-life of IgG antibodies. The mechanisms and functional significance of isotype switching are discussed in Chapter 11.

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 (see Fig. 5-15). IgA can be secreted efficiently through mucosal epithelia and is the major class of antibody in mucosal secretions and milk (see Chapter 13). Neonates are protected from infections by IgG antibodies they acquire from their mothers through the placenta during gestation and through the intestine early after birth. This transfer of maternal IgG is mediated by the neonatal Fc receptor, which we described earlier as the receptor responsible for the long half-life of IgG antibody.

gens to the spatially distant combining site in the V region.

* Monoclonal antibodies are produced from a single clone of B cells and recognize a single antigenic determinant. Monoclonal antibodies can be generated in the laboratory and are widely used in research, diagnosis, and therapy.

* Antigens are substances specifically bound by antibodies or T lymphocyte antigen receptors. Antigens that bind to antibodies represent a wide variety of biologic molecules, including sugars, lipids, carbohydrates, proteins, and nucleic acids. This is in contrast to T cell antigen receptors, which recognize only peptide antigens.

* Macromolecular antigens contain multiple epi-topes, or determinants, each of which may be recognized by an antibody. Linear epitopes of protein antigens consist of a sequence of adjacent amino acids, and conformational determinants are formed by folding of a polypeptide chain.

* The affinity of the interaction between the combining site of a single antibody molecule and a single epitope is generally represented by the dissociation constant (Kd) calculated from binding data. Polyvalent antigens contain multiple identical epitopes to which identical antibody molecules can bind. Antibodies can bind to two or, in the case of IgM, up to 10 identical epitopes simultaneously, leading to enhanced avidity of the antibody-antigen interaction.

* The relative concentrations of polyvalent antigens and antibodies may favor the formation of immune complexes that may deposit in tissues and cause damage.

* Antibody binding to antigen can be highly specific, distinguishing small differences in chemical structures, but cross-reactions may also occur in which two or more antigens may be bound by the same antibody.

* Several changes in the structure of antibodies made by one clone of B cells may occur in the course of an immune response. B cells initially produce only membrane-bound Ig, but in activated B cells and plasma cells, synthesis is induced of soluble Ig with the same antigen-binding specificity as the original membrane-bound Ig receptor. Changes in the use of C region gene segments without changes in V regions are the basis of isotype switching, which leads to changes in effector function without a change in specificity. Point mutations in the V regions of an antibody specific for an antigen lead to increased affinity for that antigen (affinity maturation).

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