Fig. 5.20 The physical and functional properties of the human immunoglobulin isotypes. IgM is so called because of its size: although monomeric IgM is only 190 kDa, it normally forms pentamers, known as macroglobulin (hence the M), of very large molecular weight (see Fig. 5.23). IgA dimerizes to give an approximate molecular weight of around 390 kDa in secretions. IgE antibody is associated with immediate-type hypersensitivity. When fixed to tissue mast cells, IgE has a much longer half-life than its half-life in plasma shown here. The relative activities of the various isotypes are compared for several functions, ranging from inactive (–) to most active (++++).
also increases the avidity of IgM for antigens before its affinity is increased through the process of affinity maturation.
IgG isotypes produced during an immune response are found in the bloodstream and in the extracellular spaces in tissues. IgM and most IgG isotypes can interact with the complement component C1 to activate the classical complement pathway (described in Section 2-7). IgA and IgE do not activate complement. IgA can be found in the bloodstream, but it also acts in the defense of mucosal surfaces; it is secreted into the gut and respiratory tract, and also into mother’s milk. IgE is particularly involved in defense against multicellular parasites (for example, schistosomes), but it is also the antibody involved in common allergic diseases such as allergic asthma. IgG and IgE are always monomers, but IgA can be secreted as either a monomer or a dimer.
Sequence differences in the constant regions of the immunoglobulin heavy chains produce the distinct characteristics of each antibody isotype. These characteristics include the number and location of interchain disulfide bonds, the number of attached carbohydrate groups, the number of C domains, and the length of the hinge region (see Fig. 5.19). IgM and IgE heavy chains contain an extra C domain that replaces the hinge region found in γ, δ, and α chains. The absence of the hinge region does not imply that IgM and IgE molecules lack flexibility; electron micrographs of IgM molecules binding to ligands show that the Fab arms can bend relative to the Fc portion. However, such a difference in structure may have functional consequences that are not yet characterized. Different isotypes and subtypes also differ in their ability to engage various effector functions, as described below.
5-13 The constant region confers functional specialization on the antibody.
Antibodies can protect the body in a variety of ways. In some cases it is enough for the antibody simply to bind antigen. For instance, by binding tightly to a toxin or virus, an antibody can prevent it from recognizing its receptor on a host cell (see Fig. 1.25). The antibody V regions are sufficient for this activity. The C region is essential, however, for recruiting the help of other cells and molecules to destroy and dispose of pathogens to which the antibody has bound.
The Fc region contains all C regions of an antibody and has three main effector functions: Fc-receptor binding, complement activation, and regulation of secretion. First, the Fc region of certain isotypes binds to specialized Fc receptors expressed by immune effector cells. Fcγ receptors expressed on the surface of macrophages and neutrophils bind the Fc portions of IgG1 and IgG3 antibodies, facilitating the phagocytosis of pathogens coated with these antibodies. The Fc region of IgE binds to a high-affinity Fcε receptor on mast cells, basophils, and activated eosinophils, triggering the release of inflammatory mediators in response to antigens. We will return to this topic in Section 10-19.