Immunoglobulins

Antibody molecules are glycoproteins called immunoglobulins (abbreviated as Ig). The term immunoglobulin is used to describe all soluble BCRs. There are five different classes (or isotypes) of immunoglobulins, which differ in their use of heavy chains. The class found in highest concentrations in serum is called immunoglobulin G (abbreviated IgG). The class with the second highest serum concentration (in most mammals) is immunoglobulin M (IgM). The third highest concentration in most mammals is immunoglobulin A (IgA). IgA is, however, the predominant immunoglobulin in secretions such as saliva, milk, and intestinal fluid. Immunoglobulin D (IgD) is primarily a BCR and is rarely encountered in body fluids. Immunoglobulin E (IgE) is found in very low concentrations in serum and mediates allergic reactions. The characteristics of each of these classes are shown in Table 16-1.

When serum is subjected to electrophoresis, its proteins separate into four major fractions (Figure 16-1). The most negatively charged fraction consists of a single homogeneous protein called serum albumin. The other three major fractions contain protein mixtures classified as α, β, and γ globulins, according to their electrophoretic mobility (Figure 16-2). Most immunoglobulins are found in the γ globulins, although IgM migrates with the β globulins.

Immunoglobulin molecules are bilaterally symmetrical with two identical Fab regions linked to a stem consisting of an Fc region. It has generally been assumed that once an antibody molecule has formed, its structure remains unchanged until it is destroyed by catabolic processes. That assumption now appears to be incorrect. The IgG4 subclass in humans can exchange subunits with other antibody molecules to generate a hybrid antibody with two different Fab arms. As a result, this antibody can cross-link two different antigens. IgG4 is the least abundant human IgG subclass. This exchange of Fab arms between IgG4 molecules is dynamic. Thus a homogeneous IgG4 antibody, when administered to a human, will rapidly begin to swap arms. It is not known whether this occurs in the domestic mammals.

IgG is produced by plasma cells in the spleen, lymph nodes, and bone marrow. It is the immunoglobulin found in highest concentration in the blood (Table 16-2) and plays the major role in antibody-mediated defenses. It has a molecular weight of about 180 kDa and a typical BCR structure with two identical light chains and two identical γ heavy chains (Figure 16-3). Its light chains may be of the κ or λ type. Because it is the smallest of the immunoglobulin molecules, IgG can escape from blood vessels more easily than can the others. This is especially important in inflammation, in which increased vascular permeability allows IgG to participate in the defense of tissues and body surfaces. IgG binds to specific antigens such as those found on bacterial surfaces. Binding of these antibody molecules to bacterial surfaces can cause clumping (agglutination) and opsonization. IgG antibodies activate the classical complement pathway only when sufficient molecules have clustered in a correct configuration on the antigenic surface (Chapter 7).

Immunoglobulin M

IgM is also produced by plasma cells in the secondary lymphoid organs. It occurs in the second highest concentration after IgG in most mammalian serum. When attached to the B cell surface and acting as a BCR, IgM is a 180-kDa immunoglobulin monomer. However, the secreted form of IgM consists of five (occasionally six) 180-kDa units linked by disulfide bonds in a circular fashion. Its total molecular weight is 900 kDa (Figure 16-4). A small polypeptide called the J chain (15 kDa) joins two of the units to complete the circle. Each IgM monomer is of conventional immunoglobulin structure and consists of two κ or λ light chains and two µ heavy chains; µ chains differ from γ chains in that they have an additional, fourth constant domain (C_H4), as well as an additional 20-amino acid segment on their C-terminus but have no hinge region. The complement activation site on IgM is located on the C_H4 domain.

IgM is the major immunoglobulin produced during a primary immune response (Figure 16-5). It is also produced in secondary responses, but this tends to be masked by the predominance of IgG. Although produced in small amounts, IgM is more efficient (on a molar basis) than IgG at complement activation, opsonization, neutralization of viruses, and agglutination. Because of their very large size, IgM molecules rarely enter tissue fluids even at sites of acute inflammation.

Immunoglobulin A

IgA is secreted by plasma cells located under body surfaces. Thus it is made in the walls of the intestine, respiratory tract, urinary system, skin, and mammary gland. Its serum concentration in most mammals is usually lower than that of IgM. IgA monomers have a molecular weight of 150 kDa, but they are normally secreted as dimers. Each IgA monomer consists of two light chains and two α heavy chains containing three constant domains. In dimeric IgA, two molecules are joined by a J chain (Figure 16-6). Higher polymers of IgA are occasionally found in serum.

IgA produced in body surfaces is transported through epithelial cells into external secretions. Thus most of the IgA made in the intestinal wall is carried into the intestinal fluid. This IgA is transported through intestinal epithelial cells bound to the polymeric immunoglobulin receptor (pIgR) or secretory component (Figure 22-13). Secretory component binds IgA dimers to form a complex molecule called secretory IgA (SIgA). It protects the IgA from digestion by intestinal proteases.

Secretory IgA is the major immunoglobulin in the external secretions of nonruminants. As such, it is of critical importance in protecting the intestinal, respiratory, and urogenital tracts, the mammary gland, and the eyes against microbial invasion. IgA does not activate the classical complement pathway, nor can it act as an opsonin. It can, however, agglutinate particulate antigens and neutralize viruses. IgA prevents the adherence of invading microbes to body surfaces. Because of its importance, IgA is examined in more detail in Chapter 22.

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