and one L chain, and thus each B cell produces only one antibody recognition site.

Activation of B Cells

During maturation of B cells, a large population of cells results, each of which has one antibody combining site. The theoretical repertoire, how many different types of B cells could conceivably be produced using the known mechanisms that are active during B-cell development, is thought to be much larger than the minimal estimate of 1014 shown in Table 8.1. In humans there may be 1010 B cells with differing specificities circulating at any time, and it is estimated that about 1 in 105 cells produces an antibody that will bind, with differing affinities, to any particular antigen that is being examined,

The antibody molecule is first produced as an integral membrane protein that is displayed on the surface of the B cell, anchored through a membrane-spanning region and containing an intracellular cytoplasmic domain, If the antibody displayed on the surface of the cell binds antigen, the B cell is activated, If the cell receives a second signal from a TH-2 cell, it proliferates to form cells that secrete antibody, Memory cells also arise that serve to protect the organism from future infection by the same pathogen,

The TH-2 cell signal may be delivered to the B cell either through a specific pathway or through a nonspecific pathway, Antigen, which could be in the form of a whole virus or in the form of a protein, that is bound to antibody present on the surface of the B cell can be internalized by the B cell and degraded by the MHC class II antigen-processing pathway, Peptides derived from the degraded virus or protein can then be presented on the surface of the B cell in the context of class II MHC molecules, Class II-restricted T-helper cells that recognize this peptide will secrete cytokines that stimulate the B cell to proliferate and secrete antibodies, Note that the peptide displayed by the class II molecule does not have to be related to the epitope recognized by the antibody displayed on the B-cell surface, It may, in fact, be derived from an entirely different protein, Thus, while T cells respond to peptide epitopes, the antibody molecules can recognize much more complex antigens, such as whole proteins or viruses, The epitopes recognized by antibodies are most often what are called conformational or nonlinear epitopes, which are formed by residues physically located at different places in the linear sequence of the protein but which form a contiguous surface in the protein after it folds into its three-dimensional conformation, Such discontinuous epitopes are destroyed if the protein is denatured and the different components of the epitope separated from one another, A certain fraction of antibodies, however, recognize continuous epitopes, which are formed by a linear sequence of amino acids present in the protein,

In addition to specific activation of B cells by T-helper cells, B cells can also be activated through area stimulation, If a B cell is in the vicinity of T-helper cells that are releasing cytokines to activate B cells, it may also be stimulated, The importance of area stimulation, and the frequency with which it occurs, in the context of fighting off a viral infection is not clear, In many cases of viral infection, a generalized and active inflammatory response occurs that involves the release of many cytokines, and in which many different antigens are being presented, Area stimulation could be important in developing a rapid response during such events, However, in such a process antibodies against self might also be produced, and such processes must be controlled,

Secretion of Antibodies

A B cell stimulated by exposure to its cognate antigen and by help from a TH-2 cell proliferates and begins to secrete antibodies. The first antibodies secreted are IgM, whose structure is illustrated in Fig. 8.8. IgM antibodies, which circulate in the blood, can be detected as early as a few days after virus infection. Their production quickly wanes and over a period of weeks or months the concentration of IgM in the blood decreases to very low or unde-tectable levels, as illustrated schematically in Fig. 8.11. Thus the presence of IgM antibodies specific for a virus is usually a sign of acute, or at least very recent, infection.

During further maturation of the B cell, class switching occurs, as illustrated in Fig. 8.12. Recombinational events in the heavy-chain region lead to the substitution of the IgG, IgE, or IgA heavy chain for that of IgM. Homologous recombination within the intron just downstream of the J gene results in deletion of the intervening DNA such that the active VDJ gene is brought into contact with the C region of a different class of heavy chain. The order of heavy-chain genes in the mouse chromosome is ¡x8ysa (Figs. 8.10 and 8.12), and class switching can happen either sequentially (IgM to IgG to IgE to IgA) or directly (e.g., IgM to IgE without passing through an IgG phase).

Production of IgG (or of IgE or IgA) thus occurs later after infection (illustrated schematically in Fig. 8.11). At least 2 weeks are required before there is production of large amounts of IgG. Once a cell begins to make IgG, it is no longer able to make IgM because the gene encoding the M heavy chain (C^ in Fig. 8.12) has been deleted. It is important to note that the antigen combining site of the IgG antibody is identical to that produced by the earlier IgM because the V region of the H chain is the same.

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