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CHAPTER 4: Antibody Structure and the Generation of B-Cell Diversity

The principal function of B lymphocytes is to produce antibodies, which are secreted immunoglobulins that bind tightly to infectious agents and tag them for destruction or elimination. Each antibody is highly specific for its corresponding antigen; the antibody repertoire of each person is enormous because it is composed of many millions of different antibodies that can bind a wide variety of different antigens. Antibodies can also be divided into five different structural classes—IgM, IgG, IgD, IgA, and IgE—that have different functions in the immune response. This chapter has provided an overview of the structure and function of the antibody molecule and of the unusual genetic mechanisms that create this diversity in specificity and effector function. Within an antibody molecule, the V regions that bind antigen are physically separated from the C region that interacts with effector molecules and cells of the immune system, such as complement, phagocytes, and other leukocytes. Antigen binding is the property of the paired V domains of the heavy and light chains, which can form an almost unlimited number of different binding sites with structural complementarity to a vast range of molecules. The immunoglobulin genes (heavy chain, κ light chain, and λ light chain) are expressed only in B cells, and their expression involves an unusual process of DNA rearrangement in which somatic DNA recombination assembles a V-region coding sequence from sets of gene segments that are present in the unrearranged gene. The random selection of gene segments for assembly creates much of the collective diversity of antigen-binding sites. The lymphocyte-specific proteins and ubiquitous enzymes of DNA repair and recombination are involved in the recombination machinery. Imprecision is inherent in some of their reactions, which creates additional diversity at the junctions between gene segments. In an individual B cell, only one rearranged heavy-chain gene and one rearranged light-chain gene become functional, ensuring that each B cell expresses immunoglobulin of a single specificity. The series of gene rearrangements that result in the production of membrane-bound IgM, the first immunoglobulin produced, is summarized in Figure 4.36.

Figure 4.36: Gene rearrangement and the synthesis of cell-surface IgM in B cells. Before immunoglobulin lightchain (center panel) and heavy-chain (right panel) genes can be expressed, rearrangements of gene segments are needed to produce exons encoding the V regions. Once this has been achieved, the genes are transcribed to give primary transcripts containing both exons and introns. The latter are spliced out to produce mRNAs that are translated to give κ or λ light chains and μ heavy chains that assemble inside the cell and are expressed as membrane-bound IgM at the cell surface. The main stages in the biosynthesis of the heavy and light chains are shown in the panel on the left.

On mature B cells, the membrane-bound immunoglobulin functions as the specific receptor for antigen; on encountering antigen, the B cell is stimulated to proliferate and differentiate into plasma cells that secrete antibody of the same specificity as the membrane-bound immunoglobulin. This ensures that an immune response is directed only against the invading pathogen or immunizing antigen. On the stimulation of a B cell by its specific antigen, a mechanism of somatic hypermutation introduces point mutations into the rearranged V-region DNA, diversifying the clone of proliferating B cells. Further selection of B cells by antigen increases the overall binding strength of the antibodies for antigen. Thus, the diversity of antibodies is due in part to inherited variation that is encoded in the genome and in part to non-inherited diversity that develops in B cells during an individual’s lifetime. The first antibody produced after an encounter with antigen is always IgM. As the immune response proceeds, the process of isotype switching further rearranges the expressed heavychain gene so that the protein made has the same V region but a different C region. The functional effect of isotype switching is to produce antibody molecules with the same antigen specificity but different effector functions—IgG, IgA, and IgE. The changes in the immunoglobulin genes that occur throughout the life of a B cell are summarized in Figure 4.37....