The genetics of antibody production

The major mucosal immunoglobulin, IgA, consists of two basic units joined by a J chain. The addition of a secretion molecule prevents its digestion by enzymes present in mucosal and intestinal secretions. Thus, IgA2 is the major IgA molecule in secretions and is quite effective in neutralizing antigens that enter via these mucosal routes. IgA1, the main IgA molecule in serum, is, however, susceptible to inactivation by serum proteases and is thus less active for defense. Its function is unclear at present. 

Two other classes are worthy of note. IgD is synthesized by antigen-sensitive B cells and is involved in the activation of these cells by antigen. IgE is produced by plasma cells and binds to specifi c IgE receptors on most cells and basophiles. This molecule (see Chapter 9) plays an extremely important role in allergic reactions and expelling intestinal parasites, which is accomplished by increasing vascular permeability and inducing chemotactive factors following mast cell degranulation. 

Given this extraordinary ability to generate large numbers of antibody molecules, how does the immune system recognize all pathogens, including past, present, and future? This diversity is achieved by the way in which the genetics of antibody production is arranged (see Figure 1.3). The light and heavy chains are carried on different chromosomes. The heavy chain genes are carried on chromosome 14. These genes are broken up into coding systems called exons with intervening segments of silent segments called entrons. The exons represent the central region of the heavy chain and a large number of V regions. Between the V and D genes are two small sets of exons called the D and J. With each single B cell, one V gene is joined to one D and J in the chromosome. The product, the VH domain, is then joined at the level of RNA processing to Cu and the B cell makes an IgM molecule. By omitting the Cu gene and joining VHDJ to a Cλ an IgG molecule is produced. This enormous versatility allows the cell to make IgM, IgD, IgG, IgA, or IgE in sequence while using the same variable regions (see Figure 1.4). The heavy chain gene recombinations are controlled by two recombination activity genes called RAG1 and RAG2. If these genes are eliminated by “knock-out” techniques in mice, profound immunodefi ciency status occurs in these animals, characterized by absent mature B and T cells. 

Thus, the diversity of antigen binding is achieved by the large number of V genes available and their combination with different D and L genes to provide different antibodies. Furthermore, the inherited set of genes may be increased by somatic mutation during multiple divisions of lymphoid cells, thereby increasing the number of antibody specifi cities to 1014, which far exceeds the number of B cells (1010) in the body. 

Once a given B cell is preselected to produce a particular VH and VL domain, all the ensuing progeny of that B cell will produce the same VH or VL domain. The sequence of events is as follows: initially, the B cell produces intracellular antigen-specific IgM, which becomes bound to the cell surface. The B cell is now antigen responsive with exposure to a given antigen. The committed B cell begins producing a certain isotype or class of immunoglobulins and begins dividing, and all the progeny will produce the identical immunoglobulin molecules. These B cells will later mature into either plasma cells or long-term memory B cells.