A. Genetic diversity. Human antibodies exhibit an enormous range (—108) of specificities. The genetic basis for this diversity involves several factors:
1. Different genes code for the variable and constant regions of the heavy (H) and light (L) chains.
2. Rearrangement of variable region and constant region genes during differentiation within the genome. Any one of many different variable region genes can be linked to a single constant region gene, thus conserving DNA.
3. Joining segment. An additional gene sequence is required during the formation of the L chain. This sequence, the joining segment, joins the Vl region gene to the Cl region gene (Figure 5-1).
4. Diversity segment. An additional gene sequence is required during the formation of the H chain. This sequence, the diversity segment, links the Vh gene to the J gene. These genes are then fused with the Ch gene (Figure 5-2).
5. H-chain class switching from \x and 8 to y,, av y2, y4, 8, and a2 is dictated by a later rearrangement of the class genes in the Ch region and is mediated by T cell cytokines (IL-4, IL-13, IFN-y, TGF-p).
B. Random selection by each B cell from the variety of V, D, and J germ line genes available results in a large number of structural possibilities for the Vl and Vh epitope binding regions of the immunoglobulins. This random selection is primarily responsible for the vast diversity of antibodies.
C. Allelic exclusion. Only one of the two parental alleles is expressed by a single B cell, resulting in a single H-chain isotype and L-chain subtype receptor capable of reacting with only one antigenic epitope.
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