The Genetic Basis of Antibody Diversity

A newborn mammal possesses a full set of genetic information for immunoglobulin synthesis. At each of the loci coding for the heavy and light antibody chains, it has one al-lele from its mother and one from its father. Throughout the animal's life, each of its cells begins with the same full set of immunoglobulin genes. However, as B cells develop, their genomes become modified in such a way that each cell eventually can produce one—and only one—specific type of antibody. In other words, different B cells develop slightly different genomes encoding different antibody specificities. How can a single organism produce millions of different genomes?

One hypothesis was that we simply have millions of antibody genes. However, a simple calculation (the number of base pairs needed per antibody gene multiplied by millions) shows that if this were true, our entire genome would be taken up by antibody genes! More than 30 years ago, an alternative hypothesis was proposed: A relatively small number of genes recombine to produce many unique combinations, and it is this shuffling of the genetic deck, plus the random pairing of light and heavy antibody chains, that produces antibody diversity. This second hypothesis is now the accepted molecular genetic theory.

In this section, we will describe the unusual events that generate the enormous antibody diversity that normally characterizes each individual mammal. Then we will see how similar events produce the five classes of antibodies by producing slightly different constant regions with special properties.

Antibody diversity results from DNA rearrangement and other mutations

Each gene encoding an immunoglobulin is in reality a "supergene" assembled from several clusters of smaller genes scattered along part of a chromosome (Figure 18.18). Every cell in the body has hundreds of genes, located in separate clusters, that are potentially capable of participating in the synthesis of the variable and constant regions of immunoglobulin polypep-tide chains. In most body cells and tissues, these genes remain intact and separated from one another. During B cell development, however, these genes are cut out, rearranged, and joined together. Most of the coding and noncoding regions of these genes are deleted, and one gene from each cluster—is chosen randomly for joining (Figures 18.18, 18.19).

In this manner, a unique antibody supergene is assembled from randomly selected "parts." Each B cell precursor in the animal assembles its own two specific antibody supergenes, one for a specific heavy chain and the other, assembled independently, for a specific light chain. This remarkable ex-

ample of essentially irreversible cell differentiation generates an enormous diversity of antibody specificities from the same starting genome, one for each individual B cell.

In both humans and mice, the gene clusters coding for im-munoglobulin heavy chains are on one pair of chromosomes and those for light chains are on others. The variable region of the light chain is encoded by two families of genes; the variable region of the heavy chain is encoded by three families.

Figure 18.18 illustrates the gene families coding for the heavy-chain constant and variable regions in mice. There are multiple genes coding for each of the four kinds of segments in the polypeptide chain: 100 V, 30 D, 6 J, and 8 C. Each B cell that becomes committed to making an antibody randomly selects one gene for each of these clusters to make the final heavy-chain coding sequence, VDJC. So the number of different heavy chains that can be made through this random recombination process is quite large.

Now consider that the light chains are similarly constructed, with a similar amount of diversity made possible by random recombination. If we assume that light-chain diversity is the same as heavy-chain diversity (144,000 possible combinations), the number of possible combinations of light and heavy chains is 144,000 different light chains x 144,000 different heavy chains = 21 billion possibilities!

Even if this number is an overestimate by severalfold (and it is), the number of different immunoglobulin molecules that B cells can make is huge. But there are other mechanisms that generate even more diversity:

► When the DNA sequences for the V, J, and C regions are rearranged so that they are next to one another, the recombination event is not precise, and errors occur at the junctions. This imprecise recombination can create new codons at the junctions, with resulting amino acid changes.

► After the DNA sequences are cut out and before they are joined, an enzyme, terminal transferase, often adds some nucleotides to the free ends of the DNAs. These additional bases create insertion mutations. ► There is a relatively high mutation rate in immunoglobulin genes. Once again, this process creates many new alleles and adds to antibody diversity.

Segments encoding variable region (V)

Segments encoding constant region (C)

V1, V2---V-100 (variable) segments

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