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Generating Antibody Diversity

The vast array of antigenic determinants that can be recognized by our immune system posed a problem that perplexed scientists for decades: How can each lymphocytes house information for antibodies with millions of different specificities? Furthermore since all cells in the body are descendants of the same zygote, they are genetically identical, so each cell would seemingly have to carry millions of baggage genes  that would never be used ( a muscle or nerve cell, for example, would  be encumbered with all the genes for responding to all possible antigens-genetic information it will never need). Encoding all these different antibody specificities would require more DNA than it is possible to fit into the nucleus of a human cell. How is it that we can generate enough antibody diversity to respond to any antigen?

Scientists found that the number of genes for antibody production in a cell is actually relative small. In fact the precursor cells that develop into B lymphocytes possess only a few hundred genes for antibody production. During the development of a mature B cell from a precursor cell, these genes recombine to give rise to the diverse population of B lymphocytes, with more than a million clones of  cells each capable of responding to a different antigen.
In each person most of the antibody molecule is constant that is identical in all antibodies regardless of their antigenic specificity. Only a few variations punctuate the protein chains and these lie in the variable region at the ends of the light and heavy chains. This means that a very small number of genes can code for a very large portion of the antibody molecule. Second a group of genes codes for different portions of the variable regions of light chains. This group of genes is located very near the genes for the constant region of the light chains. These variable genes fall into two clusters called the V (variable) and J (joining) regions.
In the mouse pre-B cell, for example, there are 350 different V-region genes and four different J-region genes. During the development of a B cell, one gene from the V region recombines with a gene from the J region. The remaining DNA is spliced out of the chromosome; this event alone creates a possible 1400 combinations of V and J genes in the mature B-cell population.
Two other factors generate additional variability. Imprecise recombination between the V and J regions creates different nucleotide sequence that ultimately translate into different amino acid sequences in the antibody. In addition mutations may develop in progeny cells during replication of activated B cells. Information for the constant region is joined to the variable region during the transcription process. The initial RNA products contain an intron separating the V-J transcript from the heavy chain transcript. Splicing combines these two exons to form a functional messenger from which the unique light chain is translated.

A similar series of events controls the development of heavy chains. The heavy chain variable region however is created from three sets of genes called V, D (diversity), and J regions. Using the Chinese menu approach to recombination (taking one from column V, one from column D and one from column J), there are more than 10,000 possible combinations  of these genes in mice. Given that any gene for a light chain may occur in the same cell as any gene for a heavy chain, there are more than 14 million different types of antibodies that may be made, not counting the additional diversity generated by mutation. Such a system guarantees that there will be a clone of antibody-producing cells for virtually any antigen that enters the body without taxing all other cells with millions of unneeded genes.
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