Germ Line and Somatic Variation Models Contended To Explain Antibody Diversity

For several decades, immunologists sought to imagine a genetic mechanism that could explain the tremendous diversity of antibody structure. Two different sets of theories emerged. The germ-line theories maintained that the genome contributed by the germ cells, egg and sperm, contains a large repertoire of immunoglobulin genes; thus, these theories invoked no special genetic mechanisms to account for antibody diversity. They argued that the immense survival value of the immune system justified the dedication of a significant fraction of the genome to the coding of antibodies. In contrast, the somatic-variation theories maintained that the genome contains a relatively small number of immunoglob-ulin genes, from which a large number of antibody specificities are generated in the somatic cells by mutation or recombination.

As the amino acid sequences of more and more im-munoglobulins were determined, it became clear that there must be mechanisms not only for generating antibody diversity but also for maintaining constancy. Whether diversity was generated by germ-line or by somatic mechanisms, a paradox remained: How could stability be maintained in the constant (C) region while some kind of diversifying mechanism generated the variable (V) region?

Neither the germ-line nor the somatic-variation proponents could offer a reasonable explanation for this central feature of immunoglobulin structure. Germ-line proponents found it difficult to account for an evolutionary mechanism that could generate diversity in the variable part of the many heavy- and light-chain genes while preserving the constant region of each unchanged. Somatic-variation proponents found it difficult to conceive of a mechanism that could diversify the variable region of a single heavy- or light-chain gene in the somatic cells without allowing alteration in the amino acid sequence encoded by the constant region.

A third structural feature requiring an explanation emerged when amino acid sequencing of the human myeloma protein called Til revealed that identical variableregion sequences were associated with both y and ^ heavy-chain constant regions. A similar phenomenon was observed in rabbits by C. Todd, who found that a particular allotypic marker in the heavy-chain variable region could be associated with a, y, and ^ heavy-chain constant regions. Considerable additional evidence has confirmed that a single variable-region sequence, defining a particular antigenic specificity, can be associated with multiple heavy-chain constant-region sequences; in other words, different classes, or isotypes, of antibody (e.g., IgG, IgM) can be expressed with identical variable-region sequences.

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  • mike
    What is germline diversity?
    8 years ago
  • outi
    How is the constant region maintained according to somatic variation theory?
    8 years ago

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