Symposium

Surv. immuno/. Res. 2:25-26 (1983) �9 1983 S. Karger AG, Basel

0252-9564/83/0021--002552.75/0

Current Problems in Antibody Diversity. Introductory Remarks

Michael Potter, Symposium Editor, Bethesda, Md.

The immunoglobulin diversity problem came into sharp focus with two historic pa- pers: the first, Niels Jerne's on the Natural Selection Theory Antibody Formation in 1955 [1]; the second, Sir MacFarlane Bur- net's clonal selection theory in 1957 [2]. These two papers provided a cellular model system for expressing diversity, mainly that a single lymphocyte and its progeny were re- stricted to produce antibody molecules with a single kind of antigen-binding site.

This, no doubt, spurred on efforts already underway on determining the molecular structure of antibodies. Since antibody to a given antigen was very heterogeneous, homo- geneous immunoglobulins were essential for the solution of this problem. The structural similarities of antibodies and myeloma pro- teins (homogeneous immunoglobulin pro- duced by neoplastic clones of plasma cells) were recognized, and immunochemists began dealing with primary structures of human and mouse myeloma proteins, in particular the kappa light chains. It soon became appar- ent from this work that one could not ex- plain, with existing dogmas, a glaring fact mainly that the carboxy half of.all the kappa light chains from one species had the same primary structure, while the amino halves of

each chain had a different sequence. Dreyer andBennett [3] in 1965 broke this logjam by proposing a radical new theory; that one im- munoglobulin polypeptide chain could be coded by two gene elements that were joined at the DNA level. This theory has now been substantiated by recently developed molecu- lar genetics of immunoglobulins and the elu- cidation of the immunoglobulin gene rear- rangement process. It is now well accepted that the major basis for diversity has been the evolutionary development of a mechanism for duplicating and retrieving V genes through gene rearrangement. Additional structural variations, however, are created by alternative gene rearrangements (i.e., forma- tion of different j unction codons or participa- tion of different joining genes themselves) and by somatic mutations and can further modify immunoglobulin V regions.

A number of unsettled questions concern- ing immunoglobulin diversity remain. We seem to have emerged from an era when spe- cific mechanisms for diversity were cham- pioned, and now most immunologists accept all three of the favorite mechanisms, i.e. mul- tiple genes, somatic mutations, and recombi- nations (in the form of gene rearrangements with J and D genes). Accepting all three kinds

26 Potter

of processes as contributing to structural di- versity, the relative importance of each must be evaluated. Further, one must now be able to show how diversity is generated during B lymphocyte development. The bone marrow can generate and release vast numbers of B lymphocytes daily; each with a rearranged VL and VH, and hence the capability for synthe- sizing a potentially unique and useful immu- noglobulin structure. Apparently, though only a limited number of these cell types ever emerges to secrete immunoglobulin, all of the potential self-destructive antibody producing cells are eliminated. Further, of the many permissive possibilities, only a characteristic few of these persist (e.g. original antigenic sin phenomenon, see Cancro). Many other ques- tions arise. What is the mechanism for differ- entiating VL and VH gene libraries? Is VI-V H pairing a stochastic process? Is the entire pos- sible repertoire of different antibody mole- cules generated continuously throughout the life of the individual? If so, how are the clones that never produce antibody elimi- nated?

Another problem area concerns antibody structure-function relationships. Where are the antigen-binding sites on immunoglobulin molecules? As we now enter the golden era of homogeneous antibodies made possible by the K6hler-Milstein hybridoma technology, it is becoming increasingly important to un- derstand the nature of antigen-binding sites. The problem of mapping the antigen-con- tacting sites on antibody molecules (particu- larly those that react with macromolecules) is a difficult one and we have only fragmentary information from a few hapten binding im- munoglobulins.

It is well accepted that the major basis for immunoglobulin gene diversity has been the evolutionary development of a mechanism for duplicating V-genes and their retrieval through gene rearrangement. Such a multi- gene system presents many genetic problems. Available evidence suggests immunoglobulin V-genes have evolved more rapidly than other gene systems and, in one species, they may be highly polymorphic. This mode of evolution - extensive gene duplication and divergence - may present special problems in immunoglobulin genetics, i.e., genetic insta- bility, redundancy, and a general panmictic genetic basis for immunoglobulin formation. Only a few of these problems can be ad- dressed at this time. However, the following discussions treat some of the current views on these problems.

References

1 Jerne, N.K.: The natural selection theory of anti- body formation. Proc. natn. Sci. USA 41:849 (1955).

2 Burnet, F.M.: A modification of Jerne's theory of antibody production using the concept of clonal selection. Aust. J. Sci. 20:67 (1957).

3 Dreyer, W.J.; Bennett, JD.: The molecular basis of antibody formation. A paradox. Proc. natn. Acad. Sci. USA 54:864 (1965).

Michael Potter, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20205 (USA)