Sequential generation of antibody diversity during B-cell development.

It has become increasingly apparent that generation of and variation in antigen-combining sites of antibodies occurs sequentially during B-cell development. Allelic and isotypic exclusion mechanisms ensure that a B cell produces antibody molecules having a single kind of combining site. A major reason for evolution of mechanisms which result in asynchronous formation of functional H and L chain genes may be the need for allelic and isotypic exclusion; but this may not be the only advantage of asynchronous formation of H and L chain genes. The evolution of mechanisms causing nonjunctional somatic mutation late in B cell development - only after antigen exposure apparently - may result from the biological advantages of: (1) 'fine tuning' of the combining site; (2) a response to an anti-idiotype regulatory network, or (3) expanded memory.