Somatic evolution of variable region structures during an immune response.

Immunization of strain A mice with p-azophenylarsonate-conjugated protein stimulates B cells that synthesize anti-p-azophenylarsonate antibodies. A large fraction of these cells produce antibodies with variable (V) regions encoded by a single heavy chain V gene segment together with multiple combinations of diversity, heavy chain joining, light chain variable, and light chain joining gene segments. Early in the immune response, these V regions are not somatically mutated. One of these V regions is initially expressed by only a minority of the responding B cells but binds p-azophenylarsonate with the highest affinity. After a secondary immunization, B cells synthesizing mutated derivatives of this single V region dominate the response and bind p-azophenylarsonate with even higher affinity than does the unmutated V region. These results suggest that antigen directs both the expression of the immune repertoire and the amplification of V region diversity by a sequential process of clonal selection of B cells expressing receptor antibodies encoded by unmutated V genes, induction of mutation in the V genes expressed by the selected cells, and reselection of B cells expressing antibodies with mutated V regions of higher affinity.