TRACKING OF THE V-4-34 (V(H)4-21) GENE IN HUMAN TONSIL REVEALS CLONALISOTYPE SWITCH EVENTS AND A HIGHLY VARIABLE DEGREE OF SOMATIC HYPERMUTATION

The V-4-34 (V(H)4-21) gene has been found to encode certain IgM autoan tibodies, and is mandatory for pathological IgM anti-erythrocyte antib odies of I/i specificity. The gene is also commonly used by normal IgM -positive B lymphocytes, but its involvement in B cells which have und ergone class switching to IgG or IgA is less clear. In order to track V-4-34 gene usage and class switching events during a normal immune re sponse, we have probed RNA in a limited area of human tonsil. Results indicate that the V-4-34 gene undergoes class switching to Ige or IgA, with the progeny either remaining unmutated or containing large numbe rs of somatic mutations. Mutational patterns indicate possible 'hot sp ots', and some mutations appear deleterious. At the level of individua l B cells, we have tracked a clonal isotype switch event from IgM to I gA, with each retaining close to germ-line configuration. In addition, we have followed a clonal switch from a mutated IgM to IgG, with no f urther accumulation of somatic mutations. These data indicate that the V-4-34 gene is involved in a maturing immune response, and that the r outes to production of IgG or IgA antibodies are various.