Potential Contribution of V H Gene Replacement in Immunity and Disease

A bstract : V H replacement occurs through RAG‐mediated recombination between a cryptic recombination signal sequence (cRSS) presented in a rearranged V H gene and a 23‐bp RSS from an upstream V H gene. V H replacement renews the entire V H coding region and extends the immunoglobulin heavy‐chain (IgH) CDR3 regions preferentially with charged amino acids. V H replacement occurs in bone marrow‐immature B cells and contributes significantly to the primary B‐cell repertoire in humans. However, the biological significance of V H replacement is not clear. Our recent studies revealed elevated frequencies of V H replacement products in different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. Moreover, elevated frequencies of V H replacement products were also found in patients with human immunodeficiency virus or hepatitis C virus infections. These results provide the first clue that V H replacement contributes to autoimmune disease and antiviral immunity, and they also suggest a potential link between viral infection and autoimmune disease.