Accumulation of V(H) Replacement Products in IgH Genes Derived from Autoimmune Diseases and Anti-Viral Responses in Human

V(H) replacement refers to RAG-mediated secondary recombination of the IgH genes, which renews almost the entire V(H) gene coding region but retains a short stretch of nucleotides as a V(H) replacement footprint at the newly generated V(H)–D(H) junction. To explore the biological significance of V(H) replacement to the antibody repertoire, we developed a Java-based V(H) replacement footprint analyzer program and analyzed the distribution of V(H) replacement products in 61,851 human IgH gene sequences downloaded from the NCBI database. The initial assignment of the V(H), D(H), and J(H) gene segments provided a comprehensive view of the human IgH repertoire. To our interest, the overall frequency of V(H) replacement products is 12.1%; the frequencies of V(H) replacement products in IgH genes using different V(H) germline genes vary significantly. Importantly, the frequencies of V(H) replacement products are significantly elevated in IgH genes derived from different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and allergic rhinitis, and in IgH genes encoding various autoantibodies or anti-viral antibodies. The identified V(H) replacement footprints preferentially encoded charged amino acids to elongate IgH CDR3 regions, which may contribute to their autoreactivities or anti-viral functions. Analyses of the mutation status of the identified V(H) replacement products suggested that they had been actively involved in immune responses. These results provide a global view of the distribution of V(H) replacement products in human IgH genes, especially in IgH genes derived from autoimmune diseases and anti-viral immune responses.