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 VH 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.