Year-end Sale % OFF 
Abstract
VH replacement refers to RAG-mediated secondary recombination of the IgH genes, which renews almost the entire VH gene coding region but retains a short stretch of nucleotides as a VH replacement footprint at the newly generated VH–DH junction. To explore the biological significance of VH replacement to the antibody repertoire, we developed a Java-based VH replacement footprint analyzer program and analyzed the distribution of VH replacement products in 61,851 human IgH gene sequences downloaded from the NCBI database. The initial assignment of the VH, DH, and JH gene segments provided a comprehensive view of the human IgH repertoire. To our interest, the overall frequency of VH replacement products is 12.1%; the frequencies of VH replacement products in IgH genes using different VH germline genes vary significantly. Importantly, the frequencies of VH 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 VH 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 VH replacement products suggested that they had been actively involved in immune responses. These results provide a global view of the distribution of VH replacement products in human IgH genes, especially in IgH genes derived from autoimmune diseases and anti-viral immune responses.
Highlights
To protect our body from various infectious agents, the adaptive immune system has evolved the capability to generate a vast number of antibody (Ab) specificities through somatic rearrangement of previously separated variable (V), diversity (D), and joining (J) gene segments to form the variable domain exons of immunoglobulin genes [1,2,3]
To explore the biological significance of VH replacement, we developed a Java-based computer program and analyzed 61,851 human IgH gene sequences from the NCBI database to determine the distribution of VH replacement products
Identical IgH gene sequences in the original NCBI database were removed based on their VH–DH–JH junctions and the remaining 39,438 unique human IgH gene sequences with identifiable VH, DH, and JH genes were further analyzed to identify potential VH replacement products and calculate the frequencies of VH replacement products in subsequent analyses
Summary
To protect our body from various infectious agents, the adaptive immune system has evolved the capability to generate a vast number of antibody (Ab) specificities through somatic rearrangement of previously separated variable (V), diversity (D) (for heavy chain only), and joining (J) gene segments to form the variable domain exons of immunoglobulin genes [1,2,3]. The diversified IgH repertoire is generated at different levels, including the random recombination of V, D, and J genes segments, imprecise processing of the coding-ends, addition of non-template nucleotides by terminal deoxynucleotidyl transferase (TdT), random pairing of IgH with Igκ or Igλ light chains, and later through somatic hypermutation and class switch recombination during antigen dependent germinal center reaction [2]. Analyses of the Ig gene repertoires of different autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) revealed skewed usages of specific germline VH genes [14,15,16], unusually long CDR3 regions within the IgH and IgL genes [17, 18], and www.frontiersin.org
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
