Natural evolution of a human virus-specific antibody gene repertoire by somatic hypermutation requires both hotspot-directed and randomly-directed processes.
Somatic hypermutation of antibody genes is mediated by activation-induced cytidine deaminase and targets primarily hotspot motifs. We tested the hypothesis that the antibody variable genes of virus-specific B cells from infants exhibit a decreased frequency of somatic mutations compared with adults. We also sought to determine whether virus-specific B cells exhibit predominantly hotspot or randomly directed processes. We analyzed somatic mutations in rotavirus (RV)-specific B cells from otherwise healthy but recently RV-infected infants or adults in comparison with B cells from healthy volunteers not recently infected. We compared these antibody variable gene sequences with those derived from RV-specific B cells from an adult patient with X-linked hyper-IgM syndrome (XHIM). We found that the overall mutational frequency within the antibody variable region was lowest in RV-specific B cells from RV-infected infants, followed by randomly selected B cells, followed by RV-specific B cells from the patient with XHIM. RV-specific memory B cells from healthy adults exhibited the highest frequency of mutations. Approximately half of mutations in random or RV-specific B cells from adults or infants occurred at the DGYW/WRCH or WA/TW hotspot motifs. These findings suggest that virus-specific antibodies require both hotspot and randomly-directed processes.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA. hendrik.weitkamp@vanderbilt.edu
Jörn-Hendrik
JH
Weitkamp
Bonnie J
BJ
Lafleur
Harry B
HB
Greenberg
James E
JE
Crowe
D000328:Adult; D020816:Amino Acid Motifs / Q000235:genetics; D000914:Antibodies, Viral / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology*; D020029:Base Pairing; D002999:Clone Cells; D019143:Evolution, Molecular; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007223:Infant; D012333:RNA, Messenger / Q000302:isolation & purification; D012401:Rotavirus / Q000276:immunology*; D012400:Rotavirus Infections / Q000276:immunology / Q000821:virology; D027041:Somatic Hypermutation, Immunoglobulin
D000914:Antibodies, Viral; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D012333:RNA, Messenger