Natural evolution of a human virus-specific antibody gene repertoire by somatic hypermutation requires both hotspot-directed and randomly-directed processes.

Weitkamp JH, Lafleur BJ, Greenberg HB, Crowe JE
Hum Immunol. 2005 66 (6): 666-76

PMID: 15993712 · DOI:10.1016/j.humimm.2005.02.008

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.

MeSH Terms (15)

Adult Amino Acid Motifs Antibodies, Viral B-Lymphocytes Base Pairing Clone Cells Evolution, Molecular Humans Immunoglobulin Heavy Chains Immunoglobulin Variable Region Infant RNA, Messenger Rotavirus Rotavirus Infections Somatic Hypermutation, Immunoglobulin

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