Somatic Mutation of Human Immunoglobulin V Genes: Bias, Rate, and Regulation

Insel, Richard A.; Varade, William S.; Chu, Yu‐Waye; Marin, Elides; Fuleihan, Ramsay; Geha, Raif S.

doi:10.1111/j.1749-6632.1995.tb55820.x

Cited by 10 publications

(1 citation statement)

References 43 publications

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“…Replacement (R) mutations, which involve amino acid changes, were present in 88% of cases and numbered 1–20 per patient. By four different methods (Jukes & King, 1979; Chang & Casali, 1994; Insel et al , 1995; Davi et al , 1996), the numbers of silent and replacement mutations in the CDR and FR regions of the Ig rearrangement were used to detect the presence of antigen selection. In the CDR:FR ratio method, 14 rearrangements showed a ratio >0·3, suggesting antigen selection (Table I; Chang & Casali, 1994; Varade et al , 1995; Davi et al , 1996; Miranda et al , 1999).…”

Section: Resultsmentioning

confidence: 99%

Somatic hypermutation and VH gene usage in hairy cell leukaemia

et al. 2006

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SummaryTo examine the usage and mutational status of VH genes in hairy cell leukaemia (HCL), we analysed 24 immunoglobulin heavy chain (IgH) sequences expressed in 23 patients. None had premature stop codons. VH3-23 was the most common gene and a VH6 gene was observed for the first time in HCL. Although the mean mutation frequency was 6AE1%, slightly higher than in previous HCL series, four patients had 99AE6-100% homology to germline sequences, three of whom had high tumour burdens and poor outcomes. Despite the high mutation frequency, only two of 24 rearrangements had clear statistical evidence of antigen-dependent somatic mutation. Our results increase the database of reported functional HCL rearrangements to 94 in 92 patients. Overall, both gene usage and mutation frequency are very similar to mucosa-associated lymphoid tissue-type marginal zone lymphoma. The data are consistent with HCL originating from post-germinal centre marginal zone B cells, although the heterogeneity observed suggests that HCL may originate differently in some patients, and this could have implications for prognosis and treatment.

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Section: Resultsmentioning

confidence: 99%

Somatic hypermutation and VH gene usage in hairy cell leukaemia

et al. 2006

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Dynamics of One-pass Germinal Center Models: Implications for Affinity Maturation

Oprea

Nimwegen

Perelson

2000

Bulletin of Mathematical Biology

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During an immune response, the affinity of antibodies that react with the antigen that triggered the response increases with time, a phenomenon known as affinity maturation. The molecular basis of affinity maturation has been partially elucidated. It involves the somatic mutation of immunoglobulin V-region genes within antigen-stimulated germinal center B cells and the subsequent selection of high affinity variants. This mutation and selection process is extremely efficient and produces large numbers of high affinity variants. Studies of the architecture of germinal centers suggested that B cells divide in the dark zone of the germinal center, then migrate to the light zone, where they undergo selection based on their interaction with antigen-loaded follicular dendritic cells, after which they exit the germinal center through the mantle zone. Kepler and Perelson questioned this architecturally driven view of the germinal center reaction. They, as well as others, argued that the large number of point mutations observed in germinal center B cell V-region genes, frequently 5 to 10 and sometimes higher, would most likely render cells incapable of binding the antigen, if no selection step was interposed between rounds of mutations. To clarify this issue, we address the question of whether a mechanism in which mutants are generated and then selected in one pass, with no post-selection amplification, can account for the observed efficiency of affinity maturation. We analyse a set of one-pass models of the germinal center reaction, with decaying antigen, and mutation occurring at transcription or at replication. We show that under all the scenarios, the proportion of high affinity cells in the output of a germinal center varies logarithmically with their selection probability. For biologically realistic parameters, the efficiency of this process is in clear disagreement with the experimental data. Furthermore, we discuss a set of, possibly counterintuitive, more general features of one-pass selection models that follow from our analysis. We believe that these results may also provide useful intuitions in other cases where a population is subjected to selection mediated by a selective force that decays over time.

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