The Role of Somatic Hypermutation in the Generation of Antibody Diversity

French, Deborah L.; Laskov, Reuven; Scharff, Matthew D.

doi:10.1126/science.2658060

Cited by 291 publications

(145 citation statements)

References 89 publications

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“…To determine whether ␣ genes in the vascular cDNA library were polyclonal or oligoclonal, we sequenced the CDR3 regions. Sequence identity between B cells in this region indicates clonal relatedness (24,25); expansion of B cells with the same VDJ rearrangements and with evidence of somatic mutation are characteristic features of an immune response to Ag (24,25).…”

Section: Analysis Of ␣ Gene Sequences From the Primary Unamplified Kmentioning

confidence: 99%

Oligoclonal IgA Response in the Vascular Wall in Acute Kawasaki Disease

Rowley

Shulman

Spike

et al. 2001

The Journal of Immunology

181

113

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Kawasaki Disease (KD) is a potentially fatal acute vasculitis of childhood. Although KD is the leading cause of acquired heart disease in children in developed nations, its pathogenesis remains unknown. We previously reported the novel observation that IgA plasma cells infiltrate the vascular wall in acute KD. We have now examined the clonality of this IgA response in vascular tissue from three fatal cases of KD to determine whether it is oligoclonal, suggesting an Ag-driven process, or polyclonal, suggesting nonspecific B cell activation or a response to a superantigen. We first sequenced VDJ junctions of 44 α genes isolated from a primary, unamplified KD vascular cDNA library. Five sets of clonally related α sequences were identified, comprising 34% (15 of 44) of the isolated α sequences. Furthermore, point mutations consistent with somatic mutation were detected in the related sequences. Next, using formalin-fixed coronary arteries from two additional fatal KD cases, we sequenced VDJ junctions of α genes isolated by RT-PCR, and a restricted pattern of CDR3 usage was observed in both. We conclude that the vascular IgA response in acute KD is oligoclonal. The identification of an oligoclonal IgA response in KD strongly suggests that the immune response to this important childhood illness is Ag-driven.

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Section: Analysis Of ␣ Gene Sequences From the Primary Unamplified Kmentioning

confidence: 99%

Oligoclonal IgA Response in the Vascular Wall in Acute Kawasaki Disease

Rowley

Shulman

Spike

et al. 2001

The Journal of Immunology

181

113

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“…The molecular basis of this process was first unveiled by the analysis of the binding affinity and primary structure of monoclonal antibodies (mAbs) generated at successive stages of murine immune responses to different conjugated haptens and antigens [2][3][4][5][6][7][8][9][10] . The first exposure to antigen results in recruitment of B-cell clonotypes that bind antigen by virtue of the combinatorial and junctional specificity of their unmutated surface receptors (Ig V segments).…”

mentioning

confidence: 99%

The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement

1994

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The variable (V) genes of antigen-selected antibodies are known to exhibit a higher frequency of amino acid replacement mutations in the sequences encoding the antigen-contacting complementarity-determining regions (CDRs) than in those encoding the 'structural' framework regions (FRs). Here, Bernard Chang and Paolo Casali analyse the impact of regional differences in the codon composition of human germline Ig V H and V L genes on regional differences in the frequency of replacement mutations in the gene products (i.e. the antigen-binding sites of antibody molecules). This analysis reveals that CDR and FR sequences can differ significantly in their inherent susceptibility to amino acid replacement given any single nucleotide change. Thus, the CDR sequences of all the Ig V H genes analysed comprise a higher frequency of codons susceptible to replacement mutations than would be expected for a random sequence. Conversely, the FR sequences comprise codons less susceptible to replacement mutations than expected. Random accumulation of nucleotide changes throughout the coding sequence of an Ig V-gene segment containing CDRs inherently more prone to replacement mutations than the respective FRs would inevitably yield a higher rate of amino acid replacements in the CDRs than in the FRs. This would provide a fertile structural substrate of hypervariability for antigen selection while still maintaining the structural integrity of the FRs.The production of antibodies with progressively higher affinity for antigen is an important feature of B-cell clonotypes recruited by repeated antigenic challenge, and is referred to as affinity maturation 1 . The molecular basis of this process was first unveiled by the analysis of the binding affinity and primary structure of monoclonal antibodies (mAbs) generated at successive stages of murine immune responses to different conjugated haptens and antigens [2][3][4][5][6][7][8][9][10] . The first exposure to antigen results in recruitment of B-cell clonotypes that bind antigen by virtue of the combinatorial and junctional specificity of their unmutated surface receptors (Ig V segments). Subsequent exposures to antigen lead to accumulation of somatic point mutations in the antibody V segments and antigen selection of the highaffinity mutated B-cell clonotypes. Sequential rounds of mutation and selection eventually result in restriction of the response to those B cells with the best 'fit' for antigen 11,12 . Somatic point mutations in Ig V-gene segmentsIn the absence of negative or positive selective pressure on the gene product, a random mutational process would entail an even distribution of nucleotide changes yielding amino HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript acid replacements (R mutations) and nucleotide changes not yielding amino acid replacements (S, or silent, mutations) throughout the coding sequence. However, antigenselected antibodies have been shown to include a higher frequency of R mutations in the Ig V-gene complemen...

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“…Maturation of antibody responses is usually associated with a progressive increase of affinity [1] that reflects the combined effects of somatic hypermutation [2,3] and of an efficient antigen-driven selection process [4,5,6]. Affinity maturation then results in increased numbers of antibody-producing cells (ASC) that produce antibodies with progressively higher affinities and faster on-rates [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%