Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus.

Berman, Jeffrey E.; Mellis, Scott; Pollock, Roberta R.; Smith, Cassandra L.; Suh, Heikyung; Heinke, Bruce; Kowal, Czeslawa; Surti, Urvashi; Chess, Leonard; Cantor, Charles R.

doi:10.1002/j.1460-2075.1988.tb02869.x

Cited by 422 publications

(232 citation statements)

References 51 publications

(51 reference statements)

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“…Human germline Ig V H -gene CDRs, particularly CDR1, are highly prone to R mutations We applied the computer algorithm to the analysis of the inherent Rf and R:S mutation ratio values of the CDRs and FRs of 24 selected human germline V H genes [21][22][23][24][25][26][27][28][29][30][31][32][33][34] , including H11 (Table 1). These V H genes are among those most-frequently expressed in the early and adult B-cell repertoires and encode natural antibodies and antibodies to foreign antigens, as well as autoantibodies in autoimmune patients.…”

Section: Hhs Public Accessmentioning

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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Section: Hhs Public Accessmentioning

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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“…Sequences were compared with the germ-line V H 6 sequence 6-1G1 [11] using the IBI MacVector software (Kodak, Rochester, NY), and point mutations were identified.…”

Section: Analysis Of V H 6-d-j H Sequencesmentioning

confidence: 99%

Somatic mutation of immunoglobulin VH6 genes in human infants

Ridings

Dinan

Williams

et al. 1998

Clinical and Experimental Immunology

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SUMMARYInfants respond to antigen by making antibody that is generally of low affinity for antigen. Somatic hypermutation of immunoglobulin genes, and selection of cells expressing mutations with improved affinity for antigen, are the molecular and cellular processes underlying the maturation of antibody affinity. We have reported previously that neonates and infants up to 2 months of age, including individuals undergoing strong immunological challenge, show very few mutated V H 6 sequences, with low mutation frequencies in mutated sequences, and little evidence of selection. We have now examined immunoglobulin genes from healthy infants between 2 and 10 months old for mutation and evidence of selection. In this age group, the proportion of V H 6 sequences which are mutated and the mutation frequency in mutated sequences increase with age. There is evidence of selection from 6 months old. These results indicate that the process of affinity maturation, which depends on cognate T-B cell interaction and functional germinal centres, is approaching maturity from 6 months old.Keywords somatic hypermutation antibody response paediatric immunology affinity maturation immunoglobulin genes V H 6

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“…This sequence was compared with the germ-line V H 6 sequence 6-1G1 [26] using the IBI MacVector software (Kodak, Rochester, NY), and any point mutations were identified. mothers also was positive for hepatitis B surface antigen.…”

Section: Analysis Of V H 6-d-j H Sequencesmentioning

confidence: 99%

Somatic hypermutation of immunoglobulin genes in human neonates

Ridings

Nicholson

Goldsworthy³

et al. 1997

Clinical and Experimental Immunology

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SUMMARYThe antibody response in the young infant is limited in several ways; in particular, responses generally are of low affinity and restricted to IgM. This raises the question whether the affinity maturation process, consisting of somatic mutation of immunoglobulin genes coupled with selection of high-affinity variants, is operative in the neonate. Re-arranged V H 6 genes were amplified by polymerase chain reaction (PCR) from cord blood and from peripheral blood of infants. Heteroduplex analysis detected mutation in only 2/18 cord blood samples, while mutations were seen from about 10 days of age onwards. Cloning and sequencing of mutated neonatal V H 6 genes showed that mutated sequences contained relatively few mutations (one to three mutations per sequence) compared with published values of about 10 in adult IgM sequences. Selection was not evident in the majority of neonatal samples. Thus mutation can occur in the human neonate, but is minimal and generally not accompanied by selection. The age at which affinity maturation develops effectively is yet to be defined.

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Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus.

Cited by 422 publications

References 51 publications

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

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

Somatic mutation of immunoglobulin VH6 genes in human infants

Somatic hypermutation of immunoglobulin genes in human neonates

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