High-frequency expression of a conserved kappa light-chain variable-region gene in chronic lymphocytic leukemia.

Kipps, Thomas J.; Fong, Sherman; Tomhave, Eric; Chen, Pojen P.; Goldfien, Robert; Carson, Dennis A.

doi:10.1073/pnas.84.9.2916

Cited by 91 publications

(48 citation statements)

References 44 publications

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“…The same families of V, and V, genes are frequently used in a proportion of patients with essential mixed cryoglobulinemia, Waldenstrom's macroglobulinemia, and CLL (26,(33)(34)(35)(36)(37). The leukemic cells in CLL express the CD5 molecule and produce autoantibodies; the same subpopulation of B cells is found in increased numbers in peripheral blood and salivary gland samples from patients with primary SS (38-40).…”

Section: Discussionmentioning

confidence: 99%

Lymphoproliferation in primary sjögren's syndrome. evidence of selective expansion of a b cell subset characterized by the expression of cross‐reactive idiotypes

Shokri

Mageed

Maziak

et al. 1993

Arthritis & Rheumatism

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Objective. To evaluate the possibility that lymphoproliferation in primary Sjogren's syndrome (SS) arises within a subset of B cells.Methods. A panel of monoclonal antibodies (MAb) specific for rheumatoid factor (RF)-associated cross-reactive idiotypes (CRI) and anti-V, and anti-V, subgroup antibodies were used to define the clonality of B lymphocytes undergoing neoplastic transformation in 5 patients with primary SS. Anti-CRI antibodies were also used to study longitudinal variations in serum paraprotein levels and in vitro regulation of IgM and IgM-RF production by peripheral blood lymphocytes. in serum and culture supernatants by enzyme-linked immunosorbent assay. Heavy and light chain isotypes and V, subgroups of the paraproteins were determined by immunoelectrophoresis, immunofixation, and Western blotting.Results. Paraproteins from all patients expressed an epitope associated with VJIIb sub-subgroup of light chains. Three of the paraproteins were cryoglobulins with RF activity, all of which expressed the VJIIbassociated CRI (detected by MAb 17-109) and the V,I-associated CRI (detected by MAb G6 and GS). None of the paraproteins expressed the V,III-associated CRI (detected by MAb B6 and D12). The CRI were consistently expressed over a period of 5-6 years. The anti-CRI and anti-subgroup antibodies substantially inhibited spontaneous production of IgM-RF and IgM by peripheral blood B lymphocytes from 3 of the SS patients.

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Section: Discussionmentioning

confidence: 99%

Lymphoproliferation in primary sjögren's syndrome. evidence of selective expansion of a b cell subset characterized by the expression of cross‐reactive idiotypes

Shokri

Mageed

Maziak

et al. 1993

Arthritis & Rheumatism

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“…Certain proteins were nonreactive with all related antisera and were designated ".. § NT, idiotype not assigned. 11 The light chain was assigned a kappa sugroup based on amino acid determination (39). 'NA, not applicable.…”

Section: Resultsmentioning

confidence: 99%

Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans.

Silverman

Goldfien²,

P³

et al. 1988

J. Clin. Invest.

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“…Calculation of the inherent Rf and R:S mutation ratio values for the CDRs and FRs of 12 human germline V L genes [35][36][37][38][39][40][41][42][43][44][45][46] (Table 2), selected by criteria similar to those used for the V H -gene sampling, revealed Rf CDR values that were higher than the expected 0.7452 Rf value (t = 11.50, p = 9.01×10 −8 ) and the respective Rf FR values (t = 10.2, p = 3.0 × 10 −7 ), but lower values overall than those calculated for the V H -segment CDRs (t = 5.45, p = 3.0 × 10 −6 ). The V L -gene Rf FR values did not significantly differ either from the expected value or from the values calculated for the 24 V H genes.…”

Section: Human Germline Ig V L -Gene Cdr Sequences Are Not Prone To Rmentioning

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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High-frequency expression of a conserved kappa light-chain variable-region gene in chronic lymphocytic leukemia.

Cited by 91 publications

References 44 publications

Lymphoproliferation in primary sjögren's syndrome. evidence of selective expansion of a b cell subset characterized by the expression of cross‐reactive idiotypes

Lymphoproliferation in primary sjögren's syndrome. evidence of selective expansion of a b cell subset characterized by the expression of cross‐reactive idiotypes

Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans.

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

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