Vλ and Jλ‐Cλ gene segments of the human immunoglobulin λ light chain locus are separated by 14 kb and rearrange by a deletion mechanism

Combriato, Gabriele; Hg, Klobeck

doi:10.1002/eji.1830210627

Cited by 112 publications

(67 citation statements)

References 55 publications

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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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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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“…Humla3c93 was most homologous to the VAIII. 1 germline gene (23), but with only 82% homology in a 288-bp overlap. This suggests that la3c93 was encoded by another VA3 germline gene, designated Humlv3c93 (Figure 3).…”

Section: Cdrz-n R P S G V P D R F S G S K S G T S Aatcggccctcaggggtccmentioning

confidence: 99%

Preferential utilization of a novel vλ3 gene in monoclonal rheumatoid factors derived from the synovial cells of rheumatoid arthritis patients

Ermel

Kenny

Wong

et al. 1994

Arthritis & Rheumatism

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Objective. To further our understanding about the molecular genetics of rheumatoid factor (RF) in rheumatoid arthritis (RA).Methods. The heavy and light chain variable region (V) genes of 5 new human monoclonal IgM RFs were cloned and sequenced using the polymerase chain reaction and the dideoxynucleotide termination method.Results. The results reveal the recurrent usage in two RA patients of a novel VA3 germline gene, designated Humlv3c93. Specifically, in 2 of 3 RFs (C93 and D53) from one patient, the light chains in the VA geneencoded region were identical to each other and to the light chain of an RF (H4) from another patient. Serologically, the light chains of these 3 RFs were classified as members of the VA3b sub-subgroup. Each of the RFs was encoded by a different VH gene. Both C93 and D53 bound specifically with human and rabbit IgG, whereas H4 was monospecific for rabbit IgG.Conclusion. Since the lv3c93 gene is not homologous to any reported VA sequence from natural autoantibodies, it is possible that lv3c93 may represent a disease-specific RF-related VA gene. Moreover, the amino acid sequence CSGGSCY in the third complementaritydetermining regions of 2 of the RF heavy chains is encoded by the DLR2 gene segment and has been found

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“…The V L sequences of CBM␣8 and LTM␣35 differed by several amino acid residues. The V H and V L sequences of both CBM␣8 and LTM␣35 belonged to the V H 5 and V 1 families (17,40), respectively (Table I). These Abs had the same canonical classes of CDR loops 1 and 2 of V H and V L .…”

Section: Cord Blood-derived Natural Ab Recognizes Fc⑀ri␣mentioning

confidence: 99%

A High-Affinity Natural Autoantibody from Human Cord Blood Defines a Physiologically Relevant Epitope on the FcεRIα

Bobrzynski

Fux

Vogel

et al. 2005

The Journal of Immunology

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Natural Abs represent the indigenous immune repertoire and are thus present at birth and persist throughout life. Previously, human autoantibodies to the α domain of the high-affinity IgE receptor (FcεRIα) have been isolated from Ab libraries derived from normal donors and patients with chronic urticaria. To investigate whether these anti-FcεRIα Abs are present in the germline repertoire, we constructed a phage Fab display library from human cord blood, which represents the naive immune repertoire before exposure to exogenous Ags. All isolated clones specific to the FcεRIα had the same sequence. This single IgM Ab, named CBMα8, was strictly in germline configuration and had high affinity and functional in vitro anaphylactogenic activity. Inhibition experiments indicated an overlapping epitope on the FcεRIα recognized by both CBMα8 and the previously isolated anti-FcεRIα Abs from autoimmune and healthy donors. This common epitope on FcεRIα coincides with the binding site for IgE. Affinity measurements demonstrated the presence of Abs showing CBMα8-like specificity, but with a significantly lower affinity in i.v. Ig, a therapeutic multidonor IgG preparation. We propose a hypothesis of escape mutants, whereby the resulting lower affinity IgG anti-FcεRIα Abs are rendered less likely to compete with IgE for binding to FcεRIα.

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V_λ and J_λ‐C_λ gene segments of the human immunoglobulin λ light chain locus are separated by 14 kb and rearrange by a deletion mechanism

Cited by 112 publications

References 55 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

Preferential utilization of a novel vλ3 gene in monoclonal rheumatoid factors derived from the synovial cells of rheumatoid arthritis patients

A High-Affinity Natural Autoantibody from Human Cord Blood Defines a Physiologically Relevant Epitope on the FcεRIα

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