Variability in the Lambda Light Chain Sequences of Mouse Antibody

Weigert, Martin; Cesari, Italo M.; Yonkovich, Shirlee; Cohn, Melvin

doi:10.1038/2281045a0

Cited by 533 publications

(293 citation statements)

References 15 publications

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“…The approach involved subclones of BL2 Burkitt's lymphoma cells and DNA sequence analysis to reveal immunoglobulin V-region induced mutagenesis [1]. We found an inverse relationship between the pol β expression level in BL2 subclones and the amount of V-region mutations after induction through activation of surface receptors (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…In humoral immunity after stimulation of mature B cells with antigen presenting cells, base substitution mutations accumulate in the genes encoding the variable regions of light and heavy chain immunoglobulin molecules [1,2]. It is thought that this process is initiated with conversion of cytosine to uracil by the enzymatic activity of the activation-induced cytidine deaminase (AID) [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

et al. 2007

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Somatic hypermutation (SHM) is a fundamental process in immunoglobulin gene maturation that results in increased affinity of antibodies toward antigens. In one hypothesis explaining SHM in human B cells, the process is initiated by enzymatic deamination of cytosine to uracil in the immunoglobulin gene V-region and this in turn triggers mutation-prone forms of uracil-DNA base excision repair (BER). Yet, an uncertainty with this model is that BER of uracil-DNA in mammalian cells is generally error-free, wherein DNA polymerase β (pol β) conducts gap-filling synthesis by insertion of bases according to Watson-Crick rules. To evaluate this inconsistency, we examined pol β expression in various SHM proficient human BL2 cell line subclones. We report that expression of pol β in SHM proficient cell lines was strongly down-regulated. In contrast, in other BL2 subclones, we found that SHM was deficient and that pol β expression was much higher than in the SHM proficient subclones. We also found that overexpression of recombinant human pol β in a SHM proficient subclone abrogated its capacity for SHM. These results suggest that down-regulation of the normal BER gap-filling DNA polymerase, pol β, accompanies induced SHM in BL2 cells. This is consistent with the hypothesis that normal error-free BER must be silenced to make way for an error-prone BER process that may be required during somatic hypermutation.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

et al. 2007

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“…Such selection of B cells bearing high affinity immunoglobulin receptors is believed to bring about an apparent predominance of somatic mutation in CDR regions in addition to an increase in the ratio of replacement mutation relative to silent mutation. At first we thought that frequent somatic mutations in CDR1 and CDR2 as well as a high ratio of replacement mutation in CDRs resulted from antigenic selection during immunization (25,41). However, a similar pattern of mutation was observed in the nucleotide sequences of unexpressed A2-chain genes.…”

Section: Somatic Mutation Of Rearranged Unexpressed V-ja2mentioning

confidence: 94%

Somatic mutation in constant regions of mouse lambda 1 light chains.

Motoyama

Okada

Azuma

1991

Proc. Natl. Acad. Sci. U.S.A.

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To study the distribution of somatic mutation, we determined nucleotide sequences of rearranged Alchain genomic DNA from four hybridomas obtained from C57BL/6 mice that had been immunized with (4-hydroxy-3-nitrophenyl)acetyl-conjugated chicken gamma globulin. In total, 114 nucleotide substitutions were observed, with neither insertion nor deletion. Sixty-one mutations occurred in the variable-joining region genes (VAI-JA1) and 49 in joiningconstant (JAI-CAl) introns. Although frequency decreased with distance from the VAI-JAl coding region, somatic mutations occurred in the entire JAI-CAI intron and even in the CAI region. We found four nucleotide substitutions in CA, genes, all of which were replacement mutations. Therefore, the mechanism responsible for somatic mutation is operative into the CA, exons. Nucleotide sequences of rearranged but inactive A2-chain genes from two hybridomas were also examined and compared with those of Al-chain genes. The clustering of replacement mutations in complementarity-determining regions in the inactive A2-chain genes similar to the active Al-chain genes suggested a mechanism that induces somatic mutation preferentially in this region even in the absence of antigenic selection.Sequence diversity in the variable (V) domains of immunoglobulins is generated by random recombination of V, diversity (D), and joining (J) gene segments of heavy (H) chains or V and J segments of light (L) chains (1). Insertion of the N region and flexibility in the recombination sites also result in the variation in the V domain sequences (2). Somatic mutation introduces additional variation to VH and VL domains (1, 3-6). It has been shown that somatic mutation is triggered by stimulation with thymus-dependent antigens (3, 4, 6, 7) and is found in rearranged immunoglobulin genes both active and inactive (8)(9)(10)(11)(12). The somatic mutation mechanism is as yet unclear, although several models have been proposed (13-15). To evaluate possible mechanisms, information on the distribution of somatic mutations is undoubtedly required (5,(16)(17)(18)(19). Both murine and human immunoglobulin gene sequences show a lack of somatic mutation in the constant (C) region exons of H and K chains (5,17,20,21). However, Cleary et al. (22) reported the occurrence of somatic mutation in the human CA exon. Because of the complex genetics and gene structure of human immunoglobulins, it is rather difficult to distinguish between nucleotide variations arising from somatic mutation and those from other mechanisms.Murine A chains are particularly useful for examining the distribution of somatic mutations because of their simple gene structures (23-25). The A-chain genes possess only two VL genes (VA1 and VA2), which recombine with JA1, JA2, orJA3.Selective recombination of VA, to JA1CA1 or JA3-CA3 has been commonly observed (26,27). Therefore, a variation in sequence as a result of somatic mutation could be easily distinguished from that generated by other mechanisms.Furthermore, the J-C introns of A-chain genes di...

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“…As early as 1957 a theory of seleetive lymphocyte multiplication was suggested by Burnet [12]. Later on Weigert et al [13] reported somatic mutations in the variable region of immunoglobulins-Werblin et al [14] thought that the diversity of genetic information required to synthesize all the various antibodies formed during the course of the normal heterogeneous immune response would be present before antigen exposure. Inananimalmodel they found that not until approximately 6 weeks after immunization did rabbits produce antibodies of the highest affinity.…”

Section: Resultsmentioning

confidence: 99%

Avidity of Aspergillus umbrosus IgG antibodies in farmer's lung disease

Kaukonen

Savolainen

Viander

et al. 1994

Clinical and Experimental Immunology

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SUMMARYFarmer's lung disease (FL)-the commonest form of allergic alveolitis caused by repeated inhalation of mouldy hay. is associated with exposure lo the fungus Aspergithis umbrosus among Einnish farmers. The antigen-binding avidity of A. j/mA/asM.s-specific IgG antibodies was measured in 12 EL patients in acute phases of initial and recurrent attacks and during 1 year foliow up as well as in 12 healthy farmers and five healthy urban controls. The farmers* groups were further divided into two subgroups: subjects with short exposure ( < 7 years) and subjects with long exposure (> 25 years). During the first acute phase PL patients with long exposure exhibited a high avidity of /I, umbrosusspecifie IgG antibodies that remained high during the I year follow up, although tlie A. umbrosusspecific IgG antibody tilre decreased. A re-exposure lo mouldy hay leading to a recurrence further enhanced ihc maturation ofthe antibody avidity, so thai an even higher A. um6r05«s-specific IgG avidity with a less signiticant increase of antibody tilre occurred than during the first acute attack. Notably higher IgG anlibody avidity was observed in FL patients with long exposure than in healthy farmers or in healthy controls.

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Variability in the Lambda Light Chain Sequences of Mouse Antibody

Cited by 533 publications

References 15 publications

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

Down-regulation of DNA polymerase β accompanies somatic hypermutation in human BL2 cell lines

Somatic mutation in constant regions of mouse lambda 1 light chains.

Avidity of Aspergillus umbrosus IgG antibodies in farmer's lung disease

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