Heavy chain variable region contribution to the NPb family of antibodies: somatic mutation evident in a γ2a variable region

Bothwell, Alfred L.M.; Paskind, Michael; Reth, Michael; Imanishi‐Kari, Thereza; Rajewsky, Klaus; Baltimore, David

doi:10.1016/0092-8674(81)90089-1

Cited by 666 publications

(355 citation statements)

References 31 publications

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“…It was not until decades later that mutations were actually observed, first in the immunoglobulin protein 32 and then at the DNA level [33][34][35][36] , providing proof that a process of adaptive mutation targeted to a single locus, not observed in any other living organism, was co-opted by the immune system.…”

Section: Somatic Hypermutation and Dna Polymerasesmentioning

confidence: 99%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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PrefaceTo cope with an unpredictable variety of potential pathogenic insults, the immune system must generate an enormous diversity of recognition structures, and it does so by making stepwise modifications of key genetic loci in each lymphoid cell. This proceeds through the action of lymphoid-specific proteins acting together with the general DNA-repair machinery of the cell. Strikingly, these general mechanisms are usually diverted from their normal functions, being used in rather atypical ways in order to privilege diversity over accuracy. In this Review, we focus on the contribution of a set of DNA polymerases discovered in the last decade to these unique DNA transactions.

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Section: Somatic Hypermutation and Dna Polymerasesmentioning

confidence: 99%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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“…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)(4)(5)(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).…”

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confidence: 99%

“…Somatic mutation introduces additional variation to VH and VL domains (1,(3)(4)(5)(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)(14)(15).…”

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confidence: 99%

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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“…This V H gene encodes the heavy chain of a monoclonal IgM autoantibody that binds spectrin, fluorescein, and interestingly, 4-hydroxy-3-nitrophenyl-acetyl [33], which is also the target of the IgG antibody having the highest V H homology with ATM-2. The germline gene having the highest homology with ATM-1 is V23 [34]. In framework one of ATM-1, one residue from the germline gene is missing, and the residue preceding the deleted residue is V instead of T. The only other differences from the germline gene occur in the CDR2.…”

Section: H Gene Usage Of Lp-bm5 Derived Monoclonalsmentioning

confidence: 99%

Retrovirally Induced Mouse Anti‐TCR Monoclonals can Synergize the In Vitro Proliferative T Cell Response to Bacterial Superantigens

Dehghanpisheh

Marchalonis

1997

Scand J Immunol

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Dehghanpisheh K, Marchalonis JJ. Retrovirally Induced Mouse Anti-TCR Monoclonals can Synergize the In Vitro Proliferative T Cell Response to Bacterial Superantigens. Scand J Immunol 1997;45:645-654 Antibodies directed against the b chain of the T-cell receptor (TCR) have been detected in animals and in humans in a number of distinct immune states that do not involve direct immunization with either T cells or TCR epitopes. When C57Bl/6 mice are infected experimentally with the LP-BM5 retrovirus mixture they produce increased titres of autoantibodies directed against TCR Vb complementarity determining region 1 (CDR1) epitopes. Here, the authors utilized hybridoma technology to isolate monoclonal immunoglobulin (Ig)M antibodies (MoAbs) that arose at the peak of infection. The authors characterized the binding specificity tested using synthetic peptides modelling the CDR1 segments of 24 distinct Vb gene products and determined the V H gene usage by two such monoclonals. One binds to a restricted set of TCR Vb CDR1 peptides, and the second reacts with approximately half of the CDR1 peptide homologues. These MoAbs are specific for T-cell receptor b chains and do not bind to immunoglobulin light chains or to unrelated protein molecules. Both MoAbs bind to intact T cells expressing the Vb domain (human Vb8 and mouse Vb11) from which selection peptides were derived, and costimulate a Vb specific in vitro T cell proliferative response induced by the staphylcoccal enterotoxin E (SEE) superantigen.

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Heavy chain variable region contribution to the NPb family of antibodies: somatic mutation evident in a γ2a variable region

Cited by 666 publications

References 31 publications

DNA polymerases in adaptive immunity

DNA polymerases in adaptive immunity

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

Retrovirally Induced Mouse Anti‐TCR Monoclonals can Synergize the In Vitro Proliferative T Cell Response to Bacterial Superantigens

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