Antibody diversity: Somatic hypermutation of rearranged VH genes

Kim, Stuart; Davis, Mark M.; Sinn, Eric; Patten, P.A.; Hood, Leroy

doi:10.1016/0092-8674(81)90399-8

Cited by 317 publications

(151 citation statements)

References 29 publications

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“…Once considered a model epitope, PC was an intensively researched topic that helped to lay the foundation of modern immunology (27)(28)(29). Although the study of PC went out of fashion during the late 1980s, in recent years, the field has undergone a renaissance.…”

Section: Discussionmentioning

confidence: 99%

“…3). Although the anti-PC repertoire is arguably skewed toward certain families of genes (IGHV3, IGKV3, and IGKV4) (28), it still does not change the narrative of a broad immune-response toward this small epitope. Although diverse, we did identify 18 clusters of highly similar clones (stereotyped BCR sets) that were present in two or more donors (Table I).…”

Section: Discussionmentioning

confidence: 99%

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Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Fiskesund

Stéen

Amara

et al. 2014

The Journal of Immunology

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Phosphorylcholine (PC) is a classic T-independent Ag that is exposed on apoptotic cells, oxidized phospholipids, and bacterial polysaccharides. Experimental as well as epidemiological studies have over the past decade implicated Abs against PC (anti-PC) as anti-inflammatory and a strong protective factor in cardiovascular disease. Although clinically important, little is known about the development of anti-PC in humans. This study was conceived to dissect the human anti-PC repertoire and generate human mAbs. We designed a PC-specific probe to identify, isolate, and characterize PC-reactive B cells from 10 healthy individuals. The donors had all mounted somatically mutated Abs toward PC using a broad variety of Ig genes. PC-reactive B cells were primarily found in the IgM+ memory subset, although significant numbers also were detected among naive, IgG+, and CD27+CD43+ B cells. Abs from these subsets were clonally related, suggesting a common origin. mAbs derived from the same donors exhibited equivalent or higher affinity for PC than the well-characterized murine T-15 clone. These results provide novel insights into the cellular and molecular ontogeny of atheroprotective PC Abs, thereby offering new opportunities for Ab-based therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Fiskesund

Stéen

Amara

et al. 2014

The Journal of Immunology

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“…Somatic hypermutation (SHM), which generates mutations in the variable region at a frequency far beyond the rate of spontaneous mutations, potentially changes the conformation of the antigen-binding site and can increase antigen recognition by up to 1,000-fold (1,2). Mutations have been observed at all four bases, but two sequence motifs, RGYW and WA (R, purine; Y, pyrimidine; W, A or T), have been shown to be the mutation hotspots (3).…”

Section: π-Cation Stacking | A-to-g Transition | Immunoglobulinmentioning

confidence: 99%

Mechanism of somatic hypermutation at the WA motif by human DNA polymerase η

Zhao

Gregory

Biertumpfel

et al. 2013

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

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Somatic hypermutation is programmed base substitutions in the variable regions of Ig genes for high-affinity antibody generation. Two motifs, RGYW and WA (R, purine; Y, pyrimidine; W, A or T), have been found to be somatic hypermutation hotspots. Overwhelming evidence suggests that DNA polymerase η (Pol η) is responsible for converting the WA motif to WG by misincorporating dGTP opposite the templating T. To elucidate the molecular mechanism, crystal structures and kinetics of human Pol η substituting dGTP for dATP in four sequence contexts, TA, AA, GA, and CA, have been determined and compared. The T:dGTP wobble base pair is stabilized by Gln-38 and Arg-61, two uniquely conserved residues among Pol η. Weak base paring of the W (T:A or A:T) at the primer end and their distinct interactions with Pol η lead to misincorporation of G in the WA motif. Between two WA motifs, our kinetic and structural data indicate that A-to-G mutation occurs more readily in the TA context than AA. Finally, Pol η can extend the T:G mispair efficiently to complete the mutagenesis.

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“…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.…”

mentioning

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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Antibody diversity: Somatic hypermutation of rearranged VH genes

Cited by 317 publications

References 29 publications

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Mechanism of somatic hypermutation at the WA motif by human DNA polymerase η

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

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