A single VH family and long CDR3s are the targets for hypermutation in bovine immunoglobulin heavy chains

Lopez, Osvaldo J.; Pérez, Claudio F.; Wylle, Dwane

doi:10.1111/j.1600-065x.1998.tb01429.x

Cited by 50 publications

(36 citation statements)

References 71 publications

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“…Several key molecular mechanisms including V(D)J recombination and somatic hypermutation are fundamental to the Ab repertoire diversification in mammals (21)(22)(23). As compared with humans and mice, cattle are characterized by having a single functional IGHV family with a very limited number of IGHV genes (24)(25)(26)(27)(28), which is similar to rabbits (29)(30)(31) and pigs (32,33). The present understanding of the mechanisms involved in bovine Ab diversification is still based on the partial characterization of germline IGHV, IGHD, and IGHJ gene segments.…”

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confidence: 99%

“…A recent study suggested that the Abs with ultralong CDRH3s can generate structural diversity via combinations of somatically generated disulfides (39). A number of studies have concluded that the bovine Ab repertoire is primarily diversified by somatic hypermutation and junctional flexibility caused by nucleotide deletions and additions during the recombination process (25,26,36,40,41). However, lack of the sufficient information (such as number and physical positions) of the bovine IGHV, IGHD segments has been an obstacle to a complete elucidation of Ab repertoire diversification in cattle.…”

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confidence: 99%

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Internal Duplications of DH, JH, and C Region Genes Create an Unusual IgH Gene Locus in Cattle

Tong

Chu

et al. 2016

The Journal of Immunology

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It has been suspected for many years that cattle possess two functional IgH gene loci, located on Bos taurus autosome (BTA) 21 and BTA11, respectively. In this study, based on fluorescence in situ hybridization and additional experiments, we showed that all functional bovine IgH genes were located on BTA21, and only a truncated μCH2 exon was present on BTA11. By sequencing of seven bacterial artificial chromosome clones screened from a Hostein cow bacterial artificial chromosome library, we generated a 678-kb continuous genomic sequence covering the bovine IGHV, IGHD, IGHJ, and IGHC genes, which are organized as IGHVn-IGHDn-IGHJn-IGHM1-(IGHDP-IGHV3-IGHDn)3-IGHJn-IGHM2-IGHD-IGHG3-IGHG1-IGHG2-IGHE-IGHA. Although both of two functional IGHM genes, IGHM1 and IGHM2, can be expressed via independent VDJ recombinations, the IGHM2 can also be expressed through class switch recombination. Likely because more IGHD segments can be involved in the expression of IGHM2, the IGHM2 gene was shown to be dominantly expressed in most tissues throughout different developmental stages. Based on the length and identity of the coding sequence, the 23 IGHD segments identified in the locus could be divided into nine subgroups (termed IGHD1 to IGHD9). Except two members of IGHD9 (14 nt in size), all other functional IGHD segments are longer than 30 nt, with the IGHD8 gene (149 bp) to be the longest. These remarkably long germline IGHD segments play a pivotal role in generating the exceptionally great H chain CDR 3 length variability in cattle.

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confidence: 99%

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confidence: 99%

Internal Duplications of DH, JH, and C Region Genes Create an Unusual IgH Gene Locus in Cattle

Tong

Chu

et al. 2016

The Journal of Immunology

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“…In sheep and cows, however, somatic hypermutation generates the primary repertoire in a foreign antigen-independent process during B-cell development in the Ileal Peyer's Patches (5,6). Generally, species that use somatic hypermutation and͞or gene conversion to generate the repertoire use only one or a few variable (V) genes, whereas those using somatic hypermutation only in secondary responses express many V families (5)(6)(7)(8)(9)(10). In the amphibian Xenopus, somatic hypermutation is not used to generate the repertoire (11), and the few examples where it is known to generate the repertoire occur in mammals.…”

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confidence: 99%

Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: Possible role in antigen-driven reactions in the absence of germinal centers

Diaz

Greenberg

Flajnik

1998

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

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The new antigen receptor (NAR) gene in the nurse shark diversifies extensively by somatic hypermutation. It is not known, however, whether NAR somatic hypermutation generates the primary repertoire (like in the sheep) or rather is used in antigen-driven immune responses. To address this issue, the sequences of NAR transmembrane (Tm) and secretory (Sec) forms, presumed to represent the primary and secondary repertoires, respectively, were examined from the peripheral blood lymphocytes of three adult nurse sharks. More than 40% of the Sec clones but fewer than 11% of Tm clones contained five mutations or more. Furthermore, more than 75% of the Tm clones had few or no mutations. Mutations in the Sec clones occurred mostly in the complementarity-determining regions (CDR) with a significant bias toward replacement substitutions in CDR1; in Tm clones there was no significant bias toward replacements and only a low level of targeting to the CDRs. Unlike the Tm clones where the replacement mutational pattern was similar to that seen for synonymous changes, Sec replacements displayed a distinct pattern of mutations. The types of mutations in NAR were similar to those found in mouse Ig genes rather than to the unusual pattern reported for shark and Xenopus Ig. Finally, an oligoclonal family of Sec clones revealed a striking trend toward acquisition of glutamic͞aspartic acid, suggesting some degree of selection. These data strongly suggest that hypermutation of NAR does not generate the repertoire, but instead is involved in antigen-driven immune responses.Like the hallmark molecules of adaptive immunity (T cell receptors, Ig, and major histocompatibility complex) and the Ig gene rearrangement machinery, somatic hypermutation of Ig genes is present in the oldest group of extant jawed vertebrates, the cartilaginous fish (1-3). Similar to mutation and selection in adaptive evolution, somatic hypermutation in mice and humans is an antigen-driven process that randomly introduces mutations to Ig genes, and B cells whose receptors have affinity-enhancing mutations are selected in the germinal centers (GC) of secondary lymphoid tissues (reviewed in ref. 4). In sheep and cows, however, somatic hypermutation generates the primary repertoire in a foreign antigen-independent process during B-cell development in the Ileal Peyer's Patches (5, 6). Generally, species that use somatic hypermutation and͞or gene conversion to generate the repertoire use only one or a few variable (V) genes, whereas those using somatic hypermutation only in secondary responses express many V families (5-10). In the amphibian Xenopus, somatic hypermutation is not used to generate the repertoire (11), and the few examples where it is known to generate the repertoire occur in mammals. Such data suggest that somatic mutation first evolved for secondary immune responses and later was recruited to generate the repertoire in some species; studies of somatic hypermutation in the cartilaginous fish address this issue.In the nurse shark, Ginglymostoma cirratum...

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“…In the naïve B cell pool, 3.5% of B cells have CDRH3 ≥ 24 residues and 0.43% of them contain very long CDRH3 ≥ 28 residues [69]. However, this percentage is substantial with consideration of the total potential number of 1012 different antibodies in the human B cell repertoire.…”

Section: Bovine Cdrh3 Length Goes Beyond Expectationmentioning

confidence: 87%

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Heydarchi¹,

Quiroz²,

Purcell³

2016

J Vaccines Vaccin

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The idea of using antibodies to restrain HIV viral replication has been a growing interest since many years ago. HIV-patient serum with elite virus-neutralizing breadth has led to the preparation of broadly neutralizing antibodies (BrNAbs) with long and highly mutated CDRH3 domains that can neutralize a broad array of viral strains and prevent transmission in animal models. Recent advances have resulted in the discovery of BrNAbs that are more potent and can neutralize many HIV-1 subtypes. However, elicitation of these antibodies in infected individuals usually requires a long time of antigen exposure. Though BrNAbs are shown to be successful either therapeutically or prophylactically against HIV-1, production of these antibodies in bulk, commercial-sized batches are expensive and non-affordable particularly for poor countries. Therefore, more durable preventative or therapeutic strategies are required. Immunization of the cows with HIV Env is shown to be capable of producing 20 kg purified anti-HIV-1 BrNAbs and this amount could be sufficient for 2 million × 10 mg doses for formulation and pre-clinical testing as an HIV microbicide. In addition, bovine immunoglobulins typically have variable third heavy complementarity determining regions (CDRH3) that may potentially facilitate access to antigenic epitopes that are very difficult for other species to engage. Thus, cows could be engaged to elicit anti-HIV antibodies with the features of human BrNAbs and bovine colostrum could be a promising and cheap resource for the development of combination microbicides.

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A single VH family and long CDR3s are the targets for hypermutation in bovine immunoglobulin heavy chains

Cited by 50 publications

References 71 publications

Internal Duplications of DH, JH, and C Region Genes Create an Unusual IgH Gene Locus in Cattle

Internal Duplications of DH, JH, and C Region Genes Create an Unusual IgH Gene Locus in Cattle

Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: Possible role in antigen-driven reactions in the absence of germinal centers

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

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