Possible deletion of a developmentally regulated heavy-chain variable region gene in autoimmune diseases.

Yang, Pei‐Ling; Olsen, Nancy J.; Siminovitch, Katherine A.; Olee, Tsaiwei; Kozin, Franklin; Carson, Dennis A.; Chen, Pojen P.

doi:10.1073/pnas.87.20.7907

Cited by 36 publications

(16 citation statements)

References 34 publications

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“…12,25 A duplication polymorphism of two genes, IGHV3-30 and IGHV4-28, was also described. [29][30][31] The duplicates in the latter case were shown to be in a tandem configuration. 31 The pseudogene IGHV3-29 was shown to be in a present/absent manner in this duplicated region.…”

Section: Discussionmentioning

confidence: 99%

Determination of gene organization in the human IGHV region on single chromosomes

Pramanik

et al. 2005

Genes Immun

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Organization of the IGHV genes (n ¼ 108) on single human chromosomes has been determined by detecting these sequences in single sperm using multiplex PCR amplification followed by microarray detection. A total of 374 single sperm samples from five Caucasian males were studied. Three deletion/insertion polymorphisms (Del I-Del III) with deletion allele frequencies ranging from 0.1 to 0.3 were identified. Del I is a previously reported polymorphism affecting three IGHV genes (IGHV1-8, IGHV3-9, and IGHV2-10). Del II affects a region 2-18 kb containing two pseudogenes IGHV(II)-28.1 and IGHV3-29, and Del III spans B21-53 kb involving genes IGHV4-39, IGHV7-40, IGHV(II)-40-1, and IGHV3-41. Deletion alleles of both Dels II and III were found in a heterozygous state, and therefore, could not be easily detected if haploid samples were not used in the study. Results of the present study indicate that deletions/insertions together with other possible chromosomal rearrangements may play an important role in forming the genetic structure of the IGHV region, and may significantly contribute to antibody diversity. Since these three polymorphisms are located within or next to the 3 0 half of the IGHV region, they may have an important role in the expressed IGHV gene repertoire during immune response.

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Section: Discussionmentioning

confidence: 99%

Determination of gene organization in the human IGHV region on single chromosomes

Pramanik

et al. 2005

Genes Immun

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“…Results from similar analysis indicated that V3-30b (hv3005) was absent in the other three patients but that one or more V3-30 elements were present in each of the controls. High frequency of deletion of V3-30b in RA patients has been shown by others [39].…”

Section: Representation Of Individual V H Genes In Peripheral Blood Bmentioning

confidence: 92%

VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA)

Huang

Jiang

Hufnagle³

et al. 1998

Clinical and Experimental Immunology

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SUMMARYThe human antibody repertoire has been demonstrated to have a marked V-gene-dependent bias that is conserved between individuals. In RA patients, certain heavy chain V genes (V H ) have been found to be preferentially used for encoding autoantibodies. To determine if such preferential use of V H genes in autoantibodies is associated with a general distortion of the V gene repertoire in RA patients, the V H composition of peripheral blood B cells was analysed among four RA patients and four age-and sexmatched healthy controls. Usage of individual V H genes (eight V H 3 and three V H 4 genes tested by hybridization with a set of gene-specific oligonucleotide probes) was highly biased among RA patients, but no evidence of a distortion in the bias was observed compared with healthy controls. However, the occurrence of somatic mutations in these V H genes (estimated by differential hybridization with motifspecific oligonucleotide probes targeted to CDR and FR of the tested genes, and by DNA sequence analysis) was strikingly different between patients and healthy subjects. The number of V H 3 rearrangements that had accumulated somatic mutations and the number of mutations per rearrangement were significantly elevated in three of the four RA patients. A slight but not significant elevation in mutations among rearranged V H 4 genes was also observed in these patients. These data suggest that although usage of individual V H genes among peripheral blood B cells is not affected by the disease, the autoimmune process may involve a significant fraction of the B cell compartment.

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“…It has been reported that certain polymorphisms within the human Ig Vk locus are associated with rheumatoid arthritis (11,12). In addition, it has been shown that polymorphisms in the two human VH genes, both of which can encode anti-DNA Abs are related with the development of autoimmune diseases (13)(14)(15). Other study has also suggested that VH haplotypes may have linkage with autoAb production (16).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a germline Vk gene encoding cationic anti-DNA antibody and role of receptor editing for development of the autoantibody in patients with systemic lupus erythematosus.

Suzuki¹,

Harada²,

Mihara³

et al. 1996

J. Clin. Invest.

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We found previously that cationic anti-DNA autoantibodies (autoAbs) have nephritogenic potential and usage of a specific germline Vk gene, A30, has major influences on cationic charge of the autoAb in human lupus nephritis. In the present study, we have characterized A30 germline Vk gene using cosmid cloning technique in patients with SLE. A30 gene locus locates in less than 250 kb from the Ck region, and the cationic anti-DNA mRNA used the upstream Jk2 gene, indicating that cationic anti-DNA mRNA is a product of primary gene rearrangement. By using PCR technique, we found that A30 gene locus in the genome was defective in eight out of nine SLE patients without nephritis.

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Possible deletion of a developmentally regulated heavy-chain variable region gene in autoimmune diseases.

Cited by 36 publications

References 34 publications

Determination of gene organization in the human IGHV region on single chromosomes

Determination of gene organization in the human IGHV region on single chromosomes

VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA)

Characterization of a germline Vk gene encoding cationic anti-DNA antibody and role of receptor editing for development of the autoantibody in patients with systemic lupus erythematosus.

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