Somatic diversification in the heavy chain variable region genes expressed by human autoantibodies bearing a lupus-associated nephritogenic anti-DNA idiotype.

Demaison, Christophe; Chastagner, Patricia; Thèze, Jacques; Zouali, Moncef

doi:10.1073/pnas.91.2.514

Cited by 57 publications

(21 citation statements)

References 23 publications

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“…In the heavy chain variable regions, mutations in CDR2 are more prevalent than mutations in CDR1. This is consistent with other studies showing an increased frequency of somatic mutation in CDR2 of V H 3 and V H 4 genes encoding autoantibodies (18,38). Radic and Weigert have suggested that CDR2 of the heavy chain plays an important role in DNA binding, and a large number of murine anti-DNA antibodies also display extensive mutation of CDR2 in the heavy chain V region (39).…”

Section: Discussionsupporting

confidence: 81%

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Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Manheimer-Lory

Zandman‐Goddard²,

Davidson³

et al. 1997

J. Clin. Invest.

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The F4 idiotype is a heavy chain determinant expressed almost exclusively on IgG immunoglobulins and is highly associated with specificity for double-stranded DNA. Since high-titered F4 expression is present predominantly in sera of patients with systemic lupus erythematosus (SLE), we thought F4ϩ IgG antibodies might constitute a useful subset of immunoglobulins in which to investigate lupus-specific alterations in variable (V) region gene expression or in the process of somatic mutation. This molecular analysis of F4 ϩ B cell lines generated from lupus patients demonstrates that despite the strong association of F4 reactivity with specificity for native DNA, there is no apparent V H gene restriction. Furthermore, V H gene segments encoding these antibodies are also used in protective immune responses.An examination of the process of somatic mutation in F4 ϩ antibodies showed no abnormality in frequency of somatic mutation nor in the distribution of mutations in complementarity-determining regions or framework regions. However, there was a decrease in targeting of mutations to putative mutational hot spots. This subtle difference in mutations present in these antibodies may reflect an intrinsic defect in mutational machinery or, more likely, altered state of B cell activation that affects the mutational process and perhaps also negative selection. (

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Section: Discussionsupporting

confidence: 81%

“…Since nephritogenic antibodies are often cationic (16)(17)(18), it was of interest to determine the isoelectric points of the heavy and light chain variable region sequences. Most F4 reactive heavy chains are cationic; only two are not, and these two derive from non-DNA-binding antibodies (Table IV).…”

Section: Resultsmentioning

confidence: 99%

Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Manheimer-Lory

Zandman‐Goddard²,

Davidson³

et al. 1997

J. Clin. Invest.

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“…The V H germlines DP33(V H 3), V H 4.18, DP53(V H 43) and V H 44.21 used by MCLs examined in the present study are frequently employed by autoantibodies such as rheumatoid factors and natural autoantibodies (Demaison et al, 1994;Huang & Stollar, 1993;Ermel et al, 1993). Thus, MCL may also be transformed from autoreactive B-cell clones.…”

Section: Discussionmentioning

confidence: 97%

Ongoing immunoglobulin gene mutations in mantle cell lymphomas

Diss

et al. 1997

Br J Haematol

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Summary.Mantle cell lymphomas (MCL) frequently show a vaguely follicular growth pattern. This phenomenon is thought to result from the colonization of reactive B-cell follicles by tumour cells. In view of the unique property of the germinal centre environment, antigen stimulation may play a role in the expansion of the tumour. To assess this, we have examined ongoing Ig mutations, which are genetic markers of B cells in persistent response to antigen stimulation, in five MCLs including two cases derived from the gastrointestinal tract known as lymphomatous polyposis (LP). We have specifically analysed Ig ongoing mutations in tumour cells from multiple lesions in one case and in tumour cells microdissected from colonized follicles in two cases. The consensus Ig V H sequences in four MCLs were identical, or almost identical (three cases 100%, one case 99% homology) to the published germlines, which in each case were those frequently employed by autoantibodies. The consensus Ig V H sequence in the remaining case displayed 95 . 5% homology to the closest published germline. This may represent derivation from an unknown V H germline or a rare instance of somatic mutations. Extensive sequencing of the rearranged Ig genes revealed ongoing mutations within the tumour clone in two cases: one was a LP with multiple lesions of the gastrointestinal tract and the other was a nodal MCL in which tumour cells from colonized follicles were analysed. Our results indicate that MCLs are derived from pre-germinal centre B cells, possibly autoreactive B-cell clones. The ongoing mutations identified suggest a possible involvement of antigen stimulation in the clonal expansion of a proportion of MCLs.

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“…The presence or absence of the 4-61 segment also could affect the relative location of 4-51. On the other hand, these two segments were shown to be involved in generating anti-DNA autoantibodies in the patients with systemic lupus erythematosus (42)(43)(44). The usage of the V H segments could be considerably affected by their organization.…”

Section: Discussionmentioning

confidence: 99%

Determination of gene organization in individual haplotypes by analyzing single DNA fragments from single spermatozoa

Cui

1998

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

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To determine human Ig heavy chain variable region (V H ) gene segment organization on individual homologous chromosomes, an efficient approach has been developed. Single spermatozoa were used as subjects for the study. Upon sperm lysis, V H regions in each sperm were randomly sheared into fragments by the random Brownian force. The fragments were separated from each other by aliquoting the lysate into a certain number of tubes. The gene segments in the V H 1 and V H 4 families in each tube were identified by denaturing gradient gel electrophoresis after PCR amplification. The polymorphic V H sequences were used to determine the parental origins of the analyzed sperm. V H segment organization in the parental haplotypes was determined by aligning the overlapping fragments from the spermatozoa with the corresponding haplotypes. Based on this comparison between the resulting haplotype maps and the composite map reported previously, the V H region on chromosome 14 could be subdivided into four portions. The numbers and compositions of the V H gene segments differ considerably among the maps in two portions, but are highly conserved in the other two. The data also indicate that the V H region on chromosome 15 may contain a large duplicated block with copy number varying among haplotypes. The approach used in the present study may be used to construct high-resolution haplotype maps without molecular cloning.For many human multigene families, determination of gene organization on individual homologous chromosomes is a challenging issue for several reasons: (i) the diploidy of the human genome, (ii) the genes sharing a high degree of sequence identity in each family, (iii) variation in DNA sequences and gene compositions among the haplotypes, (iv) different chromosomal locations, (v) occupation of large chromosomal regions, and (vi) recent duplications. In this paper, we show that all of these issues can be addressed by analyzing single DNA fragments from the haploid genomes of individual spermatozoa.Two human Ig heavy chain variable region (V H ) families, V H 1 and V H 4, were used for the analysis. Human V H gene segments are located on three chromosomes, 14q32, 15q11, and 16p11 (1-6). However, only about half of the V H segments on chromosome 14 are functional (7,8). Each haploid human genome contains Ϸ120 distinct V H gene segments (5,7,8). The V H segments are classified into seven families (V H 1-V H 7) with segments sharing Ͼ80% sequence identity in each family (9-15). Extensive polymorphisms for the V H region on chromosome 14 have been reported (16)(17)(18)(19)(20)(21)(22). A composite map for this region was constructed recently (8). Several studies showed that the number and composition of the V H gene segments in some portions of the V H region on chromosome 14 varied among the haplotypes (23-30). However, the extent of variation in the entire region remains unclear because no haplotype maps for this region have been constructed. The V H segment organization on the other two chromosomes has not been ...

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Somatic diversification in the heavy chain variable region genes expressed by human autoantibodies bearing a lupus-associated nephritogenic anti-DNA idiotype.

Abstract: Monoclonal anti-DNA antibodies bearing a lupus nephritis-associated idiotype were derived from five patients with systemic lupus erythematosus (SLE

Cited by 57 publications

References 23 publications

Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Ongoing immunoglobulin gene mutations in mantle cell lymphomas

Determination of gene organization in individual haplotypes by analyzing single DNA fragments from single spermatozoa

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