Immunoglobulin variable-region gene usage in systemic autoimmune diseases

Dörner, Thomas; Lipsky, Peter E.

doi:10.1002/1529-0131(200112)44:12<2715::aid-art458>3.0.co;2-l

Cited by 43 publications

(39 citation statements)

References 113 publications

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“…In contrast to previous reports (21,23), analysis of somatic hypermutations (SHM) revealed significantly reduced levels in IgH and Ig light (IgL) chain V region genes (VH, V, and V) cloned from SLE patients (P Ͻ 0.0001 for VH, P Ͻ 0.0001 for V, and P Ͻ 0.0001 for V; Fig. 1D, Fig.…”

Section: Resultscontrasting

confidence: 94%

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Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors

Mietzner

Tsuiji

Scheid

et al. 2008

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

210

187

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Persistent autoantibody production in patients with systemic lupus erythematosus (SLE) suggests the existence of autoreactive humoral memory, but the frequency of self-reactive memory B cells in SLE has not been determined. Here, we report on the reactivity of 200 monoclonal antibodies from single IgG؉ memory B cells of four SLE patients. The overall frequency of polyreactive and HEp-2 self-reactive antibodies in this compartment was similar to controls. We found 15% of IgG memory B cell antibodies highly reactive and specific for SLE-associated extractable nuclear antigens (ENA) Ro52 and La in one patient with serum autoantibody titers of the same specificity but not in the other three patients or healthy individuals. The germ-line forms of the ENA antibodies were non-self-reactive or polyreactive with low binding to Ro52, supporting the idea that somatic mutations contributed to autoantibody specificity and reactivity. Heterogeneity in the frequency of memory B cells expressing SLE-associated autoantibodies suggests that this variable may be important in the outcome of therapies that ablate this compartment.autoimmunity ͉ B cell ͉ repertoire ͉ self-tolerance

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Section: Resultscontrasting

confidence: 94%

“…IgGϩ memory B cells from this patient were also abnormal in that Ͼ25% of the B cells expressed a functional Ig and Ig light-chain transcript as compared with 0% in HC and 0-2% in the other SLE patients [ Fig. S3 and Table S2, Table S3, Table S4, Table S5, Table S6, and Table S7; (21,22)]. …”

Section: Resultsmentioning

confidence: 99%

Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors

Mietzner

Tsuiji

Scheid

et al. 2008

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

210

187

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“…It is interesting to note that four of the six anti-C1q IgG Fabs belong to the VH2 gene family, which has rarely been reported in that context. Along with the observed increased somatic hypermutation, this is consistent with findings that Ag selection pressure along with VL receptor editing might shape the Ig repertoire differently in autoimmune disease compared with healthy controls (59,(62)(63)(64). Nevertheless, the factors that lead to this apparent abnormal B cell tolerance accounting for B cell maturation and affinity selection remain to be explored.…”

Section: Discussionsupporting

confidence: 86%

Autoantibodies against C1q in Systemic Lupus Erythematosus Are Antigen-Driven

Schaller

Bigler

Danner

et al. 2009

The Journal of Immunology

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“…Our belief is that the BCR lacks the capacity to terminate RAG expression. Thus, uncontrolled ongoing secondary V(D)J rearrangement could account for excessive autoantibody production, [35][36][37][38] and may be a characteristic of aberrant peripheral B cells in SLE, rather than of the expansion of a B-cell subset that normally do not express RAG. 39 Furthermore, we did not observe any increase of j-and k-coexpressing B cells after anti-IgM stimulation.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐6 is responsible for aberrant B‐cell receptor‐mediated regulation of RAG expression in systemic lupus erythematosus

Hillion¹,

Garaud²,

Devauchelle³

et al. 2007

Immunology

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SummaryDefective regulation of secondary immunoglobulin V(D)J gene rearrangement promotes the production of autoantibodies in systemic lupus erythematosus (SLE). It remains unclear, however, whether the regulation of the recombination-activating genes RAG1 and RAG2 is effective in SLE. RAG1 and RAG2 messenger RNA expression was analysed before and after in vitro activation of sorted CD19 + CD5 -B cells with anti-immunoglobulin M antibodies, in 20 SLE patients and 17 healthy controls. The expression of CDK2 and p27 Kip1 regulators of the RAG2 protein, were examined. The levels of interleukin-6 (IL-6) and its influence on RAG regulation were also evaluated in vitro. SLE patients had increased frequency of RAG-positive B cells. B-cell receptor (BCR) engagement induced a shift in the frequency of j-and k-positive cells, associated with a persistence of RAG messenger RNA and the maintenance of RAG2 protein within the nucleus. While expression of the RAG2-negative regulator CDK2 was normal, the positive regulator p27 Kip1 was up-regulated and enhanced by BCR engagement. This effect was the result of the aberrant production of IL-6 by SLE B cells. Furthermore, IL-6 receptor blockade led to a reduction in p27 Kip1 expression, and allowed the translocation of RAG2 from the nucleus to the cytoplasm. Our study indicates that aberrant production of IL-6 contributes to the inability of SLE B cells to terminate RAG protein production. Therefore, we hypothesize that because of constitutive IL-6 signalling in association with BCR engagement, SLE B cells would become prone to secondary immunoglobulin gene rearrangements and autoantibody production.

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Immunoglobulin variable-region gene usage in systemic autoimmune diseases

Cited by 43 publications

References 113 publications

Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors

Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors

Autoantibodies against C1q in Systemic Lupus Erythematosus Are Antigen-Driven

Interleukin‐6 is responsible for aberrant B‐cell receptor‐mediated regulation of RAG expression in systemic lupus erythematosus

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