B Cell Clonal Expansion and Somatic Hypermutation of Ig Variable Heavy Chain Genes in the Synovial Membrane of Patients with Osteoarthritis

Da, Reng-Rong; Qin, Yingzhi; Baeten, Dominique; Zhang, Yiping

doi:10.4049/jimmunol.178.1.557

Cited by 58 publications

(39 citation statements)

References 49 publications

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“…1B), independently of potentially confounding factors such as the MHC background (HLA-DR shared epitope) and the presence of intracellular citrullinated proteins (data not shown) (31,32). These data confirm and extend our previous observations (26,28) showing that ectopic lymphoid neogenesis in the synovial membrane is neither restricted to nor preferentially associated with autoantibody positive rheumatic conditions.…”

Section: Synovial Lymphoid Neogenesis Is Not Restricted To Rasupporting

confidence: 80%

“…A mucosal B cell lymphoma and peripheral blood cells from a healthy individual were used as positive and negative control. Using exactly the same approach on OA synovial tissue, we recently demonstrated that the number of analyzed sequences is sufficient to evaluate clonal expansion and affinity maturation (28).…”

Section: Immunglobulin Variable H Chain Gene Sequencingmentioning

confidence: 99%

“…We performed Ig variable H chain (Ig V H ) gene analysis of 4 RA samples with synovial lymphoid neogenesis and 4 RA samples without synovial lymphoid neogenesis as described previously (28). Total RNA was extracted from RA synovial biopsies (6 biopsies per patient) using an RNAeasy kit (Qiagen).…”

Section: Immunglobulin Variable H Chain Gene Sequencingmentioning

confidence: 99%

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B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

Cantaert

Kölln

Timmer³

et al. 2008

The Journal of Immunology

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102

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B lymphocyte autoimmunity plays a crucial role in the pathogenesis of rheumatoid arthritis. The local production of autoantibodies and the presence of ectopic lymphoid neogenesis in the rheumatoid synovium suggest that these dedicated microenvironments resembling canonical lymphoid follicles may regulate the initiation and maturation of B cell autoimmunity. In this study, we assessed experimentally the relevance of ectopic lymphoid neogenesis for B cell autoimmunity by a detailed structural, molecular, and serological analysis of seropositive and seronegative human synovitis. We demonstrate that synovial lymphoid neogenesis is a reversible process associated with inflammation which is neither restricted to nor preferentially associated with autoantibody positive rheumatic conditions. Despite the abundant expression of key chemokines and cytokines required for full differentiation toward germinal center reactions, synovial lymphoid neogenesis in rheumatoid arthritis only occasionally progresses toward fully differentiated follicles. In agreement with that observation, we could not detect Ag-driven clonal expansion and affinity maturation of B lymphocytes. Furthermore, ectopic lymphoid neogenesis is not directly associated with local production of anti-citrullinated protein Abs and rheumatoid factor in the rheumatoid joint. Therefore, we conclude that synovial lymphoid neogenesis is not a major determinant of these rheumatoid arthritis-specific autoantibody responses.

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Section: Synovial Lymphoid Neogenesis Is Not Restricted To Rasupporting

confidence: 80%

Section: Immunglobulin Variable H Chain Gene Sequencingmentioning

confidence: 99%

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B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

Cantaert

Kölln

Timmer³

et al. 2008

The Journal of Immunology

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102

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“…32 and Figure 6C in the present study). As a consequence, B cells may expand clonally and hypermutate somatically in the presence of OA FLS (41).…”

Section: Discussionmentioning

confidence: 99%

Transmembrane BAFF from rheumatoid synoviocytes requires interleukin‐6 to induce the expression of recombination‐activating gene in B lymphocytes

Rochas¹,

Hillion²,

Saraux³

et al. 2009

Arthritis & Rheumatism

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“…Analysis of the Ig V H gene was performed as described elsewhere (37,43). Ig V H and VDJ genes were amplified by PCR and ligated into the pGEM-T vector (Promega, Madison, WI) and transfected into Escherichia coli DH5␣.…”

Section: Methodsmentioning

confidence: 99%

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Cantaert¹,

Brouard²,

Thurlings³

et al. 2009

Arthritis & Rheumatism

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Objective. The association of HLA-DRB1 alleles with anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA-seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA؉ versus ACPA-RA patients.Methods. Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA؉ RA patients, 7 ACPA-RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis.Results. ACPA؉ and ACPA-RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA؉ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA-synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis.Conclusion. The T cell repertoire is specifically restricted in RA patients with ACPA؉ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPAseropositive RA.

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B Cell Clonal Expansion and Somatic Hypermutation of Ig Variable Heavy Chain Genes in the Synovial Membrane of Patients with Osteoarthritis

Cited by 58 publications

References 49 publications

B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

Transmembrane BAFF from rheumatoid synoviocytes requires interleukin‐6 to induce the expression of recombination‐activating gene in B lymphocytes

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

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