High frequencies of identical T cell clonotypes in synovial tissues of rheumatoid arthritis patients suggest the occurrence of common antigen‐driven immune responses

Ikeda, Yoko; Masuko, Kayo; Nakai, Yoshihisa; Kato, Tomohiro; Hasanuma, T; Yoshino, Shinichi; Mizushima, Yutaka; Nishioka, Kusuki; Yamamoto, Kazuhiko

doi:10.1002/art.1780390312

Cited by 71 publications

(46 citation statements)

References 46 publications

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“…The most accepted concept is that the presence of synovial T cell expansions reflects activation and/or proliferation in response to a local antigen (54)(55)(56). This would be consistent with our finding that the profiles identified in synovium are not merely a reflection of peripheral blood alterations, as well as with our previous demonstrations of HLA-DRB-restricted presentation of autoantigens in RA synovitis (17)(18)(19).…”

Section: Discussionsupporting

confidence: 92%

“…Second, the strong association between ACPAϩ RA and HLA-DRB1 alleles does not allow for determining the extent to which the TCR repertoire restriction is shaped by the DRB-restricted antigen or by the class II molecule itself (55). It has been reported that HLA-DR4ϩ healthy control subjects do not differ from HLA-DR4-healthy controls in terms of the size of clonal expansions or the families that were expanded, but the unaffected siblings of RA patients displayed clonal CD4ϩ T cell specificities (47), which suggests that the TCR repertoire may be intrinsically shaped by the broader genetic background (46,57).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

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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“…Because each CDR3 sequence demonstrates unique mobility on nondenatured gel due to its unique singlestrand conformation, the identical mobility of the amplified V␤ CDR3 region on a gel indicates that the clones are identical. This rule has always been confirmed by sequencing (32).…”

Section: Transferred Do1110 T Cells Infiltrated Into the Arthritic Amentioning

confidence: 63%

Antigen-Specific T Cells Transduced with IL-10 Ameliorate Experimentally Induced Arthritis Without Impairing the Systemic Immune Response to the Antigen

Setoguchi

Misaki

Araki

et al. 2000

The Journal of Immunology

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For the treatment of rheumatoid arthritis, efficient drug delivery methods to the inflamed joints need to be developed. Because T cells expressing an appropriate autoantigen-specific receptor can migrate to inflamed lesions, it has been reasoned that they can be employed to deliver therapeutic agents. To examine the ability and efficiency of such T cells as a vehicle, we employed an experimentally induced model of arthritis. Splenic T cells from DO11.10 TCR transgenic mice specific for OVA were transduced with murine IL-10. Adoptive transfer of the IL-10-transduced DO11.10 splenocytes ameliorated OVA-induced arthritis despite the presence of around 95% nontransduced cells. Using green fluorescent protein as a marker for selection, the number of transferred cells needed to ameliorate the disease was able to be reduced to 104. Preferential accumulation of the transferred T cells was observed in the inflamed joint, and the improvement in the disease was not accompanied by impairment of the systemic immune response to the Ag, suggesting that the transferred T cells exert their anti-inflammatory task locally, mainly in the joints where the Ag exists. In addition, IL-10-transduced DO11.10 T cells ameliorated methylated BSA-induced arthritis when the arthritic joint was coinjected with OVA in addition to methylated BSA. These results suggest that T cells specific for a joint-specific Ag would be useful as a therapeutic vehicle in rheumatoid arthritis for which the arthritic autoantigen is still unknown.

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“…T cells are thought to play crucial roles in many autoimmune diseases. For example, CD4 ϩ T cells are the largest subpopulation of mononuclear cells and contribute the majority of lymphocytes to synovial tissue in human RA and other autoimmune diseases (26)(27)(28)(29). To identify CD4 ϩ T cells in sick mice, we stained sections of their paws with biotin-labeled rat anti-mouse CD4 antibodies and fluoresceinlabeled streptavidin.…”

Section: Gag Binding As Distinct Phenotype Of Infiltrating Cellsmentioning

confidence: 99%

Glycosaminoglycans are a potential cause of rheumatoid arthritis

Wang

Roehrl²

2002

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

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Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory disease of connective tissue with unknown etiology. We investigated whether aberrant immune responses to glycosaminoglycans (GAGs), a major component of joint cartilage, joint fluid, and other soft connective tissue, causes this disease. Here we show that injection of GAGs such as hyaluronic acid, heparin, and chondroitin sulfates A, B, and C induce arthritis, tendosynovitis, dermatitis, and other pathological conditions in mice. We developed a technique by staining tissue specimens with fluorochrome-or biotin-labeled GAGs to visualize the direct binding between cells and GAGs. We discovered that inflammatory infiltrates from the affected tissue are dominated by a distinct phenotype of GAG-binding cells, a significant portion of which are CD4 ؉ T cells. GAG-binding cells seem to be expanded in bone marrow of GAG-immunized mice. Furthermore, we identified GAG-binding cells in inflamed synovial tissue of human patients with RA. Our findings suggest that carbohydrate self-antigenic GAGs provoke autoimmune dysfunctions that involve the expansion of GAG-binding cells which migrate to anatomical sites rich in GAGs. These GAG-binding cells might, in turn, promote the inflammation and pathology seen both in our murine model and in human RA.

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High frequencies of identical T cell clonotypes in synovial tissues of rheumatoid arthritis patients suggest the occurrence of common antigen‐driven immune responses

Cited by 71 publications

References 46 publications

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

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

Antigen-Specific T Cells Transduced with IL-10 Ameliorate Experimentally Induced Arthritis Without Impairing the Systemic Immune Response to the Antigen

Glycosaminoglycans are a potential cause of rheumatoid arthritis

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