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

Abstract

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.

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

“…This is the first study, to our knowledge, of these antibodies in lung disease, and our findings will require further validation; nevertheless, it is interesting to consider their significance. The pathogenic role of ACPA in rheumatoid arthritis is thought to involve complement activation [24] and alteration of the T-cell repertoire in the joint [25], with reaction to self as a result. Our data would suggest that this may be organ specific, occurring just in the joint despite the fact that any protein containing citrulline could be a target for ACPA.…”

Interleukin‐17–positive mast cells contribute to synovial inflammation in spondylarthritis

“…In a recent study on the synovial immunopathologic processes of Behçet's disease, we observed a marked synovial infiltration with mast cells in patients with psoriatic arthritis (PsA), one of the prevalent phenotypic subtypes of SpA (19). Considering the potential role of aberrant innate immune responses in the pathogenesis of SpA (9,10), this observation urged us to investigate the presence and potential role of mast cells in SpA synovitis.…”

“…The cellular and molecular pathways responsible for the differences and commonalities between these two types of arthritis remain largely unknown. Based on a series of systematic synovial studies, we recently proposed that joint inflammation in SpA may be driven mainly by cells of the innate immune system, including specific macrophage subsets and granulocytes, whereas molecular pathways related to (auto)antigen-specific T and B lymphocyte activation predominate in RA synovitis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10).…”

Antibodies Against Citrullinated Proteins and Filaggrin

“…Besides its localization and antibody reactivity, researchers who wanted to determine the trigger for ACPA production also focused on the capacity of citrullinated proteins to induce T-cell proliferation, since there is a strong association between ACPA titers and HLA-DRB1 alleles in RA and since ACPA are class-switched antibodies [ 62 ]. The proliferative response of peripheral blood mononuclear cells to both fi laggrin and citrullinated fi laggrin was rarely observed and did not signifi cantly differ between RA patients and healthy controls [ 63 ], again indicating that (citrullinated) (pro)fi laggrin is not the trigger for RA.…”