Shift toward T helper 1 cytokines by type II collagen-reactive T cells in patients with rheumatoid arthritis

Abstract

Objective To investigate the impact of type II collagen (CII)–reactive T cells on the Th1/Th2 cytokine balance in patients with rheumatoid arthritis (RA). Methods T cell proliferative responses to bovine CII were examined in synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) by mixed lymphocyte culture. CII‐reactive T cell lines were generated from the SFMC and PBMC. Interferon‐γ (IFNγ), interleukin‐12 (IL‐12), and IL‐4 were measured by enzyme‐linked immunosorbent assay in the SF, sera, and culture supernatants of PBMC and SFMC that had been stimulated with CII. Results The frequency of CII‐reactive T cells was higher in the PBMC from RA patients than in that from osteoarthritis patients and healthy control subjects. In RA patients, CII‐reactive T cells were more prevalent in SFMC than in PBMC. The mean level of IFNγ and the ratio of IFNγ to IL‐4 were significantly higher in the culture supernatants of T cells stimulated with CII; these differences were more prominent in SFMC. Levels of IL‐12 in the culture supernatants of SFMC and PBMC stimulated with CII were significantly higher than those in unstimulated supernatants. T cell responsiveness correlated well with the level of type 1 cytokines in culture supernatants from RA T cells stimulated with CII. In the CII‐reactive cell lines, the increased production of IFNγ was consistent with clonal expansion. Conclusion CII‐reactive T cells are more abundant in SFMC than in PBMC and are strongly associated with a shift toward Th1 cytokine in the inflamed joints of RA patients. Our results suggest that a skewing toward type 1 cytokines by CII‐reactive T cells may play an important role in the chronic inflammatory process of RA.

Immunosuppressive effects of mesenchymal stem cells in collagen-induced mouse arthritis

“…T helper 1 (Th1) and CD8? T cells are reported to be involved in RA pathogenesis [15][16][17]. When triggered by antigenic peptides such as CII, a major component of hyaline cartilage acting as an auto-antigen in RA [18,19], T cells stimulate monocytes, macrophages, and synovial fibroblasts to secrete proinflammatory cytokines such as TNF-a [16].…”

Critical role of M. tuberculosis for dendritic cell maturation to induce collagen‐induced arthritis in H‐2b background of C57BL/6 mice

“…Elevated T helper 1 (Th1) responses in draining lymphnodes and arthritis joints of CIA-induced C57BL/6 mice It has been suggested that RA is mediated by IFN-c-producing Th1 cells, which stimulate inflammatory responses. 8,9 It is also reported that Th1 responses are predominant in DLN of CIA-induced mice of DBA/1 background at the time of onset of arthritis. 10 To examine whether Th1 cells are predominant also in CIA-induced C57BL/6 mice, DLN cells were isolated from mice with CIA induced by CII in CFA containing 5 mg/ml of M. tuberculosis or control mice that were immunized with CII in IFA 10 days after the second immunization and were examined for cytokine production by quantitative reverse transcription (RT)-PCR.…”

Lymphocyte Proliferation to Collagen Type I in Dogs

“…An explanation might be found in recent studies from human patients with RA studying paired PBMC and synovial fluid mononuclear cells (SFMC) samples cultured with collagen type II. These studies demonstrated that the T-lymphocyte responses were more frequent and vigorous in SFMC than in PBMC (Kim et al, 1999;Park et al, 2001;Kim and Kim, 2005) which might suggest that these collagen-specific T-lymphocytes home to joints. We have not investigated SFMC reactivity to collagen type I in this study, however, it would be worthwhile to test this concept in the future as it could result in a clearer differentiation of the immune response in dogs that will sustain a CrCL rupture in their contralateral stifle joint and dogs that will not.…”