Molecular and cellular mechanisms of joint destruction in rheumatoid arthritis: two cellular mechanisms explain joint destruction?

261

160

Objective. To investigate whether T cells in the inflamed joints of patients with rheumatoid arthritis (RA) preferentially produce the T helper 1 (Th1) cytokines, interferon‐γ (IFNγ) and interleukin‐2 (IL‐2), or the Th2 cytokine, IL‐4, when compared with corresponding peripheral blood—derived T cells. Methods. Synovial fluid mononuclear cells (SFMC) and corresponding peripheral blood mononuclear cells (PBMC) from 10 patients with RA were analyzed, either directly or after in vitro stimulation, for the intracellular presence of Th1 and Th2 cytokines. The amount of secreted cytokine in the cell culture supernatants was measured by enzyme‐linked immunosorbent assay (ELISA). Results. IFNγ‐containing cells were detected in the unstimulated SFMC, but not in the PBMC, of 3 patients with RA. Cells positive for IL‐2 or IL‐4 were not detected in the unstimulated samples. Following stimulation, the mean percentage of cells containing Th1 cytokines was significantly increased in the SFMC compared with the PBMC; no differences were found in the mean percentage of IL‐4—containing cells. A comparable shift toward Th1 cytokines was observed when the amount of secreted cytokine was determined by ELISA. Conclusion. A shift toward T cells with a Th1 cytokine profile was observed in the joints of patients with RA. Since an imbalance between Th1 and Th2 cells is thought to be of pathogenic significance, this finding might have implications for the development of new therapies for RA.

Section: A B Discussionmentioning

confidence: 99%

Shift toward T lymphocytes with a T helper 1 cytokine‐secretion profile in the joints of patients with rheumatoid arthritis

Dolhain

Heiden

Haar

et al. 1996

261

160

“…Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial proliferation and abnormal immune responses that ultimately lead to joint erosion (1). The persistent invasive and destructive growth of synovial tissue is one of the main histopathologic characteristics in patients with RA.…”

mentioning

confidence: 99%

“…The persistent invasive and destructive growth of synovial tissue is one of the main histopathologic characteristics in patients with RA. Proliferating synoviocytes in the vicinity of the affected cartilage produce matrix-degrading molecules and express growth factors, cytokines, adhesion molecules, and certain protooncogenes such as c-fos and cjun (1)(2)(3)(4).…”

mentioning

confidence: 99%

Direct evidence of high DNA binding activity of transcription factor AP‐1 in rheumatoid arthritis synovium

Asahara

Fujisawa

Kobata

et al. 1997

100

Objective. To investigate the possible activation of transcription factor AP‐1 in rheumatoid arthritis (RA) and its involvement in the pathogenesis of RA. Methods. Synovial tissues and peripheral blood samples were obtained from 25 patients with RA and 5 patients with osteoarthritis (OA) during arthroplasty and synovectomy. The synovial tissue was digested with collagenase and separated into adherent and nonadherent cells by plastic‐adhesion methods. Nuclear extracts obtained from each sample were examined by electrophoretic mobility shift assay to determine the DNA binding activity of AP‐1. The expression of c‐fos and c‐jun messenger RNA (mRNA) was examined by in situ reverse transcription assay. Results. A markedly high DNA binding activity of AP‐1 was detected in the synovial tissues of RA patients, while virtually no activity or only a little activity was observed in OA patients. Following separation of adherent and nonadherent cells, the AP‐1 activity was mainly detected in adherent cells, which consisted of synovial cells and macrophages. However, the activity was significantly higher in the mononuclear cells infiltrating into RA synovium than in RA peripheral blood mononuclear cells. The high DNA binding activity of AP‐1 in RA correlated with the expression of c‐fos and c‐jun mRNA in situ. Furthermore, AP‐1 binding activity also correlated with disease activity. Conclusion. In RA synovium, AP‐1 DNA binding activity was constitutively up‐regulated. These findings suggest that AP‐1 may play an important role in the pathogenesis of RA, including synovial hyperplasia and abnormal immune responses.

“…Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive destruction of joint cartilage and other tissue structures (1). A histologic hallmark of the disease is the formation of an aggressive pannus, which invades cartilage and bone (2).…”

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confidence: 99%

Comparative analysis of cathepsin l, cathepsin d, and collagenase messenger rna expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis, by in situ hybridization

Keyszer

Heer²,

Kriegsmann³

et al. 1995

Objective. To compare the expression of cathepsin L, cathepsin D, and collagenase messenger RNA (mRNA) in synovial specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA).Methods. The expression of cathepsins L and D as well as collagenase mRNA in synovial tissues from 8 patients with RA, 6 patients with OA, and 2 patients with noninflamed joints was evaluated using in situ hybridization with digoxigenin-labeled RNA probes.Results. Both RA and OA synovial tissue expressed cathepsins L and D as well as collagenase mRNA. The expression of the cathepsins was markedly higher in interstitial regions and, to some extent, in perivascular infiltrates of RA synovial tissue compared with OA specimens. Conclusion. Cathepsins L and D mRNA are expressed differently in RA and OA synovial tissues, supporting the concept that these enzymes may contribute to the influx of mononuclear cells into RA synovium. Moreover, the data reveal that the expression of collagenase and cathepsins in RA and OA synovial lining is otherwise largely similar, and suggest that the adhesion