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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.

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beta 2-Microglobulin (beta 2m)-deficient non-obese diabetic (NOD) mice were established by crossing beta 2m-deficient 129/Sv mice with NOD mice, and used to examine the possible involvement of MHC class I molecules and CD8+ T cells in the development of insulitis and diabetes. In these mice, MHC class I molecules were not expressed, resulting in no generation of CD8+ T cells. None of eight lines of beta 2m-deficient NOD mice (-/-) established developed overt diabetes by 32 weeks, while control littermates (+/+) became diabetic by 22 weeks. histological studies showed no significant lymphocyte infiltration of the islets (insulitis score: 0.03 +/- 0.03) in any of the beta 2m-deficient NOD mice (-/-) compared with littermate NOD mice (+/+) with overt insulitis (1.42 +/- 0.28). These findings support the notion that the expression of MHC class I molecules and/or CD8+ T cells plays an essential role in the infiltration of CD4+ T cells in islets as well as the development of diabetes in NOD mice.

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