The T lymphocytes that reside in the synovium of the inflamed joints in patients with rheumatoid arthritis display severe hyporesponsiveness upon antigenic stimulation, which is probably due to their constant subjection to high levels of oxidative stress. Here we report that the synovial fluid T lymphocytes exert severely impaired phosphorylation of the adaptor protein linker for activation of T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated by ζ-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular basis underlying the deficient phosphorylation of LAT and consequently the hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane displacement of LAT. We demonstrate that the subcellular localization of LAT is sensitive to changes in the intracellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activation of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glutathione levels with N-acetyl-l-cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial fluid T lymphocytes as a consequence of oxidative stress.

The integral membrane protein linker for activation of T cells (LAT) is a central adapter protein in the T-cell

The data demonstrate significantly increased concentrations of TRX in the SF and ST of RA patients when compared with the levels in patients with other joint diseases. Evidence is presented that the local environment in the rheumatic joint contributes to increased TRX production. Based on its growth-promoting and cytokine-like properties, it is proposed that increased expression of TRX contributes to the disease activity in RA.

Objective. In rheumatoid arthritis (RA), treatment with tumor necrosis factor ␣ (TNF␣) binding agents has proven to be highly effective. Downregulation of the proinflammatory cytokine cascade and a reduced migration of leukocytes into the joints have been proposed as modes of action of TNF␣ blockade. We investigated whether alterations in the number of circulating pro-and antiinflammatory T cell subsets contribute to the therapeutic effect of monoclonal antibodies (mAb) against TNF␣ in RA patients.Methods. Phenotypic analysis of peripheral blood T cell subsets was performed on blood from RA patients before and after treatment with an anti-TNF␣ mAb.Results. An accumulation of primed CD45RA؊ T cells of both the CD4؉ and the CD8؉ T cell population was seen shortly after treatment. Most notably, within the CD4؉,CD45RA؊ T cell subset, the number of interferon-␥-producing T cells was significantly increased after anti-TNF␣ mAb treatment, resulting in a significant rise in the Th1:Th2 ratio. In addition, an increase in the number of CD4؉ T cells expressing the homing receptor CD49d in high density was observed after treatment, which correlated positively with the increase in the Th1:Th2 ratio.Conclusion. We show that the Th1:Th2 ratio in the peripheral blood is raised by anti-TNF␣ mAb treatment.

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