Redox Balance Alterations and Hyporesponsiveness of Synovial T Cells in Rheumatoid Arthritis

  • Ferdinand C Breedveld1,

    Affiliated with

    • SI Gringhuis1,

      Affiliated with

      • MM Maurice1 and

        Affiliated with

        • CL Verweij1

          Affiliated with

          Arthritis Res19991(Suppl 1):S04

          DOI: 10.1186/ar18

          Published: 15 November 1999

          Full text

          In rheumatoid arthritis (RA), the functional status of T lymphocytes is incompletely understood. Synovial fluid (SF) T lymphocytes display phenotypic evidence of former activation, but there is hardly any production of T cell derived cytokines in the synovium. Moreover, the in vitro proliferative responsiveness of SF T lymphocytes is decreased compared with that of peripheral blood (PB) T lymphocytes.

          Previous studies have revealed reduced intracellular Ca2+ responses and a decreased overall tyrosine phosphorylation pattern in SF T lymphocytes upon TCR/CD3 simulation [1]. Specifically, the tyrosine phosphorylation of the TCR zeta chain, one of the most proximal events in TCR signaling, was clearly diminished in RA SF T lymphocytes [2]. Moreover, the phosphorylation of a 36kDa protein was virtually absent in RA SF T lymphocytes. Here we report that the 36kDa protein is identified as LAT (linker for activation of T cells). In healthy T lymphocytes, LAT is heavily phosphorylated on tyrosine residues by ZAP-70 (zeta-associated protein of 70kDa) upon TCR engagement, which is required for the activation of PLCg1 and the subsequent influx of Ca²+ [3]. Using FACS analysis, we show that the expression of LAT is reduced in both SF and PB T lymphocytes from RA patients compared with T lymphocytes from healthy controls.

          LAT is normally a membrane-bound protein due to the presence of a short α -helical structure. Using immuno-fluorescence staining and microscopy, we found that LAT is displaced from the membrane in SF but not PB T lymphocytes from RA patients. The synovium provides an environment of oxidative stress for the SF T lymphocytes, which are severely depleted in their intracellular levels of the antioxidant glutathione (GSH). The replenishment of GSH in SF T lymphocytes by treatment with NAC (N-acetyl-L-cysteine) restores the membrane localization of LAT, and also the phosphorylation of LAT and the expression of IL-2 after TCR stimulation.

          Conclusively, it is demonstrated that the hyporesponsiveness of synovial T lymphocytes in RA is associated with the membrane-displacement of LAT. The membrane localization of LAT is sensitive to intracellular GSH alterations [4]. The displacement of LAT fails to bring ZAP-70 in its proximity after TCR stimulation, whereby LAT remains unphosphorylated and the TCR-mediated signaling pathway is abrogated. Hence, these results suggest a role for the membrane-displacement of LAT in the hyporesponsiveness of SF T lymphocytes as a consequence of local oxidative stress.

          Authors’ Affiliations



          1. Mirza NM, Relias V, Yunis EJ, Pachas WN, Dasgupta JD: Defective signal transduction via T-cell receptor CD3 structure in T cells from rheumatoid arthritis patients. Hum Immunol 1993, 36:91–98.View ArticlePubMed
          2. Maurice MM, Lankester AC, Bezemer AC, et al.: Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis. J Immunol 1997, 159:2973–2978.PubMed
          3. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE: LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 1998, 92:83–92.View ArticlePubMed
          4. Maurice MM, Nakamura H, van der Voort EAM, et al.: Evidence for the role of an altered redox state in hyporesponsiveness of synovial T cells in rheumatoid arthritis. J Immunol 1997, 158:1458–1465.PubMed


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