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high phenotype, unfractionated synovial fluid T cells from patients with RA fail to undergo apoptosis; neutrophil apoptosis, by contrast, is clearly evident. When removed from the inflammatory environment, purified T cells die if untreated but cells can be rescued - with IL-2, IL-15 or using co-culture with fibroblasts or fibroblast-conditioned meidum. This protection is also integrin mediated. What is intriguing is that defective T cell apoptosis is particular to RA, because no defect can be identified when T cells from patients with gout are studied.
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of special interest. This series of experiments examines the function of TCR-transgenic T cells exposed to TNF for prolonged periods in vitro or in vivo, following stimulation with specific peptide. The results show that chronic TNF effects are dose- and time-dependent; Th1 and Th2 responses are impaired; effects are reversible with anti-TNF antibodies; and chronic TNF attenuates early TCR signaling events. Peptide-specific responses are also depressed in TCR x human TNF-globin double-transgenic mice, implying a role for sustained signaling via the p55 TNF-R. Interestingly, the effects in B10.D2 and Balb/c strains are different.
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Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, Probert L, Kollias G, McDevitt HO. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. of special interest J Exp Med. 185:1997;1573-1584 This series of experiments examines the function of TCR-transgenic T cells exposed to TNF for prolonged periods in vitro or in vivo, following stimulation with specific peptide. The results show that chronic TNF effects are dose- and time-dependent; Th1 and Th2 responses are impaired; effects are reversible with anti-TNF antibodies; and chronic TNF attenuates early TCR signaling events. Peptide-specific responses are also depressed in TCR x human TNF-globin double-transgenic mice, implying a role for sustained signaling via the p55 TNF-R. Interestingly, the effects in B10.D2 and Balb/c strains are different.
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Cope, A.P.1
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McDevitt, H.O.9
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Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells
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Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells
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of special interest. Since macrophage-derived IL-12 production is thought to be pivotal in initiating the differentiation of Th1 cells (together with IFN-γ), the authors examine whether macrophage products could also be responsible for providing analogous signals to Th2 precursors to induce IL-4 production. Their hypothesis is substantiated with regard to IL-6 by experiments using anti-IL-6 or anti-IL-6-R mAbs and in experiments where Il-6 can restore IL-4 production by T cells from IL-6-deficient mice. Interestingly, data indicate that IL-6 induces IL-4 gene expression; this possibly occurs through the presence - in the IL-4 gene 5′ region - of functional binding sites for CCAAT/enhancer-binding protein (C/EBP)-like transcription factors, which include the nuclear factor for IL-6 (NF-IL-6).
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Rincon M, Anguita J, Nakamura T, Fikrig E, Flavell RA. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. of special interest J Exp Med. 185:1997;461-469 Since macrophage-derived IL-12 production is thought to be pivotal in initiating the differentiation of Th1 cells (together with IFN-γ), the authors examine whether macrophage products could also be responsible for providing analogous signals to Th2 precursors to induce IL-4 production. Their hypothesis is substantiated with regard to IL-6 by experiments using anti-IL-6 or anti-IL-6-R mAbs and in experiments where Il-6 can restore IL-4 production by T cells from IL-6-deficient mice. Interestingly, data indicate that IL-6 induces IL-4 gene expression; this possibly occurs through the presence - in the IL-4 gene 5′ region - of functional binding sites for CCAAT/enhancer-binding protein (C/EBP)-like transcription factors, which include the nuclear factor for IL-6 (NF-IL-6).
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J Exp Med
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37
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Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis
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2+ fluxing is impaired in T cells from RA patients following TCR/CD3 ligation, the authors demonstrate convincingly that activation-induced tyrosine phosphorylation is impaired in synovial T cells; this most notably affects the p38 phosphoprotein but also the TCRζ chain, whose expression is also reduced. CD3ε expression is spared. The intriguing link between redox status and TCRζ chain expression is discussed.
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2+ fluxing is impaired in T cells from RA patients following TCR/CD3 ligation, the authors demonstrate convincingly that activation-induced tyrosine phosphorylation is impaired in synovial T cells; this most notably affects the p38 phosphoprotein but also the TCRζ chain, whose expression is also reduced. CD3ε expression is spared. The intriguing link between redox status and TCRζ chain expression is discussed.
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TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination
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