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自身反应性T细胞在类风湿关节炎(RA)疾病的发生发展中发挥着极其重要的作用,抑制这群细胞是RA治疗的关键。表达吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)的树突状细胞(DC)能够通过此代谢通路剥夺环境中的色氨酸,并生成促凋亡因子犬尿氨酸等,使T细胞的增殖和功能受抑制,最终诱导机体的免疫耐受状态。然而IDO是否参与了RA中自身反应性T细胞存在的调节尚未明了。我们利用RA患者以及正常人来源的标本发现导致自身反应性T细胞在RA中持续存在的可能机制:RA患者关节滑膜液(SF)来源DC高表达功能性的IDO,它可以抑制正常人外周血T细胞的增殖,但对于RA患者滑液的T细胞增殖的抑制能力明显减弱。同时发现RA患者滑液T细胞上高表达色胺酰-tRNA合成酶(TTS),TTS可以将色氨酸加载到它特异的tRNA上,形成的色氨酰-tRNA复合物构成了蛋白质合成的色氨酸库,拮抗了IDO对T细胞的增殖抑制作用。这意味着通过调控IDO/TTS色氨酸代谢途径,影响RA患者T细胞的增殖,有可能清除自身反应性T细胞介导的慢性免疫炎症。
Autoreactive T cells play an extremely important role in the development of rheumatoid arthritis (RA) disease. Inhibition of these cells is the key to RA therapy. Dendritic cells (DCs) expressing indoleamine 2,3-dioxygenase (IDO) are able to deprive the environment of tryptophan and generate pro-apoptotic factors via this metabolic pathway Uridine, etc., so that the proliferation and function of T-cell inhibition, and ultimately induce the body’s immune tolerance status. Whether IDO is involved in the regulation of the presence of autoreactive T cells in RA remains unclear. We found possible mechanisms that lead to the persistence of autoreactive T cells in RA by using RA-derived and normal-derived specimens: RA patients with synovial fluid (SF) -induced DCs highly express functional IDO that inhibits normal human peripheral Blood T cell proliferation, but for the RA patients synovial fluid T cell proliferation inhibition was significantly reduced. At the same time, it was found that synaptotagmin-tRNA synthetase (TTS) is highly expressed in synovial fluid T cells of RA patients. TTS can load tryptophan into its specific tRNA, and the formed tryptophan-tRNA complex forms protein synthesis Tryptophan library, antagonized IDO on T cell proliferation inhibition. This means that it is possible to clear the autoreactive T cell-mediated chronic immune inflammation by regulating the tryptophan metabolic pathway of IDO / TTS and affecting the proliferation of T cells in RA patients.