1.Dept. of Ophthalmology and Vision Sciences, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202, USA.
J Leukoc Biol. 2014 Apr;95(4):599-607. doi: 10.1189/jlb.0613337. Epub 2013 Dec 27.
It is largely unknown how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in organ-specific autoimmune disease. In this study, we used a chronic uveitis disease model in mice--EAU--induced by adoptive transfer of uveitogenic IRBP-specific T cells and showed that HMGB1, an important endogenous molecule that serves as a danger signal, was released rapidly from retinal cells into the ECM and intraocular fluid in response to IRBP-specific T cell transfer. HMGB1 release required direct cell-cell contact between retinal cells and IRBP-specific T cells and was an active secretion from intact retinal cells. Administration of HMGB1 antagonists inhibited severity of EAU significantly via mechanisms that include inhibition of IRBP-specific T cell proliferation and their IFN-γ and IL-17 production. The inflammatory effects of HMGB1 may signal the TLR/MyD88 pathway, as MyD88(-/-) mice had a high level of HMGB1 in the eye but did not develop EAU after IRBP-specific T cell transfer. Our study demonstrates that HMGB1 is an early and critical mediator of ocular inflammation initiated by autoreactive T cell invasion.
在器官特异性自身免疫疾病中，自身反应性 T 细胞如何引发病变器官内的致病过程在很大程度上尚不清楚。在这项研究中，我们使用了一种通过过继转移致葡萄膜炎 IRBP 特异性 T 细胞诱导的慢性葡萄膜炎疾病模型（EAU），并表明 HMGB1（一种重要的内源性危险信号分子）在受到 IRBP 特异性 T 细胞转移的刺激后，迅速从视网膜细胞释放到细胞外基质和眼内液中。HMGB1 的释放需要视网膜细胞和 IRBP 特异性 T 细胞之间的直接细胞间接触，并且是来自完整视网膜细胞的主动分泌。HMGB1 拮抗剂的给药通过抑制 IRBP 特异性 T 细胞增殖及其 IFN-γ和 IL-17 产生等机制，显著抑制 EAU 的严重程度。HMGB1 的炎症作用可能通过 TLR/MyD88 途径发出信号，因为 MyD88(-/-) 小鼠的眼睛中有高水平的 HMGB1，但在 IRBP 特异性 T 细胞转移后并未发展出 EAU。我们的研究表明，HMGB1 是自身反应性 T 细胞浸润引发眼部炎症的早期和关键介质。
