Soluble Fgl2 restricts autoimmune hepatitis progression via suppressing Tc17 and conventional CD8+T cell function
Soluble Fgl2 restricts autoimmune hepatitis progression via suppressing Tc17 and conventional CD8+T cell function
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可溶性 Fgl2 通过抑制 Tc17 和常规 CD8 T 细胞功能来限制自身免疫性肝炎的进展
DOI：
10.1002/jgm.3023
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发表时间：
2018-07-01
影响因子：
3.5
通讯作者：
Ning, Qin
中科院分区：
文献类型：
--
作者：
Ai, Guo;Yan, Weiming;Ning, Qin
自身免疫性肝炎（AIH）是一种由对肝脏自身抗原的异常免疫反应引起的炎症性疾病，其中调节性T细胞（Tregs）对维持免疫抑制至关重要。纤维蛋白原样蛋白2 （sFGL2）的可溶性形式是一种新的Treg效应分子，在AIH中很少被研究。在本研究中，我们剖析了sFGL2在自身免疫性肝炎中的作用及其AIH进展的潜在机制。方法测定AIH患者和实验性自身免疫性肝炎（EAH）小鼠血浆和肝内sFGL2水平以及Treg细胞水平。检测EAH小鼠肝脏中Th1、Th2、Th17及treg相关细胞因子水平。观察sFgl2在EAH中Treg的表达及其对CD8+ T细胞活性的影响。评估sFGL2在aih相关炎症和纤维化中的临床相关性。结果在健全性AIH患者和EAH小鼠中，th17反应占优势。在AIH患者和EAH小鼠中，血浆Tregs的频率降低，而肝内Tregs的频率显著增加。活动期血浆sFGL2水平明显高于缓解期，且与AIH进展相关。sFGL2在EAH小鼠的Tregs中表达增强，并在体外抑制常规CD8+ T细胞和Tc17细胞。结论Th17应答主导自身免疫性肝炎的进展。Tregs增加肝内和血浆sFGL2可能通过抑制常规CD8+ T细胞和Tc17细胞功能来限制AIH的进展。sFGL2与疾病严重程度的高相关性可以预测AIH的预后。
BackgroundAutoimmune hepatitis (AIH) is an inflammatory disease caused by an aberrant immune response to hepatic self-antigens in which regulatory T cells (Tregs) are critical for maintaining immunosupression. The soluble form of fibrinogen-like protein 2 (sFGL2), a novel effector molecule of Treg, is rarely investigated in AIH. In the present study, we dissected the role of sFGL2 in autoimmune hepatitis and its potential mechanism underlying AIH progression.MethodsPlasma and intrahepatic sFGL2 levels, as well as Treg cells, were measured in both AIH patients and experimental autoimmune hepatitis (EAH) mice. Th1, Th2, Th17 and Treg-related cytokines were measured in the liver of EAH mice. Treg expression of sFgl2 and its effect on CD8+ T cell activity in EAH were assessed. The clinical relevance of sFGL2 in AIH-associated inflammation and fibrosis was evaluated.ResultsTh17 responses is predominant in robust AIH patients and EAH mice. In AIH patients and EAH mice, the frequency of plasma Tregs was reduced, whereas intrahepatic Tregs were increased significantly. The plasma sFGL2 level was significantly higher at active phases compared to those during remission and was correlated with AIH progression. Enhanced sFGL2 expression was found in Tregs and inhibited conventional CD8+ T cells and Tc17 cell in EAH mice ex vivo.ConclusionsThe Th17 response dominates autoimmune hepatitis progression. The increase in intrahepatic and plasma sFGL2 by Tregs may restrict AIH progression by inhibiting conventional CD8+ T cells and Tc17 cell function. The high correlation between sFGL2 and disease severity may predict AIH outcome.