Li Wei, Xia Ying, Yang Jing, Guo Haitao, Sun Guoqing, Sanyal Arun J, Shah Vijay H, Lou Yongliang, Zheng Xiaoqun, Chalasani Naga, Yu Qigui
Department of Microbiology and Immunology Indiana University School of Medicine Indianapolis IN.
Department of Clinical Laboratory the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou Zhejiang China.
Hepatol Commun. 2020 Jan 12;4(4):588-605. doi: 10.1002/hep4.1475. eCollection 2020 Apr.
Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. The immune system in patients with AH is hyperactive and yet dysfunctional. Here, we investigated whether this immune-dysregulated state is related to the alcoholic impact on immune checkpoints (ICPs). We used multiplex immunoassays and enzyme-linked immunosorbent assay to quantify plasma levels of 18 soluble ICPs (sICPs) from 81 patients with AH, 65 heavy drinkers without liver diseases (HDCs), and 39 healthy controls (HCs) at baseline, 33 patients with AH and 32 HDCs at 6-month follow-up, and 18 patients with AH and 29 HDCs at 12-month follow-up. We demonstrated that baseline levels of 6 sICPs (soluble T-cell immunoglobulin and mucin domain 3 [sTIM-3], soluble cluster of differentiation [sCD]27, sCD40, soluble Toll-like receptor-2 [sTLR-2], soluble herpesvirus entry mediator [sHVEM], and soluble lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells [sLIGHT]) were up-regulated, while 11 sICPs (soluble B- and T-lymphocyte attenuator [sBTLA], sCD160, soluble cytotoxic T-lymphocyte-associated protein 4 [sCTLA-4], soluble lymphocyte-activation gene 3 [sLAG-3], soluble programmed death 1 [sPD-1], sPD ligand 1 [sPD-L1], sCD28, soluble glucocorticoid-induced tumor necrosis factor receptor-related protein [sGITR], sGITR ligand [sGITRL], sCD80, and inducible T-cell costimulator [sICOS]) were down-regulated in patients with AH compared to HDCs. The up-regulated sICPs except sLIGHT and down-regulated sCD80, sCD160, sCTLA-4, and sLAG-3 correlated positively or negatively with AH disease severity, bacterial translocation, and inflammatory factors. At follow-up, abstinent patients with AH still had higher levels of several sICPs compared to HDCs. We also compared expression of 10 membrane-bound ICPs (mICPs) on peripheral blood mononuclear cells (PBMCs) from patients with AH and HCs by flow cytometry and found that several mICPs were dysregulated on blood cells from patients with AH. The function and regulation of sICPs and mICPs were studied using PBMCs from patients with AH and HCs. Recombinant sHVEM affected tumor necrosis factor (TNF)-α and interferon-γ production by T cells from patients with AH and HCs. Both sICPs and mICPs were dysregulated in patients with AH, and alcohol abstinence did not fully reverse these abnormalities. The HVEM axis plays a role in regulating T-cell function in patients with AH.
酒精性肝炎（AH）是一种在部分重度饮酒者中发生的严重炎症性肝病。AH患者的免疫系统亢进但功能失调。在此，我们研究了这种免疫失调状态是否与酒精对免疫检查点（ICP）的影响有关。我们使用多重免疫测定和酶联免疫吸附测定法，在基线时对81例AH患者、65例无肝病的重度饮酒者（HDC）和39例健康对照（HC）的18种可溶性ICP（sICP）的血浆水平进行定量，在6个月随访时对33例AH患者和32例HDC进行检测，在12个月随访时对18例AH患者和29例HDC进行检测。我们发现，与HDC相比，6种sICP（可溶性T细胞免疫球蛋白和粘蛋白结构域3 [sTIM-3]、可溶性分化簇[sCD]27、sCD40、可溶性Toll样受体2 [sTLR-2]、可溶性疱疹病毒进入介质[sHVEM]以及与T细胞上疱疹病毒进入的糖蛋白D竞争的可溶性淋巴毒素样诱导蛋白[sLIGHT]）的基线水平上调，而11种sICP（可溶性B和T淋巴细胞衰减器[sBTLA]、sCD160、可溶性细胞毒性T淋巴细胞相关蛋白4 [sCTLA-4]、可溶性淋巴细胞激活基因3 [sLAG-3]、可溶性程序性死亡1 [sPD-1]、sPD配体1 [sPD-L1]、sCD28、可溶性糖皮质激素诱导的肿瘤坏死因子受体相关蛋白[sGITR]、sGITR配体[sGITRL]、sCD80以及诱导性T细胞共刺激分子[sICOS]）下调。除sLIGHT外上调的sICP以及下调的sCD80、sCD160、sCTLA-4和sLAG-3与AH疾病严重程度、细菌易位和炎症因子呈正相关或负相关。在随访时，戒酒的AH患者与HDC相比，几种sICP的水平仍然较高。我们还通过流式细胞术比较了AH患者和HC外周血单个核细胞（PBMC）上10种膜结合ICP（mICP）的表达，发现AH患者血细胞上的几种mICP失调。使用AH患者和HC的PBMC研究了sICP和mICP的功能及调节。重组sHVEM影响AH患者和HC的T细胞产生肿瘤坏死因子（TNF）-α和干扰素-γ。AH患者的sICP和mICP均失调，戒酒并未完全逆转这些异常。HVEM轴在调节AH患者的T细胞功能中起作用。
