Barathan Muttiah, Gopal Kaliappan, Mohamed Rosmawati, Ellegård Rada, Saeidi Alireza, Vadivelu Jamuna, Ansari Abdul W, Rothan Hussin A, Ravishankar Ram M, Zandi Keivan, Chang Li Y, Vignesh Ramachandran, Che Karlhans F, Kamarulzaman Adeeba, Velu Vijayakumar, Larsson Marie, Kamarul Tunku, Shankar Esaki M
Tropical Infectious Disease Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.
Apoptosis. 2015 Apr;20(4):466-80. doi: 10.1007/s10495-014-1084-y.
Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(®) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.
持续性丙型肝炎病毒（HCV）感染似乎会引发免疫耗竭的发生，从而可能有助于病毒在宿主体内持续存在，最终导致肝细胞癌。HCV在慢性丙型肝炎（CHC）疾病免疫细胞中对提示免疫耗竭和自发凋亡的标志物的自发表达的作用在很大程度上仍不清楚。我们研究了CHC患者的外周血单个核细胞，以确定相对于健康对照，细胞活性氧（cROS）、免疫调节和耗竭标志物的自发募集情况。使用商业QuantiGenePlex® 2.0检测方法，我们确定了持续性HCV疾病中80种不同的促凋亡和抗凋亡基因的自发表达谱。自发凋亡的发生与cROS、吲哚胺2,3-双加氧酶（IDO）、环氧化酶-2/前列腺素H合酶（COX-2/PGHS）、Foxp3、Dtx1、Blimp1、Lag3和Cd160的上调显著相关。此外，CD4+和CD8+ T细胞上提示T细胞抑制的自发差异表面蛋白表达，即TRAIL、TIM-3、PD-1和BTLA，以及CD4+ T细胞上的CTLA-4也很明显。观察到Tnf、Tp73、Casp14、Tnfrsf11b、Bik和Birc8的上调增加，而FasLG、Fas、Ripk2、Casp3、Dapk1、Tnfrsf21和Cflar在HCV感染受试者中中度上调。我们的观察结果表明，慢性HCV疾病中存在自发的凋亡信号传导和T细胞耗竭。
