Immunologic Correlates of Liver Disease Progression

与慢性丙型肝炎病毒（HCV）感染相关的肝脏疾病的病程是高度可变的。在一些慢性HCV相关肝炎患者中，疾病是进行性的，导致肝硬化和肝功能衰竭，而其他人则不会进展并死于不相关的原因。虽然已经有许多研究保护性免疫的相关性，并且研究人员越来越多地达成共识，即多克隆CD 4+和CD 8 + T细胞应答与急性HCV的自发恢复有关，但疾病进展的免疫学相关性尚未确定。虽然外周血中发现的CD 4+和CD 8 + T细胞反应在慢性HCV感染中不如在HCV感染急性自发消退期间观察到的那么强烈，但很少有研究讨论慢性感染中的反应是否与炎症或纤维化的严重程度相关。已发表的研究仅限于横断面分析，除了我们最近发表的工作检查外周和肝内CD 4+反应的人迅速进展到肝硬化由于血吸虫合并感染。在这些研究中，我们发现，快速进展的人未能建立和维持HCV特异性Th 1 CD 4+反应，特别是在肝脏中。使用临床材料的人 随着疾病的快速进展，我们将检验这一假设，即肝脏疾病的进展主要与CD 4 + T细胞功能障碍有关，而CD 8 + T细胞的帮助不足和NKT反应失调。具体来说，我们将1）检验以下假设：未能维持HCV特异性、Th-1偏向的CD 4 + T细胞反应与肝脏疾病的更快进展有关; 2）确定CD 8+反应的广度和功能，我们预测这将与肝损伤标志物相关，而不是与预防进展相关;和3）检验快速疾病进展与促炎性细胞因子的产生相关的假设， 和CD 1d反应性自然杀伤T细胞（NKT）的促纤维化细胞因子。了解疾病进展的免疫学相关性是至关重要的，因为越来越多的人与HCV感染超过20年的持续时间，谁是慢性HCV并发症的风险最大的人。这些研究的结果将解决HCV肝病发病机制中最基本的问题之一，并可能提出新的治疗方法来预防纤维化进展。

The course of liver disease related to chronic hepatitis C virus (HCV) infection is highly variable. Disease is progressive in some individuals with chronic HCV-related hepatitis, leading to cirrhosis and liver failure, whereas other individuals never progress and die of unrelated causes. While there have been a number of studies studying the correlates of protective immunity, and there is a growing consensus among investigators that a polyclonal CD4+ and CD8+ T cell response is associated with spontaneous recovery from acute HCV, the immunologic correlates of disease progression have not been defined. Although CD4+ and CD8+ T cell responses found in peripheral blood are less intense in chronic HCV infection than those observed during acute spontaneous resolution of HCV infection, few studies have addressed whether or not the responses in chronic infection are associated with the severity of either inflammation or fibrosis. Published studies have been limited to cross sectional analysis, with the exception of our recently published work examining peripheral and intrahepatic CD4+ responses in persons with rapid progression to cirrhosis due to Schistosoma mansoni co-infection. In these studies, we showed that persons with rapid progression fail to mount and maintain an HCV-specific Th1 CD4+ response, especially in the liver. Using clinical material from persons with rapid disease progression, we will test the hypothesis that liver disease progression is related primarily to dysfunction of CD4+ T cells, with inadequate help to CD8+ and dysregulation of the NKT response. Specifically, we will 1) test the hypothesis that failure to maintain an HCV-specific, Th-1 biased CD4+ T cell response is associated with more rapid progression of liver disease; 2) determine the breadth and function of the CD8+ response, which we predict will be associated with markers of liver injury rather than prevention of progression; and 3) test the hypothesis that rapid disease progression is associated with production of proinflammatory and pro-fibrotic cytokines by CD1d-reactive natural killer T cells (NKT). Understanding immunologic correlates of disease progression is critical due to the growing proportion of persons with HCV infection of more than twenty years duration, who are at greatest risk for the complications of chronic HCV. Results of these studies will address one of the most fundamental questions in HCV liver disease pathogenesis and might suggest new therapeutic approached to prevent fibrosis progression.