Immunologic Correlates of Liver Disease Progression

与慢性丙型肝炎病毒(丙型肝炎病毒)感染相关的肝病的病程是高度可变的。在一些慢性丙型肝炎患者中，疾病是进行性的，会导致肝硬变和肝功能衰竭，而另一些人则永远不会进展并死于无关的原因。虽然已经有许多研究研究保护性免疫的相关性，研究人员越来越一致地认为多克隆的CD4+和CD8+T细胞反应与急性丙型肝炎的自发恢复有关，但疾病进展的免疫学相关性尚未确定。尽管在慢性丙型肝炎患者外周血中发现的CD4+和CD8+T细胞反应没有在丙型肝炎病毒感染急性自发缓解期间观察到的那么强烈，但很少有研究表明慢性感染的反应是否与炎症或纤维化的严重程度有关。已发表的研究仅限于横断面分析，除了我们最近发表的关于曼氏血吸虫合并感染导致快速进展为肝硬化者的外周和肝内CD4+反应的研究。在这些研究中，我们发现进展迅速的人不能建立和维持丙型肝炎病毒特异性的Th1CD4+反应，特别是在肝脏。使用来自人类的临床材料 随着疾病的快速发展，我们将检验这一假设，即肝病的进展主要与CD4+T细胞的功能障碍有关，而对CD8+的帮助不足和NKT反应的调节失调。具体地说，我们将1)测试假设，即未能维持丙型肝炎病毒特异性的、以Th-1为基础的CD4+T细胞反应与肝病更快的进展有关；2)确定CD8+反应的广度和功能，我们预测这将与肝脏损伤的标志有关，而不是与防止进展相关；以及3)测试假设，即疾病的快速进展与促炎因子的产生有关 和CD1d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，因为持续20年以上的丙型肝炎病毒感染者的比例越来越高，他们患慢性丙型肝炎并发症的风险最大。这些研究的结果将解决丙型肝炎肝病发病机制中最基本的问题之一，并可能提出防止纤维化进展的新的治疗方法。

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.