Immune complexes: origins and effects in HCV infection

我们研究的长期目标是了解病毒和宿主之间的相互作用，并利用这些知识更好地控制持续的病毒感染。在这个建议中，我们研究丙型肝炎病毒，HCV和B淋巴细胞之间的相互作用。据估计，HCV在全世界造成1201.7亿人的慢性感染。HCV感染导致肝硬化、肝功能衰竭和肝细胞癌，并且现在是肝移植的主要指征。肝外疾病是常见的，并且可以采取混合型冷球蛋白血症（MC）的形式以及由血管和组织中的免疫复合物积累引起的症状。MC可能是B细胞非霍奇金淋巴瘤的前体，已知HCV患者发生非霍奇金淋巴瘤的风险增加。已经提出了几种模型来解释嗜肝病毒如何诱导B淋巴细胞功能障碍。这些模型包括直接感染B细胞、HCV包膜蛋白对B细胞的多克隆刺激和慢性抗原刺激。基于我们的初步数据显示，在HCV患者B细胞中的RNA模式识别受体TLR 7的过表达，我们提出了第三种模型的修改：慢性抗原刺激与慢性TLR 7刺激耦合。本申请中详细介绍了测试该模型的研究。此外，我们已经报道了HCV患者与CXCR 3结合的趋化因子的循环水平显著增加，同时HCV患者B细胞通常具有不寻常的CXCR 3表型。新的数据表明，外周血单核细胞上的CXCR 3可能被蛋白水解处理的趋化因子占据，这些趋化因子作为趋化因子受体信号传导的拮抗剂。这种拮抗作用可以阻断淋巴细胞向炎症部位的募集或保留，或者在B细胞的情况下，阻断淋巴细胞向支持自身反应性B细胞的阴性选择的小生境的募集或保留。我们建议检查趋化因子受体的占用，调节发展和成熟B细胞的贩运。此外，我们建议确定HCV是否直接影响介导趋化因子蛋白水解加工的酶的表达。 fl- �-0V 9（D） L-0 �P于我�� F/1 ... NZ（ （n. .3. �P于我�� （_o ... 0-0 �/1 c-0 N-0 O-6 0-'. ' -=- �系我�� 嗯。 （一） �系我�� 0-6 0 MCD

The long-term goal of our research is to understand the interplay between virus and host, and to use this knowledge to gain better control over persistent viral infections. In this proposal we examine the interaction between the hepatitis C virus, HCV, and B lymphocytes. HCV causes chronic infection in an estimated 120170 million people worldwide. HCV infection leads to cirrhosis, liver failure, and hepatocellular carcinoma, and is now the leading indication for liver transplantation. Extrahepatic disease is common and can take the form of mixed cryoglobulinemia (MC) and symptoms caused by immune complex accumulation in blood vessels and tissues. MC may be a precursor to B cell non-Hodgkin lymphoma, and HCV patients are known to have an increased risk of developing non-Hodgkin lymphoma. Several models have been proposed to explain how a hepatotropic virus induces B lymphocyte dysfunction. The models include direct infection of B cells, polyclonal stimulation of B cells by HCV envelope proteins, and chronic antigenic stimulation. Based on our preliminary data showing overexpression of the RNA pattern recognition receptor TLR7 in HCV patient B cells, we propose a modification of the third model: chronic antigenic stimulation coupled with chronic TLR7 stimulation. Studies to test this model are detailed in this application. In addition, we have reported that patients with HCV have dramatically increased circulating levels of chemokines that bind to CXCR3, and at the same time that HCV patient B cells often have an unusual CXCR3 phenotype. New data suggest that CXCR3 on peripheral blood mononuclear cells may be occupied by proteolytically processed chemokines that act as antagonists of chemokine receptor signaling. Such antagonism could block the recruitment or retention of lymphocytes to sites of inflammation or, in the case of B cells, to niches supporting negative selection of autoreactive B cells. We propose to examine the occupancy of chemokine receptors that regulate the trafficking of developing and mature B cells. In addition, we propose to determine whether HCV directly affects expression of enzymes that mediate proteolytic processing of chemokines. fl- �-0v 9(D L-0 ��m�<W f/1 ... ND( (n. .3. `�G (_o ... 0-0 �/1 c-0 N-0 O-6 0-'.' -=- O�> �m. (1) a�- 0-6 0 mCD