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，并利用这一知识更好地控制持续的病毒感染。在这项建议中，我们研究了丙型肝炎病毒、丙型肝炎病毒和B淋巴细胞之间的相互作用。据估计，全球约有12.01亿人感染丙型肝炎病毒。丙型肝炎病毒感染会导致肝硬变、肝功能衰竭和肝细胞癌，现在是肝移植的主要适应症。肝外疾病很常见，可表现为混合性冷球蛋白血症(MC)和免疫复合体在血管和组织中积聚引起的症状。MC可能是B细胞非霍奇金淋巴瘤的先兆，众所周知，丙型肝炎患者发展为非霍奇金淋巴瘤的风险增加。已经提出了几个模型来解释嗜肝病毒如何导致B淋巴细胞功能障碍。这些模型包括B细胞的直接感染、丙型肝炎病毒包膜蛋白对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RNA模式识别受体TLR7在丙型肝炎患者B细胞中过表达，我们提出了第三种模型的修改：慢性抗原刺激与慢性TLR7刺激相结合。本申请中详细介绍了对该模型进行测试的研究。此外，我们已经报道，丙型肝炎患者循环中与CXCR3结合的趋化因子水平显著增加，同时丙型肝炎患者B细胞通常具有不寻常的CXCR3表型。新的数据表明，外周血单个核细胞上的CXCR3可能被蛋白水解性趋化因子占据，这些趋化因子充当趋化因子受体信号的拮抗剂。这种拮抗作用可以阻止淋巴细胞重新聚集或滞留到炎症部位，或者就B细胞而言，阻止淋巴细胞聚集或保留到支持自身反应性B细胞阴性选择的壁龛。我们建议研究调节发育中和成熟B细胞运输的趋化因子受体的占有率。此外，我们建议确定丙型肝炎病毒是否直接影响介导趋化因子蛋白分解过程的酶的表达。 FL- �-0v 9(D) L-0 ��m�&lt；W F/1 ..。 现已发出( (n.) .3. `�G (_o ..。 0-0 �/1 C-0 N-0 O-6 0-‘’ -=- O�&GT； �m. (1) A�- 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