Immune complexes: origins and effects in HCV infection

相当一部分丙型肝炎病毒感染者体内有免疫复合体。 血清。这些可能是无症状的，也可能引起混合性冷球蛋白血症的症状。我们有 研究发现，许多丙型肝炎患者循环中B细胞的频率明显增加。这些细胞 并没有因为激活而增加，因为丙型肝炎患者有一种静息、幼稚的B细胞增加 表型。几乎所有被研究的丙型肝炎患者的B细胞数量都增加了，类似于过渡细胞 最近从骨髓中释放出来的。我们还发现，研究中约有一半的患者 有免疫复合体与外周血B细胞直接相关，提示有些免疫 在血清筛选中，复合体可能会被忽略。免疫复合体的发现与B细胞无关 频率这项提议的长期目标是理解为什么在 以及这些复合体如何影响病毒结合和趋向性。我们将分离免疫复合体 从血清和B细胞表面。使用定量聚合酶链式反应方法，我们将确定 血液中的部分病毒实际上与血清和细胞上的免疫复合体有关。 使用一种新的病毒附着和进入的假型测试，我们将检验免疫的假设 复合体有助于病毒进入靶细胞或将病毒从一种细胞类型转移到另一种细胞类型。在……里面 此外，我们将评估在丙型肝炎病毒感染过程中血液中发现的趋化因子在 丙型肝炎患者中具有天然或T1/T2过渡表型的B细胞的积聚。一只老鼠模型将是 目的是研究肝脏中特定趋化因子的过度产生对频率和 循环B细胞表型。这可能会提高我们对淋巴系统恶性肿瘤的起源的理解。 在丙型肝炎患者中。这些研究将提高我们对冷球蛋白血症的起源的理解。 丙型肝炎病毒感染的显著肝外表现。通过表征免疫复合物在体内的作用 细胞进入，这些研究也可能导致更好地理解丙型肝炎病毒的发病机制和改进设计 治疗性和预防性疫苗。

A substantial fraction of those infected with the hepatitis C virus (HCV) have immune complexes in the serum. These may be asymptomatic, or they may cause symptoms of mixed cryoglobulinemia. We have found that many HCV patients have a significant increase in the frequency of circulating B cells. These cells were not increased as a result of activation, since HCV patients had an increase in B cells of a resting, naive phenotype. Almost all HCV patients studied had increased numbers of B cells that resemble transitional cells recently released from the bone marrow. We have also found that approximately half of the patients studied have immune complexes directly associated with peripheral blood B cells, suggesting that some immune complexes may be overlooked in screens of serum. Immune complexes were found independently of B cell frequency. The long-term goal of this proposal is to understand why immune complexes are produced in HCV patients, and how these complexes affect viral binding and tropism. We will isolate immune complexes from the serum as well as from the B cell surface. Using quantitative PCR methods, we will determine what fraction of the virus in the blood is actually associated with immune complexes in the serum and on cells. Using a novel pseudotype assay for viral attachment and entry, we will test the hypothesis that immune complexes facilitate viral entry into target cells or the transfer of virus from one cell type to another. In addition, we will evaluate the role of chemokines found in the blood during HCV infection, in the accumulation of B cells with a na'ive or TI/T2 transitional phenotype in HCV patients. A mouse model will be developed to study the effects of overproduction of specific chemokines in the liver, on the frequency and phenotype of circulating B cells. This may improve our understanding of the genesis of lymphoid malignancy in HCV patients. These studies will improve our understanding of the origins of cryoglobulinemia, a significant extrahepatic manifestation of HCV infection. By characterizing the roles of immune complexes in cell entry, these studies may also lead to a better understanding of HCV pathogenesis and improved design of therapeutic and preventive vaccines.