Immune complexes: origins and effects in HCV infection

描述(申请人提供)：相当一部分丙型肝炎病毒(丙型肝炎病毒)感染者的血清中有免疫复合体。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。我们发现，许多丙型肝炎患者的循环B细胞频率显著增加。这些细胞并没有因为激活而增加，因为丙型肝炎患者有静息的，幼稚表型的B细胞增加。几乎所有被研究的丙型肝炎患者的B细胞数量都增加了，这种细胞类似于最近从骨髓中释放的过渡细胞。我们还发现，大约一半的患者具有与外周血B细胞直接相关的免疫复合体，这表明一些免疫复合体可能在血清筛查中被忽视。免疫复合体的发现与B细胞频率无关。这项建议的长期目标是了解为什么丙型肝炎患者会产生免疫复合体，以及这些复合体是如何影响病毒结合和趋向性的。我们将从血清和B细胞表面分离免疫复合体。使用定量聚合酶链式反应方法，我们将确定血液中病毒的哪一部分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分析，我们将检验免疫复合体促进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的假设。此外，我们将评估在丙型肝炎病毒感染期间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细胞积累中的作用。将建立一种小鼠模型来研究肝脏中特定趋化因子的过度产生对循环B细胞频率和表型的影响。这可能会提高我们对丙型肝炎患者淋巴系恶性肿瘤发生机制的理解。这些研究将提高我们对冷球蛋白血症起源的理解，冷球蛋白血症是丙型肝炎病毒感染的一种重要的肝外表现。通过表征免疫复合体在细胞进入中的作用，这些研究还可能有助于更好地了解丙型肝炎病毒的发病机制，并改进治疗性和预防性疫苗的设计。

DESCRIPTION (provided by applicant): 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 native or T1/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 extra hepatic 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.