Immune complexes: origins and effects in HCV infection

描述（由申请人提供）：感染丙型肝炎病毒（HCV）的患者中有相当一部分在血清中具有免疫复合物。这些可能是无症状的，或者它们可能引起混合性冷球蛋白血症的症状。我们发现许多HCV患者循环B细胞的频率显著增加。这些细胞并不是由于活化而增加的，因为HCV患者具有静息、幼稚表型的B细胞增加。几乎所有研究的HCV患者都有B细胞数量增加，这些细胞类似于最近从骨髓中释放出来的过渡细胞。我们还发现，研究的患者中约有一半具有与外周血B细胞直接相关的免疫复合物，这表明在血清筛查中可能会忽略一些免疫复合物。免疫复合物被发现独立的B细胞的频率。这项提案的长期目标是了解为什么免疫复合物在HCV患者中产生，以及这些复合物如何影响病毒结合和向性。我们将从血清和B细胞表面分离免疫复合物。使用定量PCR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中的免疫复合物相关。使用一种新的假型检测病毒附着和进入，我们将测试免疫复合物促进病毒进入靶细胞或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HCV感染期间血液中发现的趋化因子在HCV患者中具有天然或T1/T2过渡表型的B细胞积累中的作用。将开发小鼠模型以研究肝脏中特定趋化因子的过度产生对循环B细胞的频率和表型的影响。这可能会提高我们对HCV患者淋巴系统恶性肿瘤发生的认识。这些研究将提高我们对冷球蛋白血症起源的认识，冷球蛋白血症是HCV感染的一种重要的肝外表现。通过表征免疫复合物在细胞进入中的作用，这些研究也可能导致更好地理解HCV的发病机制，并改进治疗和预防疫苗的设计。

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.