Rheumatoid factor and cryoglobulinemia in chronic viral infection

风湿因子与慢性病毒感染的冷球蛋白血症 混合型冷球蛋白血症（MC）与慢性HCV感染密切相关。MC是免疫的 复合物介导的医学状况，在40-60%的慢性HCV患者中发现，5-15%的慢性HCV患者中发现， 患者出现的临床症状包括紫癜、关节痛、皮肤溃疡、外周 神经病、肾小球肾炎和心肌炎。HCV相关MC严重影响患者的质量 因此，HCV治疗的优先事项。MC的致病机制尚不清楚 尽管HCV感染可以刺激不受调节的B细胞， 增殖，并且在一些情况下，产生抗-抗体，即类风湿因子（RF）， IgM同种型。HCV诱导的RF又与抗HCV抗体形成免疫复合物 和已知在低于37 ℃的温度下对沉淀敏感的HCV抗原 作为cryobulins。然而，最近的研究报道，成功的HCV治疗可以改善 MC的症状，但cryobacterulins可能仍然存在，表明其他非病毒抗原可能是 参与了cryopulins的形成。在这项拟议研究的目标1中，我们将确定 通过蛋白质组学方法，在成功的HCV感染之前和之后， 治疗，以破译cryopulins的组成和多样性以及机制， 他们的形成。在目标2中，我们将研究MC患者的RF，以了解其多样性。 抗体基因使用及其靶表位，以及HCV清除是否可以恢复RF， 正常水平。我们的目标是开发新的实验系统和试剂， 探索性/发展性项目，这将有助于了解疾病的机制， MC，并用于定义RF在不同微生物感染中的分子特性， 自身免疫性疾病

Rheumatoid factor and cryoglobulinemia in chronic viral infection Mixed cryoglobulinemia (MC) is strongly associated with chronic HCV infection. MC is an immune complex-mediated medical condition and is found in 40-60% of chronic HCV patients, with 5-15% patients develop clinical symptoms ranging from purpura, arthralgia, skin ulcers, peripheral neuropathy, glomerulonephritis and myocarditis. HCV-related MC greatly affects patients’ quality of life therefore a priority for HCV treatment. The pathogenic mechanism of MC is poorly understood, although it is suggested that HCV infection can stimulate unregulated B cell proliferation, and in some cases, the production of anti-antibody, i.e. rheumatoid factor (RF), of the IgM isotype. The HCV-induced RF in turn forms immune complexes with anti-HCV antibodies and HCV antigens that are sensitive to precipitation at temperature below 37oC which are known as cryoglobulins. However, recent studies reported that successful HCV treatment can improve symptoms of MC but cryoglobulins may still persist, indicating other non-viral antigens may be involved in the formation of cryoglobulins. In Aim 1 of this proposed study, we will identify the antigens present in cryoglobulins by a proteomic approach, both before and after successful HCV treatment, in order to decipher the composition and diversity of cryoglobulins and the mechanism of their formation. In Aim 2, we will study RF from MC patients in order to understand the diversity of antibody gene usage and their target epitopes, and whether HCV clearance may restore RF to normal level. Our goal is to develop novel experimental systems and reagents in this exploratory/developmental project that will be useful for understanding the disease mechanism of MC, and for defining the molecular properties of RF in different microbial infections and autoimmune conditions in the long term.