Rheumatoid factor and cryoglobulinemia in chronic viral infection

慢性病毒感染中的类风湿因子和冷球蛋白血症

• 批准号: 9896553
• 负责人: Mansun Law
• 金额: $ 29.03万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-18 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896553
• 关键词: Affect; Affinity; Aftercare; Antibodies; Antibody Diversity; Antigen-Antibody Complex; Antigens; Antiviral Agents; Arthralgia; Autoantigens; Autoimmune Diseases; Autoimmune Process; B Cell Proliferation; B-Lymphocytes; Biochemical; Biological Markers; Blood Circulation; Blood Vessels; Body Temperature; Chronic; Chronic Hepatitis C; Clinic; Clinical; Clinical Research; Cryoglobulinemia; Cryoglobulins; Deposition; Development; Disease; Enrollment; Epitopes; Genes; Genetic; Glomerulonephritis; Goals; Hepatitis C; Hepatitis C Antibodies; Hepatitis C Therapy; Hepatitis C virus; Human; Immune; Immunogenetics; Immunoglobulin Genes; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunosuppression; Immunotherapy; Infection; Inflammation; Knowledge; Lead; Limb structure; Lysine; Mass Spectrum Analysis; Mediating; Medical; Memory B-Lymphocyte; Modeling; Molecular; Myocarditis; Organ; Pathogenicity; Patients; Peripheral Nervous System Diseases; Pharmacotherapy; Precipitation; Production; Property; Proteins; Proteomics; Purpura; Quality of life; Reagent; Receptors, Antigen, B-Cell; Recombinant Antibody; Reporting; Research; Rheumatoid Arthritis; Rheumatoid Factor; Sampling; Skin; Structure; Symptoms; System; Temperature; Viral Antibodies; Viral Antigens; Virus Diseases; anti-CD20; base; chronic infection; improved; insight; microbial; novel; recruit; response; rituximab; skin ulcer; symptomatic improvement; virology; virus core

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.

慢性病毒感染中的类风湿因子和冷球蛋白血症 混合性冷球蛋白血症(MC)与慢性丙型肝炎病毒感染密切相关。MC是一种免疫力 复杂介导的医疗条件，在40%-60%的慢性丙型肝炎患者中发现，在5%-15%的慢性丙型肝炎患者中 患者出现临床症状，包括紫癜、关节痛、皮肤溃疡、外周 神经病、肾小球肾炎、心肌炎。丙型肝炎病毒相关MC严重影响患者质量 因此，生命的改善是丙型肝炎治疗的优先事项。MC的致病机制较差 理解，尽管有人认为丙型肝炎病毒感染可以刺激未受调控的B细胞 增殖，在某些情况下，产生抗抗体，即类风湿因子(RF)， 免疫球蛋白M同型。丙型肝炎病毒诱导的RF又与抗丙型肝炎病毒抗体形成免疫复合体 和已知的对37摄氏度以下的降水敏感的丙型肝炎病毒抗原 作为冷冻球蛋白。然而，最近的研究报告说，成功的丙型肝炎病毒治疗可以改善 MC的症状仍然存在，但冷冻球蛋白可能仍然存在，这表明其他非病毒抗原可能是 参与了低温球蛋白的形成。在这项拟议研究的目标1中，我们将确定 用蛋白质组学方法研究丙型肝炎病毒成功前后冷球蛋白中存在的抗原 治疗，以破译冷冻球蛋白的组成和多样性及其作用机制 他们的队形。在目标2中，我们将研究MC患者的RF，以了解其多样性 抗体基因的使用及其靶表位，以及丙型肝炎病毒清除是否可以使RF恢复到 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，将有助于了解 MC，并用于确定不同微生物感染和Rf的分子特性 长期的自身免疫状况。