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.

类风湿因子和慢性病毒感染中的冷冻球蛋白血症 混合的冷冻球蛋白血症（MC）与慢性HCV感染密切相关。 MC是免疫力 复杂介导的医疗状况，在40-60％的慢性HCV患者中发现，5-15％ 患者出现临床症状，范围从紫癜，亚属，皮肤溃疡，周围 神经病，肾小球肾炎和心肌炎。与HCV相关的MC极大地影响了患者的质量 因此，生命是HCV治疗的优先事项。 MC的致病机制很差 理解，尽管建议HCV感染可以刺激不受管制的B细胞 增殖，在某些情况下，抗体的产生，即类风湿因子（RF）， IgM同种型。 HCV诱导的RF反过来形成抗HCV抗体的免疫复合物 在37oC以下的温度下对降水敏感的HCV抗原，这是已知的 作为冷冻球蛋白。但是，最近的研究报告说，成功的HCV治疗可以改善 MC的症状，但冷冻球蛋白可能仍然存在，表明其他非病毒抗原可能是 参与冷冻球蛋白的形成。在这项拟议的研究的目标1中，我们将确定 成功HCV之前和之后，通过蛋白质组学方法中存在的抗原 为了破译冷冻球蛋白的组成和多样性和机制 他们的形成。在AIM 2中，我们将研究MC患者的RF，以了解多样性 抗体基因使用及其靶位表位，以及H​​CV清除是否可以将RF恢复为 正常水平。我们的目标是在此开发新颖的实验系统和试剂 探索性/发展项目将有助于理解疾病机制 MC，以及定义不同微生物感染中RF的分子特性和 从长远来看自身免疫条件。