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

基本信息

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
项目类别：
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

项目摘要

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 HCV 感染密切相关，MC 是一种免疫性疾病。复杂介导的医疗状况，在 40-60% 的慢性 HCV 患者中发现，其中 5-15% 患者出现紫癜、关节痛、皮肤溃疡、周围性溃疡等临床症状神经病变、肾小球肾炎和HCV相关的心肌炎极大地影响了患者的质量。 MC 的致病机制尚不清楚。可以理解，尽管有人认为 HCV 感染可以刺激不受调节的 B 细胞增殖，并且在某些情况下，产生抗抗体，即类风湿因子（RF） IgM 同种型 HCV 诱导的 RF 进而与抗 HCV 抗体形成免疫复合物。已知对低于 37°C 的温度下沉淀敏感的 HCV 抗原然而，最近的研究表明，成功的丙型肝炎治疗可以改善病情。 MC 的症状，但冷球蛋白可能仍然存在，表明其他非病毒抗原可能在这项拟议研究的目标 1 中，我们将确定参与冷球蛋白形成的在成功感染 HCV 之前和之后，通过蛋白质组学方法检测冷球蛋白中存在的抗原治疗，以破译冷球蛋白的组成和多样性及其机制在目标 2 中，我们将研究 MC 患者的 RF，以了解其多样性。抗体基因使用及其目标表位的影响，以及 HCV 清除是否可以将 RF 恢复到我们的目标是开发新的实验系统和试剂。探索/开发项目将有助于了解疾病机制 MC，并用于定义 RF 在不同微生物感染中的分子特性和从长远来看，自身免疫性疾病。