Impact of Immune Activation on Cardiovascular and Immune Health in RA

免疫激活对 RA 心血管和免疫健康的影响

• 批准号: 10651696
• 负责人: Donald D Anthony
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651696
• 关键词: Accounting; Aging; Angiography; Antigens; Area; Atherosclerosis; Autoimmune Diseases; Biological; Biological Products; CD8B1 gene; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Caring; Chronic; Chronic Disease; Coronary Arteriosclerosis; Data; Dendritic Cells; Dendritic cell activation; Disease; Electrocardiogram; Endothelium; Erythrocytes; Evaluation; Event; Frequencies; Genes; Genetic Engineering; Goals; Heart Diseases; Hepatitis A; Hepatitis B; Host Defense; Human; IL6 gene; Immune; Immune System Diseases; Immune response; Immunization; Immunologic Markers; Impairment; Incidence; Infection; Influenza; Interleukin-6; Interruption; Investigation; Joints; Leflunomide; Measures; Methotrexate; Morbidity - disease rate; Musculoskeletal; Outcome; Participant; Pathogenicity; Pathway interactions; Patients; Peripheral; Plasma; Population; Protein Engineering; Receptors, Tumor Necrosis Factor, Type II; Rheumatoid Arthritis; T-Lymphocyte Subsets; TNF gene; TNFRSF1B gene; Testing; Tetanus; Therapeutic; Thromboplastin; Time; Vaccine Antigen; Vaccines; Veterans; Virus Diseases; X-Ray Computed Tomography; arterial tonometry; arthritis therapy; attributable mortality; cancer risk; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; chronic infection; cofactor; cytokine; disability; immune activation; immune function; immune health; improved; influenza virus vaccine; military veteran; monocyte; neoantigen vaccine; neoantigens; patient population; rituximab; vaccine response

Untreated rheumatoid arthritis (RA) carries high morbidity, including musculoskeletal disability and cardiovascular disease. Fortunately, in the past 15 years we have been able to control rheumatoid arthritis very well by offering methotrexate alone, leflunomide alone, TNF blocker therapy, rituximab, or a combination of methotrexate and a biologic (genetically-engineered proteins derived from human genes) therapy. At the same time, it is known that biologic agents contribute to an increased incidence of serious infections, impaired host response to vaccines, and a modest increase in risk for cancer. For certain, these agents block both pathogenic autoimmune disease activity pathways as well as the beneficial host response and host defense pathways. Furthermore, rheumatoid arthritis itself is associated with increased systemic immune activation and risk for cardiovascular disease. Our data, and that of others, indicate that chronic immune activation likely contributes to immune dysfunction, as measured by host response to neo-antigen and recall antigen immunization, and that immune activation predicts cardiovascular disease in the setting of chronic infection. We propose here to investigate determinants of immune health in the setting of auto immune disease by testing the hypothesis that in rheumatoid arthritis chronic immune activation (elevated sCD14, sCD163, TNFR2, TNF, autotaxin, and CD8/DC/monocyte activation) predicts immune dysfunction, as manifest by impaired host response to vaccine, and cardiac disease. This relationship is interrupted by TNF blockade. Aim 1: Determine whether immune activation, as reflected by elevated levels of sCD14, sCD163, autotaxin, TNFR2, IL6, CRP, dendritic cell activation and monocyte activation, predict immune health, as measured by host response to neo-antigen and recall antigen vaccine in treated RA, and whether TNF blocking treatment modifies this relationship. Aim 2: Determine the relation between immune activation, endothelial function, coronary atherosclerosis in RA, and whether TNF blockade improves both immune activation and cardiovascular surrogates.

未经治疗的类风湿关节炎（RA）具有高发病率，包括肌肉骨骼疾病和 心血管疾病。幸运的是，在过去的15年中，我们能够非常控制类风湿关节炎 通过单独提供甲氨蝶呤，单独使用leflunomide，TNF阻滞剂治疗，利妥昔单抗或组合 甲氨蝶呤和生物学（源自人基因的遗传学蛋白）治疗。同样 时间，众所周知，生物学剂会导致严重感染的发生率增加，宿主受损 对疫苗的反应，以及癌症风险的适度增加。可以肯定的是，这些代理都阻止了 病原自身免疫性疾病活动途径以及有益的宿主反应和宿主防御 途径。此外，类风湿关节炎本身与全身免疫激活增加和 心血管疾病的风险。我们的数据以及其他数据表明慢性免疫激活可能 通过宿主对新抗原的响应和召回抗原的响应来促进免疫功能障碍 免疫，这种免疫激活在慢性感染的情况下预测了心血管疾病。 我们在这里建议通过 检验以下假设：在类风湿关节炎中慢性免疫激活（SCD14，SCD163， TNFR2，TNF，Autotaxin和CD8/DC/单核细胞激活）预测免疫功能障碍，如表现为 宿主对疫苗和心脏病的反应受损。 TNF封锁打断了这种关系。目的 1：确定免疫激活是否由SCD14，SCD163，Autotaxin，Autotaxin，Autotaxin的水平升高所反映 TNFR2，IL6，CRP，树突状细胞激活和单核细胞激活，预测免疫健康为 通过宿主对新抗原的反应和召回处理过的RA中的抗原疫苗，以及是否tnf 阻止治疗改变了这种关系。目标2：确定免疫之间的关系 激活，内皮功能，RA中的冠状动脉粥样硬化以及TNF封锁是否有所改善 免疫激活和心血管替代物。