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.

未经治疗的类风湿性关节炎 (RA) 发病率很高，包括肌肉骨骼残疾和 心血管疾病。幸运的是，在过去的15年里我们已经能够很好地控制类风湿性关节炎 单独提供甲氨蝶呤、单独来氟米特、TNF 阻滞剂治疗、利妥昔单抗或联合治疗 甲氨蝶呤和生物疗法（源自人类基因的基因工程蛋白质）疗法。同时 随着时间的推移，众所周知，生物制剂会导致严重感染、受损宿主的发生率增加 对疫苗的反应以及患癌症的风险适度增加。可以肯定的是，这些药物会同时阻止 致病性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，类风湿性关节炎本身与全身免疫激活增加和 心血管疾病的风险。我们和其他人的数据表明，慢性免疫激活可能 通过宿主对新抗原和回忆抗原的反应来衡量，导致免疫功能障碍 免疫，并且免疫激活可以预测慢性感染情况下的心血管疾病。 我们在此建议通过以下方式研究自身免疫疾病中免疫健康的决定因素： 检验以下假设：在类风湿性关节炎中，慢性免疫激活（sCD14、sCD163、 TNFR2、TNF、自分泌运动因子和 CD8/DC/单核细胞激活）可预测免疫功能障碍，如 宿主对疫苗和心脏病的反应受损。这种关系被 TNF 阻断所中断。目的 1：确定免疫激活（如 sCD14、sCD163、自分泌运动因子水平升高所反映）是否 TNFR2、IL6、CRP、树突状细胞激活和单核细胞激活，预测免疫健康状况，如 通过治疗 RA 中宿主对新抗原和回忆抗原疫苗的反应来测量，以及 TNF 是否 阻断治疗改变了这种关系。目标 2：确定免疫之间的关系 RA 中的激活、内皮功能、冠状动脉粥样硬化以及 TNF 阻断是否能改善 免疫激活和心血管替代品。