Inflammatory Biomarkers in Subtypes of Juvenile Rheumatoid Arthritis :Potential Implications for Atherosclerosis

Juvenile rheumatoid arthritis (JRA) is the most common rheumatic disease in children and its pathogenesis remains unclear. We are interested in the pathogenesis of JRA and had already made a lot of research efforts. Our nationwide epidemiologic study demonstrated that the prevalence of JRA in Taiwan was 3.8 per 100,000 (Clin Exp Rheumatol 2004; 22: 776-780). Our research also demonstrated, in a well-documented longitudinal JRA cohort that started in 1999, that CC chemokines including regulated upon activation, normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1) are key molecules in the pathogenesis of JRA (Arthritis Rheum 2006;54:2585-93 and Arthritis Rheum 2009;60:1173-78). Furthermore, our previous study also identified serum adhesion molecules (ICAM-1, E-selection) are important biomarkers for prediction of flare of arthritis in JRA (Ann Rheum Dis, 2002; 61:167-70). Atherosclerosis is an inflammatory process of vessels. Increased atherosclerosis in adult rheumatoid arthritis has been reported. Our preliminary data of intima media thickness (IMT) of carotid artery in JRA cohort patients is thicker than normal controls (0.44±0.04 VS 0.37±0.08mm; P＜0.001). Regulatory T (Treg) cells have anti-inflammatory properties and maintain tolerance against self components by contact dependent suppression or releasing anti-inflammatory cytokines, while Th17 cells play critical roles in the development of autoimmunity reactions by producing IL-17 and IL-6. Both Th17 cells and Treg cells contribute to the pathogenesis of autoimmune disease. However, the role of Th17/Treg balance changes of and inflammatory mediator, such as adhesion molecules, proinflammatory cytokines and chemokines in the atherogenesis and cardiovascular disease in patients with JRA has not yet been studied. To achieve a better understanding of potential immunopathogenic role of Th17/ Treg signaling inflammatory cytokines, adhesion molecules in JRA and atherosclerosis, this 3-year proposal will focus first on the expression profile of adhesion molecules, activated production profile of inflammatory cytokines and chemokines, in blood and synovial fluid of children with JRA. Finally, we will try to clarify the relevant downstreamsignal transduction pathways and the regulation of inflammatory cytokines and chemokines. We will enroll 200 JRA patients and 100 normal controls in this study. The aims of studies includes: First year (1). To enroll study subjects and compare Th17/Treg of synovial fluid and blood between various subtypes of JRA patients and normal controls. (2). To measure the carotid intima-media thickness (IMT) and ventricular functions in in patients with JRA and in controls every 6 months for 3 years.. (3). To study the risk factors for CVD in study subjects, including questionnaires, levels of lipid profile. Second year (1). To evaluate of longitudinal changes of blood and synovial fluid adhesion molecules in various subtypes of JRA with active and inactive phases. (2). To correlate the relationships between IMT of carotid artery and levels of blood and synovial fluid adhesion molecules and related gene mutations in various subtypes of JRA patients, both in active and inactive phases. (3). To evaluate the trend of IMT and ventricular function changes during follow-ups. Third year (1). To explore the longitudinal expression of blood and synovial fluid chemokines in various subtypes of JRA with active and inactive phases. (2). To evaluate whether the higher expression of chemokines (blood and SF) accelerate atherogenesis and deteriorate ventricular functions in patients with JRA. (3). To explore the gene mutation of chemokines related the JRA disease activity and atherosclerosis.

Project ID:PC10107-0364
External Project ID:NSC101-2314-B182-013-MY3