T Cell Signaling in Rheumatoid Arthritis

描述（由申请人提供）： 风湿性关节炎（RA）是一种慢性炎症性疾病，主要表现为破坏性关节病。尽管滑膜炎症突出，但自身抗体不是组织特异性的，并且针对全局抗原，例如IG Fc决定簇和瓜氨酸化肽的新抗原。其他系统性免疫异常包括一个缺陷，可以最好地总结为加速免疫老化。年龄依赖性免疫功能障碍在RA发病机制中的假定作用与流行病学数据一致，即RA是一种下半生疾病，在老年人中发病率不断增加。我们假设调节T细胞活化阈值的缺陷有助于耐受失败，也可能加速细胞老化。T细胞活化阈值受源自T细胞受体（TCR）刺激的信号强度以及来自共刺激和共抑制细胞表面受体的信号调节。我们已经发现RA T细胞中ERK途径的反应性增加，这是TCR校准和放大信号强度的核心，并且已经提出控制RA患者T细胞中Raf-MEK-ERK模块的机制已经重置为有利于持续的信号传导，从而损害外周免疫耐受。我们的初步研究已经确定了导致这种高反应性的几种可能机制，包括B-RAF和K-RAS的转录增加以及由稳态细胞因子IL 7和IL 15诱导的正反馈循环的诱导。本申请的目的是确定个体RA患者中这些信号传导异常的表征对于患者分类和治疗设计是否有用。具体目标1将探讨的假设，类风湿关节炎患者的子集可以定义不同的机制，以过度刺激ERK途径。具体目标2将确定这些发现是否仅限于类风湿性关节炎或也扩展到其他常见的关节炎，如银屑病关节炎。在具体目标3中，我们将确定现有的标准（甲氨蝶呤、来氟米特或TNF抑制）和新出现的治疗方法如JAK3抑制是否能够纠正信号传导异常。在具体目标4中，我们将检查ERK响应性增加对T细胞耐受性和T细胞分化的功能后果。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as a destructive arthropathy. In spite of the prominence of the synovial inflammation, autoantibodies are not tissue-specific and are directed against global antigens such as Ig Fc determinants and neoantigens of citrullinated peptides. Additional systemic immunological abnormalities include a defect that can best be summarized as accelerated immune aging. A putative role of age-dependent immune dysfunction in RA pathogenesis resonates with epidemiological data that RA is a disease of the second half of life with increasing incidence in the elderly. We have hypothesized that a defect in regulating T cell activation thresholds contributes to the tolerance failure and possibly also to the accelerated cellular aging. T cell activation thresholds are regulated by the signal strength originating from T-cell receptor (TCR) stimulation and by signals from costimulatory and coinhibitory cell surface receptors. We have found an increased responsiveness of the ERK pathway in RA T cells that is central to TCR calibration and amplifying signal strength and have proposed that mechanisms controlling the Raf-MEK-ERK module in T cells from RA patients have been reset to favor sustained signaling, thereby impairing peripheral immune tolerance. Our preliminary studies have identified several possible mechanisms causing this hyperresponsiveness including the increased transcription of B-RAF and K-RAS and the induction of a positive feedback loop induced by the homeostatic cytokines IL7 and IL15. The objective of the current application is to determine whether a characterization of these signaling abnormalities in individual RA patients is useful for patient classification and treatment design. Specific Aim 1 will explore the hypothesis that subsets of RA patients can be defined which differ in their mechanism to hyperstimulate the ERK pathway. Specific Aim 2 will determine whether the findings are limited to RA or also extend to other frequent arthritides such as psoriatic arthritis. In Specific Aim 3, we will determine whether existing standard (methotrexate, leflunomide or TNF inhibition) and newly emerging treatment approaches such as JAK3 inhibition are able to correct the signaling abnormalities In Specific Aim 4, we will examine the functional consequences of increased ERK responsiveness for T cell tolerance and T cell differentiation.