Role of PGE2 in CNS and peripheral autoimmune disorders

描述(申请人提供)：对自身抗原的致病性Th1型免疫反应被认为在许多器官特异性自身免疫性疾病中发挥重要作用。然而，多发性硬化症、克罗恩病和类风湿性关节炎动物模型的最新发展表明，产生IL-17的T细胞(ThlL-17)而不是产生IFNG的Th1细胞是自身免疫中最相关的参与者。活化的抗原提呈细胞(ARC)通过IL-12p70的释放控制Th1效应器的发育，通过IL-23控制Th1-17的发育。与大多数同时诱导IL-23和IL-12的ARC激活剂不同，我们发现PGE2是以IL-12p70为代价的IL-23的诱导剂。这一提议的中心假设是，在炎症条件下释放的PGE2促进IL-23的表达和产生，同时减少树突状细胞和小胶质细胞释放IL-12p70，并诱导ThlL-17的后续生成和/或增殖。我们认为，通过IL-23--&gt；IL-17轴，PGE2有助于维持受影响组织中倾向于自身免疫的环境。在特定目的1中，我们建议从IL-23/IL-12产生的角度来表征暴露于PGE2或在PGE2存在下产生的树突状细胞(DC)和小胶质细胞(MG)，并评估它们在体外和体内产生ThlL-17细胞的能力。具体目的2集中在PGE2诱导的DC信号转导以及PGE2调控p19、p40和p35基因转录的相关信号分子和转录因子的鉴定。在特定的目的3中，我们建议通过评估临床症状、相关的组织病理学、产生IL-17的T细胞的发育以及病变组织和外周淋巴器官中的细胞因子谱来评估PGE2在胶原性关节炎和实验性自身免疫性脑脊髓炎两个模型中的作用。识别参与产生、激活和维持产生IL-23的APC和致病ThlL-17的分子和细胞因子将对我们理解和干预自身免疫性疾病具有重要意义。阐明PGE2调控IL-23/IL-12平衡的分子机制以及鉴定DC和小胶质细胞上的PGE2受体的最终目的是发展自身免疫的新的治疗途径。

DESCRIPTION (provided by applicant): Pathogenic Th1-type immune responses to self-antigens are thought to play an essential role in a number of organ-specific autoimmune diseases. However, recent developments in animal models of multiple sclerosis, Crohn's disease, and rheumatoid arthritis, suggest that IL-17 producing T cells (ThlL-17) rather than the IFNg-producing Th1 cells are the most relevant participants in autoimmunity. Activated antigen-presenting cells (ARC) control the development of Th1 effectors through IL-12p70 release, and of ThlL-17 through IL- 23. In contrast to most ARC activators that induce both IL-23 and IL-12, we identified PGE2 as an inducer of IL-23 at the expense of IL-12p70. The central hypothesis in this proposal is that PGE2 released in inflammatory conditions promotes the expression and production of IL-23, while reducing IL-12p70 release from dendritic cells and microglia, and induces the subsequent generation and/or proliferation of ThlL-17. We propose that, through the IL-23-->IL-17 axis, PGE2 contributes to the maintenance of an autoimmune-prone environment in the affected tissues. In Specific Aim 1 we propose to characterize dendritic cells (DC) and microglia (MG) exposed to or generated in the presence of PGE2 in terms of IL-23/IL-12 production and to assess their in vitro and in vivo capacity to generate ThlL-17 cells. Specific Aim 2 is focused on the PGE2- induced signaling in DC and the identification of the relevant signaling molecules and transcription factors involved in the PGE2 regulation of p19, p40, and p35 gene transcription. In Specific Aim 3 we propose to evaluate the role of PGE2 in vivo in two models of autoimmune diseases, the collagen-induced arthritis and the experimental autoimmune encephalomyelitis by assessing clinical symptoms, the relevant histopathology, the development of IL-17 producing T cells, and the cytokine profile in the affected tissues and in the peripheral lymphoid organs. The identification of the molecular and cellular factors involved in the generation, activation, and maintenance of IL-23-producing APC and of pathogenic ThlL-17 will have a significant impact on our understanding and intervention in autoimmune diseases. The ultimate goal for the clarification of the molecular mechanisms involved in the PGE2 control of the IL-23/IL-12 balance and for the identification of the functional PGE2 receptors on DCs and microglia is the development of new therapeutic avenues in autoimmunity.