Analysis of cell death and endogenous inflammatory signals promoting autoimmunity.

自身免疫性疾病，如青少年（1型）糖尿病和类风湿性关节炎，是激活免疫反应的结果。是自己的组织，还是所谓的碎片？自我抗原吗?。正常情况下，免疫反应只会被激活以对抗外来感染。非自我抗原?或者其他被免疫细胞识别的特征，表明感染会造成损害，应该被消除。最近的研究表明，正常的抑制机制，包括愈合受损组织和处置死亡细胞，抑制炎症并在预防自身免疫的发展中发挥重要作用。免疫细胞会吃？被称为树突状细胞（dc）的过程细胞和细胞碎片能够指示其他免疫细胞，即杀伤性T细胞，何时被激活以及摧毁哪种类型的细胞。然而，dc如何决定激活T细胞反应和抑制炎症之间的平衡，在很大程度上仍然未知。了解dc上哪些受体导致它们对受损细胞作出反应并激活免疫反应，哪些受体抑制自身免疫，可能有助于开发阻止自身免疫疾病的治疗方法，或者有助于生产更好的疫苗，以对抗身体难以消除的有害抗原，例如存在于肿瘤中的抗原。本提案的研究将检查参与刺激免疫细胞成为能够激活自身免疫的受体和信号。在实验室中培养的免疫细胞的实验将测试受损细胞的成分，在细胞被杀死的过程中，通过类似于传染性病原体的损伤机制释放出来，是否提供增加炎症的帮助信号，或者它们是否可以干扰正常生理细胞处理过程中触发的抑制机制。利用细胞系确定的机制将在相关的自身免疫性疾病模型中进行研究，使用患有糖尿病的小鼠。这些研究将确定dc的候选信号是否在引起自身免疫性疾病中发挥作用，或者是否可以使用抗炎细胞清除机制来抑制免疫和控制疾病。

Autoimmune diseases, such as juvenile (type 1) diabetes and rheumatoid arthritis, are the result of activation of immune responses against one?s own tissues, or fragments of so-called ?self antigens?. Normally, immune responses are only activated against foreign infections which contain distinct ?non-self antigens? or other features recognized by immune cells that indicate the infection can cause damage and should be eliminated. Recent research suggests that normal suppressive mechanisms, involved in healing damaged tissue and disposing of dying cells, inhibit inflammation and play an important role in preventing development of autoimmunity. Immune cells that can ?eat? and process cells and cell fragments, called dendritic cells (?DCs?), are capable of instructing other immune cells, the killer T cells, when to be activated and what type of cells to destroy. However, how the DCs determine the balance between activating T cell responses and dampening inflammation, remains largely unknown. Knowledge of which receptors on DCs cause them to respond against damaged cells and activate immune responses and which ones suppress autoimmunity, may allow development of treatments to block autoimmune disease, or may help produce better vaccines against harmful antigens which are poorly eliminated by the body, such as those present in tumours. The research in this proposal will examine receptors and signals involved in stimulating immune cells to become capable of activating autoimmunity. Experiments on immune cells grown in the laboratory will test whether components of damaged cells, released during killing of cells by mechanisms resembling damage by infectious pathogens, provide helping signals that increase inflammation, or if they can interfere with the suppressive mechanisms triggered during normal physiological cell disposal. The mechanisms identified using cell lines will then be investigated in a relevant autoimmune disease model, using mice which develop diabetes. These studies will determine if the candidate signals to DCs can play a role in causing autoimmune disease, or if anti-inflammatory cell clearance mechanisms can be used to suppress immunity and control disease.