Analysis of cell death and endogenous inflammatory signals promoting autoimmunity.

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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.