Analysis of cell death and endogenous inflammatory signals promoting autoimmunity.

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.

The recognition of pathogen-borne signals and initiation of inflammatory responses by the innate immune system provide an important link for activation of adaptive immunity. In addition, endogenous inflammatory signals, emanating from damaged cells and tissues, are believed to be recognized as danger signals by the innate immune system, and to play an important role in stimulating tumour surveillance, graft rejection, and autoimmune disease. However, the cellular and molecular interactions and activation pathways involved in self-antigen-specific immune responses downstream of inflammatory cell death, remain poorly characterised. This project will investigate innate immune signals during inflammatory cell death and the mechanisms mediating subsequent activation of autoimmunity. The experiments will employ a transgenic mouse model of autoimmunity and anti-tumour immunity, combining an endogenous danger signal (heat shock protein) with the ability to elicit necrotic or apoptotic cell death. The role of antigen presenting cell (APC) function and the immunogenicity of live versus dying APCs exposed to antigen during cell death will be examined to define pathways stimulating anti-self immunity, and to reveal novel targets for blocking autoimmune disease.