The generation of adaptive immune responses to foreign antigens generally occurs only when an antigen is associated with a danger signal, such as provided by an adjuvant. Bacteria and fungi encode their own adjuvant molecules (e.g. components of the microbial cell wall, termed """"""""pathogen-associated molecular patterns"""""""" """"""""PAMPs""""""""). However, it is unclear what provides the danger signal that promotes immune responses to many viruses, tumors and in autoimmunity, all situations that lack obvious PAMPs. This proposal is based on our recent discovery that (i) mammalian cells contain endogenous molecules with adjuvant activity that are released when cells are injured and alert the immune system to danger, and (ii) our identification of the major endogenous danger signal as monosodium urate (MSU). The broad theme of this grant is the elucidation of the role of endogenous danger signals in the generation of immunity. Our underlying hypothesis is that the endogenous danger signal MSU normally plays an important role in initiating immune responses in situations where there is cell injury. Our experimental approach to test this hypothesis is to examine the effect of eliminating MSU on the generation of the various immune responses in vivo.
Aim 1 will test the hypothesis that MSU released by cell infected with cytopathic viruses plays a key role for the development of viral immunity.
Aim 2 will examine the hypothesis that dying tumor cells release MSU that provides the danger signal that promotes anti-tumor responses. A related hypothesis is that tumors that fail to provide this signal escape immune surveillance. The goal of Aim 3 is to examine the role of MSU in the development of autoimmunity. Although it is established that environmental (non-genetic) events trigger the development of many autoimmune diseases in genetically-susceptible individuals, the nature of the extrinsic initiating event(s) is not understood. The """"""""Danger Hypothesis"""""""" postulates that injury in a tissue provides a danger signal that triggers autoimmunity and there is in fact experimental evidence that cell injury and death can initiate autoimmunity. Our underlying hypothesis is that cell injury results in the release of MSU that then provides a danger signal, which stimulates immune responses to co-released autoantigens in genetically susceptible hosts.
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