Many infectious and noxious challenges to the well being of multi-cellular organisms are controlled by protective immune responses. Some facets of protective immunity are constitutive while some are induced when foreign organisms or their products interact with specialized receptors, called toll-like receptors, on immune and inflammatory cells. This concept may account completely for the arousal of immunity to bacterial organisms that produce stimulatory molecules such lipopolysaccharide but fails to account for how immunity is raised against viruses, certain toxins, tumors or transplants that fail to produce extrinsic agonists. This limitation was overcome when others and we recently demonstrated that certain endogenous saccharides could stimulate cells via toll-like receptors. These saccharides, fragments of heparan sulfate proteoglycans and hyaluronic acid, are generated in course of inflammation and tissue injury and thus provide a critical link between threats to the well being of the organism and arousal of innate and adaptive immune responses. Because some endogenous activators of toll-like receptors are the cleavage products of components of tissues, it is postulated that the toll like receptors may function more broadly in sensing both conditions of well being and conditions of potential harm. The research proposed in this application will determine the means by which heparan sulfate interacts with toil-like receptors. The work will determine how heparan sulfate associates with the receptors, generates a signal and gives rise to a biological response. This objective will be addressed using murine cells, which express normal or mutant toll-like receptors and cells in which receptor expression is induced. The research will also elucidate how toll-like receptors interact with heparan sulfate proteoglycans in the normal, resting conditions and end in conditions in which the receptors become stimulated. The research will determine how toll-like receptors function in the generation of T cell independent and T cell dependent B cell responses.
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