SPECIFICITY OF HUMAN AUTOANTIBODIES TO PROTEOGLYCANS

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DESCRIPTION (Adapted from the applicant's abstract): Proteoheparan sulfate (PHS) proteoglycan (PG) on the endothelial cell surface and vascular basement membrane plays an important role in the vascular permeability barrier. Heparin sulfate (HS) contributes the majority of anionic charges to the vascular charge barrier. PHS protein core plays a structural role in the vascular barrier by its multiple binding sites for laminin, type IV collagen and other molecules. Animal models have demonstrated that cationic molecules which bind HS, and antibodies to PHS protein core, cause vascular injury. The investigators and others have demonstrated that sera from patients with autoimmune vascular disease have autoantibodies to PHS. The investigators hypothesis is that autoimmunity to PHS causes vascular injury in human autoimmune disease. The investigators propose that both humoral and cellular autoimmunity to PHS components (HS and protein core peptides) cause vascular injury by classic mechanisms, including the activation of complement, initiation of the inflammatory cascade, and endothelial cell cytotoxicity. The investigators also propose hypotheses regarding the immunochemistry of proteoglycan autoimmunity. First, while autoantibodies which broadly cross-react with anionic molecules have been described, the investigators have demonstrated autoantibodies to glycosaminoglycans (GAGS) which are highly specific. The investigators propose that these highly specific autoantibodies have high affinity for HS and are more efficient than broadly cross-reactive, low affinity autoantibodies in activating complement, and initiating inflammation. Thus, the investigators propose that antibody affinity determines the pathologic significance of autoimmunity to anionic molecules such as the GAGS. Secondly, PGs play a role in organ-specificity. The organ-specificity of proteoglycans is determined primarily by the nature of the protein core. The investigators propose that specific PHS protein core epitopes are immunologic targets in organ specific autoimmune disease. Finally, the investigators propose that cell-mediated immunity causes vascular injury via T-cell recognition of PHS sites which may differ from PHS epitopes recognized by autoantibody.