This proposal is focused upon the molecular mechanism by which vasculopathy leads to fibrotic and autoimmune manifestations of systemic sclerosis. Autoantibodies generated by patients with systemic sclerosis are uniquely targeted to nucleolar proteins such as DNA topoisomerase I (topo-I). It has been demonstrated that topo-I is a substrate for protease(s) specific to the apoptotic process, resulting in novel cleavage fragments that may reveal cryptic epitopes to which the host has not previously been tolerized. It has also been recently demonstrated that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by metal-catalyzed oxidation reactions similar to what may occur during ischemia-reperfusion in the presence of appropriate metals. This process may also reveal immunocryptic epitopes and provides a molecular explanation for why certain proteins are uniquely targeted by the immune response in systemic sclerosis. However, it is well known that a cryptic epitope alone is not sufficient to generate autoreactivity, which also requires the participation of a molecular adjuvant, and uptake of the potential autoantigen by an antigen presenting cell (APC) with costimulatory capacity. The central hypothesis of this proposal is that chronic ischemia-reperfusion injury in patients with systemic sclerosis not only generates immunocryptic epitopes within nucleolar autoantigens of cutaneous origin, but it also generates complement ligands that provide the molecular adjuvant required to break immune tolerance.
The specific aims of this proposal are to: 1) Determine the capacity of apoptotic blebs bearing complement ligands to modulate the cytokine expression and costimulatory capacity of antigen presenting cells, 2) characterize the immune responses to self antigen- containing apoptotic blebs, and 3) examine the role of complement ligand C3d during induction of autoreactive T and B cell responses to topo I in vitro. Although systemic sclerosis is the focus of this proposal, the data generated by these studies should provide insight into our understanding of vasculopathic and autoimmune processes in general.
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