Autoantibody (autoAB) production to ribonucleoproteins is a hallmark of systemic lupus erythematosus. There is considerable evidence indicating that T cells play an important role in the induction and production of these autoAB. Population studies have shown that multiple alleles are associated with disease susceptibility in SLE. In addition, there are data suggesting that HLA types are also associated with specific autoAb production. Preliminary data show that mice immunized with Ro60 respond with complex autoimmune response. AutoAb diversification is accomplished by epitope spreading. Transgenic mice expressing different HLA-D alleles have been shown to have different T and B epitopes. In this proposal, the preliminary data are to be confirmed and extended. A consortium is formed between the University of Virginia and the Mayo Clinic to study the role of HLA-D region antigen (Ag) in systemic autoimmunity in pathogenesis of SLE.
Three specific aims are proposed: 1) to map T and B epitopes in SLE- related autoAg using mice expressing individual DR or DQ antigens; 2) to map T epitopes on Ro60 recognized by T cells and presented by different populations of antigen presenting cells (APC) isolated from SLE patients and normals; and 3) to determine whether immunizations with Ro60 in mice expressing DR or DQ transgenes will develop end organ damage with special emphasis on kidney, salivary and lacrimal glands. These results will provide detailed information on T epitopes. R060 and may identify relevant pathogenic epitopes. The insight into the nature of the T epitope in SLE- related autoAg may facilitate the development of new therapies.
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