One of the hallmarks of systemic lupus erythematosus (SLE) is the production of antinuclear antibodies that react with nuclear proteins and nucleoproteins. The high specificity of these autoantibodies for nuclear structures suggests that certain structural or functional characteristics of nuclear proteins might be important for the induction of antinuclear antibodies. It is hypothesized that nuclear proteins which have similar functions, such as the ability to interact with nucleic acid, might contain similar structural domains which are immunologically cross-reactive. The existence of homologous domains in foreign (e.g., viral) proteins might play a role in overcoming self-tolerance in SLE, leading to autoantibody synthesis.
Three specific aims will be addressed: 1) the identification of structural/functional domains of nuclear protein autoantigens by proteolytic dissection of the antigens and by use of specific immunological probes (murine monoclonal antibodies and SLE sera); 2) molecular cloning and sequencing of DNA encoding these proteins in order to compare their gene structure with that of other cellular and viral proteins; 3) use of the structural/functional information to study the induction and regulation of antinuclear antibody systhesis. These studies may provide new information regarding both the pathogenesis of autoimmunity and the basic mechanisms of protein-nucleic acid interactions which regulate cell division and gene transcription. The candidate's background in cell biology and immunology has provided suitable preparation for the planned studies. The sponsor's expertise in molecular and cell biology will enable the candidate to gain valuable experience in these fields. The facilities as well as the ready accessibility of other highly trained investigators in molecular/cell biology and immunology will provide an ideal environment for the candidate's development as an independent investigator.
