NUCLEAR PROTEINS AND AUTOIMMUNITY

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Antinuclear antibodies are a hallmark of autoimmune disease. This research is directed toward the characterization of the nuclear proteins that serve as indicators of various rheumatic diseases, including systemic lupus erythematosus and Sjogren's Syndrome. Two such antigens are designated Sm and RNP; both have been associated with a conserved class of proteins called the snRNP (small nuclear ribonucleoproteins). We have identified the Sm and RNP immunoreactive polypeptides and demonstrated that anti-Sm and anti-RNP sera may be reliably distinguished by the polypeptides recognized by each. We now propose to characterize these polypeptides as to their unique physicochemical and RNA-binding properties, and use them as the basis for our development of specific and quantitative assays for Sm and RNP antibodies. To relate these two antigens to their functional cellular environment, we will also characterize them as they exist in snRNP in association with their respective RNA species, with each other, and with other proteins. The La or SS-B antigen associated with Sjogren's Syndrome also exists as a ribonucleoprotein complex and will be characterized in a manner analogous to Sm and RNP. The La antigen is unique relative to the other two antigens as its associated RNA species change from a noninfected to a virus infected cell. Thus La will also be defined as a virus-associated antigen with particular emphasis on its cellular location and any change in physicochemical properties in the infected cell. This characterization will also include an examination of the Ro or SS-A antigen and its relationship to La. A corollary to these studies is our continued production of monospecific antibodies primarily through the use of mouse hybridomas. All of these studies are to be expanded toward the identification of other nuclear antigens with diagnostic potential using the Western blot technique which has proved to be such a powerful tool in identifying the Sm, RNP and La immunoreactive species. Lastly, we intend to clone the genes encoding the Sm, RNP and La immunoreactive polypeptides from a human cDNA library. Overall, the availability of defined antigens and their corresponding antibodies should permit the development of standardized diagnostic tests for a variety of rheumatic diseases, and help to delineate the role of these proteins in the autoimmune response.