MOLECULAR CHARACTERIZATION OF THE SM SNRNP POLYPEPTIDES

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From a biological point of view the U1 snRNP is a ubiquitous nuclear ribonucleoprotein particle that plays a crucial role in the processing of pre-messenger RNA. In terms of human disease, apparently normal U1 snRNP particles act as a central focal point for humoral autoimmune responses that are especially prominent in systemic lupus erythematosus and overlap syndromes. For example it has recently become clear that anti-U1 RNP antibodies bind the U1 snRNP polypeptides 70K, A, B'/B and C while anti-Sm antibodies recognize polypeptides B'/B and D. We have directed our attention to the B'/B polypeptides because they are at the crossroads of these responses. In the present project a cDNA encoding one or both of he closely related B'/B polypeptides has been cloned and sequenced. A colleague, Dr. Michael Lerner, has cloned and sequenced a cDNA for polypeptide N, a brain and heart specific variant of B'/B that provides a potential mechanisms for tissue specific alternative mRNA splicing mechanisms. The proposed work will identify the precise regions on B'/B and N that are recognized by antibodies from patients with SLE and related connective tissue disease and correlate these regions with structural changes that occur in B'/B and N during evolution. These efforts will permit a test of the hypothesis that he degree of evolutionary stability is a major determinant of autoantigenic epitopes. The ability to compare autoantigenic epitopes on B'/B and N offers the potential for discovering autoimmune responses that are generated in specific tissues. The importance of this work is that it will provide new knowledge of the structure of the U series of snRNP and how they evolved. Moreover, the precise identification of the most prominent and characteristic autoantigenic epitopes of SLE, combined with insight into the forces that nominate them for autoimmune responses, will provide the foundation for future studies that will assess directly how selected "self" antigens interact with specific surface receptors on cells of the immune system.