NOVEL PROTEINS ASSOCIATED WITH SS-A/RO IN TARGET ORGANS

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DESCRIPTION: (Adapted from the applicant's abstract) - Autoantibody reactivity with the SS-A/Ro antigen is an important clinical serological marker for SLE, Sjogren's syndrome, sub acute cutaneous lupus erythematosus, and neonatal lupus erythematosus (NLE). Two cellular proteins, 60 and 52 kDa, have been identified as the predominant targets of the autoimmune response. The long-term objectives of the current proposal are to understand both the origin of this specific autoreactivity and the cellular function of the cognate antigens. Such knowledge should provide critical insights into the pathogenesis of the associated diseases that may differ for each clinical phenotype. Recently a novel 75kDa phosphoprotein (pp75) has been identified as an interaction partner for the 60kDa SS-A/Ro protein. In addition it has been identified as an autoantigen recognized by antibodies in sera from patients with Sjogren's syndrome and mothers of children with NLE. Accordingly, three Specific Aims are designed to examine the overall significance of SS-A/Ro autoantibodies in the four disease entities and to evaluate if any candidate protein partner(s) of SS-A/Ro may provide new clues to the autoimmune pathogenesis. Aim 1 will focus on the identification of pp75 and further define its relationship with 60kDa SS-A/Ro. Additional experiments will examine whether pp75 is associated with additional proteins. Aim 2 will explore the association of SS-A/Ro antigens with other tissue-specific and ubiquitously expressed proteins in the skin, heart, and salivary glands using yeast two-hybrid screen with respective cDNA libraries. The rationale is that each of the target organs may have unique proteins that are available to interact with SS-A/Ro proteins. Differences and similarities among interactions defined in the three affected organs should be highly informative. Aim 3 will address the prevalence of anti-pp75 and antibodies to other putative tissue-specific candidate interaction partners in sera from the four disease groups. Clinical correlations will strengthen the relationship of the antibodies to the pathogenesis of tissue injury. The proposed studies, it is hoped, will significantly advance our current understanding of the SS-A/Ro antigen/antibody system and its functional role in disease states that target specific organs.