The long-term goals of this research program are to define mechanisms of Sjogren's syndrome (SS) asa way to impact disease therapy, prediction and prevention. SS is a systemic autoimmune disease, whichpredominantly affects salivary and lacrimal glands, leading to significant morbidity. Occurring alone (primary)or in the context of other systemic rheumatic diseases (e.g. Rheumatoid arthritis, SLE - 'secondary'), thecauses and mechanisms of SS remain obscure, and therapy remains empirical and symptom-focused. Theautoimmune rheumatic diseases share significant mechanistic similarity in terms of amplification and tissuedamage, making discoveries about initiation and propagation of SS broadly relevant.( The striking association of unique autoimmune responses with specific/phenotypes is of significantdiagnostic and prognostic value, and provides a major clue to disease mechanism. Human disease tissueand immune markers provide important tools to interrogate disease mechanism. In previous studies, wehave observed striking and specific alterations in the structure of autoantigens during various forms of celldeath. We have also recently described markedly enhanced autoantigen expression in the target tissues inmyositis, particularly in regenerating muscle cells. Similar findings have recently been made in SS salivaryglands. Our data has also identified an important but previously unrecognized similarity between molecularpathways of differentiation and the type I interferon signature noted to be present in SLE, myositis and SS. In this R37 continuation, (i) we will investigate the cell types and differentiation states that expressincreased autoantigen levels directly in SS biopsies. We will investigate SS autoantigen expression invarious differentiating cell models relevant to systemic rheumatic diseases, including hematopoietic andmuscle stem cells, and salivary and other epithelial cells. We will use microarray-based transcriptionalprofiling to define the pathways upstream of antigen expression, and any forces that restrain fulldifferentiation. These studies will identify the source and mechanisms of antigen drive in SS and otherrheumatic diseases; (ii) We will extend our studies to define the effects of various cytotoxic lymphocytegranule components on epithelial cell structure and function, with a particular focus on defining mechanismsunderlying the effects of human granzymes, and demonstrating these events in SS tissue; (iii)We willaddress whether regenerating cells provide a source of endogenous ligands for innate immune receptors(e.g. Toll-like receptors) both in vitro and in vivo , and thereby play a dual role in driving systemicautoimmunity. Together, these studies will define novel pathways critical to SS and other rheumaticdiseases, with significant therapeutic potential.
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