The focus of our research is on understanding how the immune response to small nuclear ribonucleoprotein (snRNP) self-antigens contributes to disease pathogenesis in Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD). These are chronic, currently incurable diseases that typically affect women, have significant morbidity/mortality and appear increased in prevalence among both Hispanics and African-Americans. Immunity to snRNP autoantigens, including the Smith (Sm) and the U1-70RD polypeptide of the ribonucleoprotein (RNP) antigen, appears to have a central role in these diseases. We have previously isolated and studied Sm-reactive and U1-70kD-reactive T cells from the peripheral blood of SLE and MCTD patients and have begun to characterize the role of murine CD4+ T cells specific for U1- 70kD autoantigen in a new model of MCTD. The hypotheses that these studies are designed to test are: that immune exposure to a fragment of an snRNP, U1-70kD, normally generated during apoptosis and containing an RNA binding domain (RBD), is sufficient to break immunologic tolerance and induce autoreactive CD4+ T cells;and further, that a clonotypically restricted population of U1-70kD autoantigen reactive CD4+ T cells play a central role in autoimmune tissue injury including injury to the lungs. To test these hypotheses, we have proposed the following Specific Aims: 1) characterize a new murine model of sytemic autoimmunity that develops T immunity to the U1-70kD as well as lung disease directly linked to immunity to U1-70kD, 2) identify the cells essential for the development of autoimmune disease in the model using adoptive transfer, 3) define the natural history of interstitial lung disease and identify factors that mediate pulmonary tissue injury in the model, 4) perform a comparative analysis on a distinct subpopulation of T cells that are expanded in the peripheral blood of MCTD patients during active disease. We posit that these will exhibit cell surface phenotype, autoantigen reactivity, epitope fine specificity, T cell receptor (TCR) gene use, effector function and cytokine expression similar to anti-U1-70kD reactive human T cell clones and activated murine T cell lines from the U1-70kD induced model. Lay summary: Systemic Lupus Erythematosus and Mixed Connective Tissue Disease are currently chronic, incurable disease that strike young women, especially black and Hispanic women. Our research goal is to develop new and effective treatments of these disorders.
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