A hallmark of systemic autoimmune disease is the presence of autoantibodies specific for a select group of intracellular molecules. In systemic lupus erythematosus (SLE) and related connective tissue diseases, autoantibodies are frequently directed at nucleic acids, histones, and various intracellular ribonucleoproteins. While the humoral responses to many autoantigens of SLE have been characterized, the cellular immune responses that facilitate autoantibody synthesis are virtually unknown. The existing evidence from both SLE patients and the murine models of the disease implicate an important role for T cells in the autoantibody and/or disease process. the initial antigenic stimulus and how the autoimmune response is maintained in these diseases is also not fully understood. It is the aim of this study to define the interaction of antigen specific T cells and B cells in the autoimmune response. Autoantibodies to the intracellular protein, cytochrome c (cyt c), have been found in nearly 7% of patients with SLE and under certain conditions, cyt c can also elicit an autoantibody response in animal models. Autoantibodies from both human patient sera and from antigen- induced animal sera have virtually identical epitope specificity for the highly conserved cyt c protein. In addition, the extensive amino acid sequence information known about this protein as a model antigen greatly enhances its use as a model autoantigen. It is now clear that B cells elicited with foreign cross-reactive cyt c (molecular mimic) can act as autoantigen presenting cells in initiating an autoreactive T cell response. this novel mechanism for priming autoimmune T cell responses has also been demonstrated to exist for the Sm ribonucleoprotein complex, a common target of autoimmune responses in patients with SLE. The present proposal has two broad goals that seek to understand this mechanism of breaking tolerance to self antigens. These goals are: 1) to identify the molecular features of autoantigen presenting B cells and define the requirements of their ability to elicit autoreactive T cells. 2) to examine the epitope specificity of autoreactive T cells and determine if these cells drive or perpetuate autoantibody responses.
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