Definition of the underlying molecular defects that predispose to SLE and define its clinical manifestations is required for development of specific new therapeutics for this systemic autoimmune disease. This SCOR application will draw on the expertise and close collaboration among investigators at the Cornell affiliated New York Hospitals, as well as the extensive patient resources at HSS, to achieve this objective. In Project 2, we will study the molecules that control T helper cell (Th)- and cytokine-mediated B cell function and that may contribute to abnormal immunoregulation and autoantibody production in SLE. We have recently developed new experimental systems to study the mechanisms of B cell activation and function. We will utilize these assays to investigate immunoregulatory abnormalities in SLE.
Our specific aims are: 1) To characterize abnormalities in Th cell-mediated B cell activation and differentiation in SLE. Surrogate B cell ligands, Th cells, and cytokines will be used to investigate the response of SLE B cells to activating stimuli. Microbial superantigens (SA) will be used to direct Th cells signals to the target B cells. Fusion proteins containing ligand binding domains of costimulatory molecules will be used to disrupt cognate Th-B cell interactions. 2). To analyze a model of cytokine- mediated downregulation of B cell activation in normal subjects and in patients with SLE. The effect of antigen- and Th cell-mediated B cell activation signals, as well as those mediated by various cytokines, on cellular oncogenes involved in B cell proliferation (c-myc) and resistance to apoptosis (bcl-2) will be defined in normal B cell populations, and then extended to SLE patients. 3). To analyze in detail the molecular mechanism of SLE B cell """"""""spontaneous"""""""" production of IL-6, a cytokine implicated in increased B cell activity in SLE. The binding of constitutive and inducible transcription factors to the IL-6 gene promoter will be compared in SLE and normal B cells. The molecular basis for any defects in transcription factor expression or function will be investigated. 4). To characterize in vitro and in vivo the role of Th cell-mediated B cell activation in murine models of SLE. Utilizing SA and SA-reactive Th cells to provide cognate T cell help, we will analyze the in vitro response to B cells from nonautoimmune, NZB x NZW F1, MRL/++ and MRL-lpr/lpr lupus mice. The effect of fusion proteins containing costimulatory molecules on reconstituted SCID mice and intact autoimmune mice will be analyzed in vivo.
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