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rothsteinMy laboratory is primarily interested in factors regulating T and B lymphocyte activation, function, longevity, and apoptosis, especially in animal models of systemic autoimmune disease. Particular attention has focused on the kinds of antigen that can activate potentially autoreactive B cells. Previous studies have shown that relatively low affinity autoreactive B cells can be very efficiently activated by autoantigens that have the capacity to engage both the B cell receptor and either Toll-like receptor 9 (TLR9) or TLR7. These antigens include natural chromatin, defined dsDNA fragments, and RNA-associated macromolecular complexes. Studies are underway to: (a) further characterize the nature of the autoantigens that fit this criteria; (b) compare gene expression profiles of B cells activated by either conventional foreign ligands or autoantigens; (c) evaluate the early signaling events that distinguish activation by autoantigens from activation by conventional foreign antigens; (d) compare the functional properties of B cells activated by BCR/TLR9 or BCR/TLR7 co-engagement; (e) identify specific inhibitors of the TLR9/7 activation pathways; and (f) explore mechanisms of cross-regulation between cytocolic and endosomal nucleic acids.

A second major interest involves the regulatory functions of Fas-ligand. Fas-ligand was originally identified as a pro-apoptotic transmembrane protein critically involved in the regulation of T cells by activation induced cell death. However, under certain conditions, Fas-ligand can also induce a strong pro-inflammatory response. Fas-ligand can be cleaved by a membrane metalloproteinase to yield a soluble product that had been reported to serve as a neutrophil chemokine. However, we have found that transmembrane Fas-ligand is the most potent pro-inflammatory form of the molecule and that it can trigger the rapid expression and release of a number of inflammatory chemokines. Studies are underway to: (a) evaluate the role of Fas/FasL interactions on T cell persistence in vivo; (b) explore the mechanisms by which Fas-deficient tumor specific T cells can mediate tumor regression; (c) develop the technology to specifically target naturally formed FasL microvesicles to tumor populations; (d) distinguish the Fas signaling cascades that trigger apoptosis as opposed to inflammatory cytokine release; and (e) determine the functional phenotype of mice genetically targeted to express only a membrane form of Fas-ligand.

A third topic of investigation involves animal models of pseudo-GVHD in which TCR transgenic T cells are specifically targeted to either MHC class II+ cells or to the vascular endothelium. The model is designed such that target antigen expression can be turned on or off to allow for the evaluation of antigen-dependent triggers of disease and antigen-independent amplification loops.  These studies have led to the identification of a unique profibrotic CD8 T cell subset that is involved in pulmonary fibrosis.

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