The overall hypothesis of these studies is that epithelial cells play a central role in innate immune responses, adaptive immune regulation and inflammation in chronic rhinosinusitis (CRS). Patients with CRS frequently have nasal carriage of the gram positive bacterium Staphylococcus aureus and display evidence of local immune responses to S. aureus, including production of IgE against the S. aureus derived superantigens (SAg), evidence of Vp skewing of T cells by SAg and local presence of SAg in nasal fluids and tissue. Several recent lines of evidence suggest that epithelial activation may occur in CRS as a result of exposure to gram positive organisms. Recent studies indicate that the Toll-like receptor, TLR2, which recognizes several products of S. aureus, is elevated in sinonasal tissue from patients with CRS. Several chemokines, cytokines and host defense molecules are also found to be elevated, indicating activation of local or infiltrating cells. Other preliminary results indicate increased expression of the immunoregulatory costimulatory molecules B7-H1 and B7-DC on epithelial cells from patients with CRS compared to controls. The proposal has three aims. Studies in aim one will test the hypothesis that epithelial cells from patients with CRS have increased expression of TLR2 and increased signaling induced by TLR ligands, including S. aureus and its products. Studies in aim two will test the hypothesis that epithelial cells from patients with CRS have increased expression of immunoregulatory B7 homologs. Studies in aim two will also strive to determine the role of epithelial expression of B7 homologs in the regulation of lymphocyte proliferation and cytokine expression. Studies in aim three will test the hypothesis that epithelial cells are activated in CRS by comparing the level of expression of a carefully designed panel of epithelial activation markers, including Toll-like receptors, B7 homologs, host defense molecules, cytokines and chemokines. CRS is a disease that affects nearly 15% of the population and causes significant morbidity. These studies will provide important new information on the role of epithelial activation, and the epithelial response to S. aureus, in the pathogenesis of chronic rhinosinusitis. ? ?
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