Atopic dermatitis (AD) and psoriasis are the two most common chronic inflammatory skin diseases in the general population. Colonization and infection with S. aureus has been reported to exacerbate AD and psoriasis. The mechanisms by which bacteria participate in the pathogenesis of these skin diseases are unknown. Recent studies demonstrating that approximately 60% of Staphylococcus aureus from AD and psoriasis patients produce superantigens (SAgs) provide a plausible mechanism by which S. aureus could exacerbate skin inflammation. In particular, it has been shown that staphylococcal SAgs can engage HLA-DR on macrophages and activated keratinocytes to induce the release of cytokines and cause the selective stimulation of T cells expressing specific T cell receptor(TCR) Vbeta regions. Indeed in AD, SAg production has been associated with more severe skin disease. S aureus, which do not secrete SAgs, produce alpha toxin, a potent keratinocyte activator in vitro whose effects on the immune response in vivo is unknown.
The specific aims of this competing renewal grant application will be: First, to determine whether AD and psoriasis skin lesions and their respective peripheral blood skin homing receptor positive T cells are associated with a selective expansion of T cells expressing TCR Vbeta regions that react with SAgs on lesional skin. Second, to investigate whether SAgs contribute to the severity of AD by inducing glucocorticoid insensitivity in skin homing T cells, and to assess the mechanisms by which this occurs. Third, to determine the histologic and immunologic effects of staphylococcal alpha toxin vs SAgs on the skin of normal controls vs patients with AD or psoriasis. Genetically-engineered mutant SAgs incapable of binding to either HLA-DR or the TCR will be used to decipher the molecular mechanisms of SAg-mediated skin inflammation in vivo. Fourth, to investigate the mechanisms leading to enhanced colonization of S aureus on the skin of patients with AD and psoriasis. Mutant S. aureus selectively deficient in various adhesin genes will be used to define the precise molecules involved in the attachment of S. aureus to inflamed skin surfaces. The role of bacterial toxins in the pathogenesis of skin diseases are poorly understood. The skin is an important model to study the pathogenesis of immunologic reactions in tissues. Thus, the elucidation of immune mechanisms by which SAgs exacerbate AD and psoriasis should have important consequences for the development of effective therapeutic modalities in the treatment of a variety of inflammatory diseases. With the increased prevalence of antibiotic resistant S. aureus and drug allergy, it is essential to develop new non-antibiotic strategies in combating bacterial toxin-mediated skin diseases.
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