ROLE OF THE SELECTINS IN THE DEVELOPMENT OF VASCULITIS

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The inflammatory events which lead to the development of vasculitis in diseases such as lupus erythematosis, Wegener's granulomatosis, and vasculitic disorders are poorly understood. The expression of adhesion molecules on leukocytes and endothelial cells is thought to be critical for both the initiation and progression of vasculitic lesions in these and other diseases. The selectin family of adhesion proteins (P-, E-, and L-selectin) mediate leukocyte rolling, the initial step in leukocyte emigration from the vasculature into tissue during an inflammatory response. Inhibition or loss of one or more of the selectins has been shown to reduce leukocyte Recruitment and subsequent tissue damage during both acute and chronic inflammatory responses. However, it remains to be determined the exact roles, if any, of the selectins in the pathogenesis of vasculitis. MRL/MpJ- Fas/lpr mice develop a systemic autoimmune disease characterized by immune complex-based vasculitis and glomerulonephritis and these mice serve as an excellent mode system for studies of vasculitic diseases. We have now generated MRL/MpJ-Fas/lpr mice with mutations in P- and/or E-selectin in order to analyze the in vivo role of these adhesion molecules in the development of vasculitis in this model. The specific aims are to: (i) Determine the temporal and vascular specific expression patterns of P- and E-selectin in MRL/MpJ-Fas/lpr mice, and (ii) Determine whether MRL/MpJ-Fas/lpr mice with null mutations in P-selectin, E-selectin, or both P-and E-selectin expression is an important determinant in the initiation and progression of vasculitis in this model and may identify these adhesion proteins as possible molecular targets for pharmacologic intervention in the treatment of vasculitic diseases.