Skin ranks second only to synovium as the organ most commonly affected in systemic lupus erythematosus. This development and feasibility study focuses primarily on pathogenetic mechanisms operative in cutaneous and systemic lupus. We will take advantage of an excellent animal model of SLE, the MRL/lpr mouse. These mice have a high incidence of skin lesions which resemble those of human lupus, and will be used to perform a careful temporal analysis of pathogenetic changes in lesional skin. Skin biopsies from fresh, early acute cutaneous LE lesions and from non- lesional skin can easily be obtained and will be examined by the sensitive techniques of in situ hybridization and immunohistochemistry.
In Aim 1 we will determine the nature of the cellular infiltrate and the expression of activation, adhesion, costimulatory molecules and cytokines in lesions in murine lupus. Early events and the temporal sequence of events involved in the initiation and propagation of inflammatory skin lesions in MRL/lpr mice will be examined. The proposed studies will allow us to examine the earliest possible events occurring in skin prior to clinically apparent skin disease.
In Aim 2 we will utilize a unique model of MHC class II immunodeficiency recently produced in our laboratory to examine the role of two key members of the immune response - CD4 helper T cells and MHC class II proteins - in SLE pathogenesis. By repeated backcrossing, an MRL/lpr class II transgenic model will be produced and analyzed for the presence of nephritis, skin lesions, autoantibody production and lymphadenopathy. Finally, in Aim 3 we will test the efficacy of blocking the CD28/B7 costimulatory pathway in MRL/lpr mice on disease initiation and progression. The MRL/lpr mouse strain offers a rich resource for the identification of pathogenetic mechanisms operative in SLE. These studies should allow us to identify the immune cell types and molecules involved in the pathogenesis of cutaneous and systemic lupus.
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