Bullous pemphigoid (BP) is an autoimmune blistering disease of human skin in which circulating IgG autoantibodies bind to bullous pemphigoid antigens (BPA's) located in the epidermal basement membrane. BP autoantibodies are thought to play a pathogenic role in the initiation of disease, however the factor which stimulate autoantibody production are unknown. Ultrastructural studies reveal that BPA's localize to the hemidesmosomal plaque of basal epidermal cells. It is planned to test the hypothesis that BPA's are tightly associated with other hemidesmosomal components in human epidermis. We will isolated and immunoprecipitate BPA's from normal human skin using various detergent extraction conditions and seek associations between the 230 and 180 KD BPA's by means of double immunoprecipitation assays. We will examine the association of the alpha6Beta4 integrin, another hemidesmosomal component, and epiligrin, a recently described hemidesmosomal associated component, with BPA's by double (using fusion proteins, derived from BP cDNA clones, bound to affinity columns) and other hemidesmosome associated molecules including epiligrin and the a6B4 integrin. Additionally, immunoelectron microscopy will be used to probe for interactions among these hemidesmosomal components. We will also seek association between BPA's and particular regions of the basal keratinocyte specific keratins by means of keratins fusion proteins bound to columns. We will determine the baseline localization of the BPA genes in normal skin. In addition, we will characterize the autoantibody specificity of the in vivo bound antibodies in patients with BP to further characterize the importance of these two antibody systems in BP. skin and will allow us to expand our knowledge of epidermal basement membrane structure. Furthermore, this research may lead to insights into the pathogenesis of BP which could yield ideas relevant to better patient management. The long term objective of this project is to develop an understanding of the biological significance in health and disease of the BPA's.
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