Antibody-mediated, inflammatory injury of epidermal cells is the characteristic feature seen in the skin of patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP). These patients produce autoantibodies specific for differentiating keratinocytes (PV) and epidermal basal cells (BP). Humoral mediated interactions between the epidermis and the inflammatory system will be studied, emphasizing the role of proteases and inflammatory mediators released from epidermal cells and mast cells. It is known that PV autoantibodies bind epidermal cell surface antigens and trigger an IgG dose-dependent, highly specific cell detachment in epidermal cell cultures. This cell detachment is inhibited by certain protease inhibitors and according to our preliminary studies, is independent of plasminogen activator/plasmin activation. This proposal will investigate the role of epidermal proteases which produce the immunologic injury of the epidermis resulting in the cell detachment phenomenon. These enzymes will be isolated and characterized. Furthermore, epidermal basal cells expressing BP antigen on their surfaces will be activated with BP autoantibodies and/or Phorbol Myristate acetate (PMA). The proteases and inflammatory mediators which may be produced be these cells will also be isolated and characterized. The same approach will be taken to study proteases and inflammatory mediators of mast cell origin that, according to our preliminary studies, are present in BP blister fluids. Using highly sensitive assays for mast cell proteases, we will study blister fluids from spontaneous and experimentally-induced blisters of PV and BP patients and compare to blister fluids obtained from normal donors. The same studies will be performed on the supernatants of epidermal cell cultures activated with BP or PV autoantibodies and/or PMA. The studies to be carried out in this proposal will bring some insight into the molecular pathogenetic mechanisms operating in the skin of patients with pemphigus vulgaris and bullous pemphigoid.
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