Our laboratory has described an animal model for the study of the autoimmune disease, pemphigus (NEJM 306:1189-1196). The goal of this study is to define the mechanisms by which these autoantibodies produce epidermal injury in the mouse. There are several clinical subsets of pemphigus; all are characterized by the presence of squamous epithelial autoantibodies. Little is known about the pathophysiological mechanisms which make these diseases distinct. For example, it is unknown if there is more than one cell surface antigen reactive with pemphigus autoantibodies, or if a single pemphigus antigen may have different distributions amongst individuals. The relationship of the variants of pemphigus, will be studied by injecting mice with IgG from the sera of these patients. Several autoimmune disorders with autoantibodies against cell surface receptors (myasthenia gravis, insulin resistant diabetes, etc.) show a common pathogenic mechanism, i.e.: a """"""""surface receptor crosslinking"""""""" induced by the antibodies. Our data suggests that the same crosslinking phenomenon is the initial step in the induction of tissue injury by pemphigus autoantibodies (disease is easily produced by injections of bivalent pemphigus F(ab')2 antibody fragments, but not by their monovalent Fab' fragments). We will clarify these findings by testing the following: a) After receiving injections of monovalent pemphigus Fab' fragments, an Fab specific anti-human immunoglobulin will be injected. This may crosslink the already epidermal-bound Fab' fragments and induce scantholysis, b) The ability of pemphigus Fab1 fragments to competitively inhibit the binding and induction of disease by intact pemphigus IgG. These studies will clearly define the role of cell surface crosslinking in the initiation of cellular injury in pemphigus in vivo. Examination of lesional skin in pemphigus demonstrates local activation of the complement system and infiltration of polymorphonuclear leucocytes. We will attempt to define the role of complement and neutrophils in the disease process in vivo. Pemphigus IgG will be injected into a) Balb/C neonates depleted of complement by cobra venom factor and genetically C5 deficient mice, and b) Balb/C neonates depleted of neutrophils by prior injection of rabbit anti-mouse neutrophil serum. We feel that this animal model provides us an unique opportunity to define the pathophysiology of pemphigus, in vivo, and to reveal whether these autoantibodies induce cellular injury by mechanisms which may be common to other immunological diseases.
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