An animal model of bullous pemphigoid: what can it teach us?

BP is an organ-specific autoimmune disease characterized by blistering of the skin due to a detachment of the epidermis from the underlying connective tissue layer and by the production of autoantibodies directed against the cutaneous basement membrane zone. A 180-kD epidermal protein, BP180, has been identified as one of the major antigenic targets of these autoantibodies and, interestingly, has been localized to the epidermal hemidesmosome, a cellular structure involved in anchoring basal epithelial cells to the basement membrane. An immunodominant and potentially pathogenic epitope associated with BP has recently been mapped by our laboratory to a site on the extracellular domain of the human BP180 antigen. This antigenic site, designated the MCW-1 epitope, has been shown to be recognized by the majority of sera from patients with either BP or HG, a pregnancy-associated subepidermal bullous disease. Unfortunately, the MCW-1 epitope is absent from the murine BP180 molecule; therefore, human autoantibodies directed against this site could not be tested directly for pathogenicity using the conventional passive transfer mouse model. As an alternative approach, rabbit antibodies were prepared against the segment of murine BP180 that is homologous with the MCW-1 epitope region and were tested for pathogenicity by passive transfer experiments. Remarkably, neonatal mice injected with these antibodies developed a subepidermal blistering disease that faithfully reproduced all of the key immunopathological features of BP and HG--deposition of lgG and complement at the dermal-epidermal junction, inflammatory infiltration of the upper dermis, and frank, subepidermal blistering. These results strongly suggest that the autoimmune response against the human BP180 MCW-1 epitope is relevant in the pathogenesis of blister formation in BP and HG patients. This animal model is currently being used to further dissect the pathophysiology of these autoimmune disorders.