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IntroductionBullous pemphigoid (BP) is an acquired autoimmune skin disease characterized by autoantibodies against two hemidesmosomal antigens, BP230 (BPAG1) and BP180 (BPAG2), and subepidermal blisters (1). These antihemidesmosomal autoantibodies can be detected, along with complement proteins, bound to the dermal-epidermal junction (DEJ) of perilesional skin. In the skin lesions of these patients, basal keratinocytes detach from the underlying dermis at the level of the lamina lucida, leading to subepidermal blistering (1, 2). Eosinophils (3, 4), neutrophils (5), lymphocytes (6), monocyte/macrophages (7,8), and mast cells (MCs; 7, 9) are present in the upper dermis of lesional areas in patients with BP. Interestingly, MC degranulation is a feature of BP (7, 9). Chemoattractants from MCs, including eosinophilic/neutrophilic chemotactic factors and histamine, are present at high concentrations in BP blister fluids (10, 11). Similar skin lesions are observed in the pregnancy-associated nonviral disorder herpes gestationis (12). These observations imply that MCs may play a role in blister formation.We have used an experimental model of BP that involves the passive transfer of anti-mBP180 antibodies into neonatal BALB/c mice to reproduce the key immunopathological features of this human autoimmune disease: IgG and complement deposition at the DEJ, inflammatory infiltration of the upper dermis, and subepidermal blistering (13). The pathogenicity of anti-mBP180 antibodies depends on complement activation (14) and polymorphonuclear leukocyte (PMN) recruitment (15). In the present study, we have investigated the role of MCs in experimental BP using mice genetically deficient in MCs. Preparation of pathogenic rabbit anti-mouse IgG. The preparation of recombinant mBP180 and the immunization of rabbits were performed as described previ- Methods Laboratory animals. Breeding pairs of MC-deficient WCB6F1-Mgf

Bullous pemphigoid (BP) is an autoimmune disease characterized by subepidermal blistering. Based on previous work, IgG autoantibodies directed against BP180 are thought to be the primary pathogenic agent in BP. In addition to these IgG autoantibodies, however, most BP patients produce IgE class autoantibodies that also react with BP180, and total IgE levels are often elevated in this disease. To directly test whether BP IgE is pathogenic, 6 ng of total IgE isolated from two BP and two normal sera were injected into human skin grafted onto athymic, nude mice. Twenty-four hours after injection, erythematous, elevated plaques were observed in all human skin grafts receiving BP IgE (n=11), but not control IgE (n=9). Histologic and ultrastructural examination of the lesions showed engorgement of blood vessels and a dermal infiltrate composed of neutrophils, eosinophils, and mast cells, many of which were degranulated. At a higher dose of BP IgE (47 ng), histological separation of the epidermis from the dermis was observed in two of the three grafts. The BP IgE-induced erythematous plaques were reminiscent of those clinically seen in BP. This provides early evidence of a direct demonstration of a pathogenic role for IgE class autoantibodies in a human autoimmune disease.

IntroductionBullous pemphigoid (BP) is an acquired autoimmune skin disease characterized by autoantibodies against two hemidesmosomal antigens, BP230 (BPAG1) and BP180 (BPAG2), and subepidermal blisters (1). These antihemidesmosomal autoantibodies can be detected, along with complement proteins, bound to the dermal-epidermal junction (DEJ) of perilesional skin. In the skin lesions of these patients, basal keratinocytes detach from the underlying dermis at the level of the lamina lucida, leading to subepidermal blistering (1, 2). Eosinophils (3, 4), neutrophils (5), lymphocytes (6), monocyte/macrophages (7,8), and mast cells (MCs; 7, 9) are present in the upper dermis of lesional areas in patients with BP. Interestingly, MC degranulation is a feature of BP (7, 9). Chemoattractants from MCs, including eosinophilic/neutrophilic chemotactic factors and histamine, are present at high concentrations in BP blister fluids (10, 11). Similar skin lesions are observed in the pregnancy-associated nonviral disorder herpes gestationis (12). These observations imply that MCs may play a role in blister formation.We have used an experimental model of BP that involves the passive transfer of anti-mBP180 antibodies into neonatal BALB/c mice to reproduce the key immunopathological features of this human autoimmune disease: IgG and complement deposition at the DEJ, inflammatory infiltration of the upper dermis, and subepidermal blistering (13). The pathogenicity of anti-mBP180 antibodies depends on complement activation (14) and polymorphonuclear leukocyte (PMN) recruitment (15). In the present study, we have investigated the role of MCs in experimental BP using mice genetically deficient in MCs. Preparation of pathogenic rabbit anti-mouse IgG. The preparation of recombinant mBP180 and the immunization of rabbits were performed as described previ- Methods Laboratory animals. Breeding pairs of MC-deficient WCB6F1-Mgf

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