These observations imply that MCs may play a role in blister formation. Similar skin lesions are observed in the pregnancy-associated nonviral disorder herpes gestationis ( 12). Chemoattractants from MCs, including eosinophilic/neutrophilic chemotactic factors and histamine, are present at high concentrations in BP blister fluids ( 10, 11). Interestingly, MC degranulation is a feature of BP ( 7, 9). 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. 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). These anti-hemidesmosomal autoantibodies can be detected, along with complement proteins, bound to the dermal-epidermal junction (DEJ) of perilesional skin. Introductionīullous 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 findings provide the first direct evidence to our knowledge that MCs play an essential role in neutrophil recruitment during subepidermal blister formation in experimental BP. The lack of response due to MC deficiency was overcome by intradermal administration of a neutrophil chemoattractant, IL-8, or by reconstitution of the injection sites with neutrophils. Despite the activation of complement to yield C3a and C5a, in the absence of MCs, accumulation of neutrophils at the injection site was blunted. Further, MC-deficient mice reconstituted in skin with MCs became susceptible to experimental BP. In contrast, mice genetically deficient in MCs or MC-sufficient mice pretreated with an inhibitor of MC degranulation failed to develop BP. Wild-type mice injected intradermally with pathogenic anti-mBP180 IgG exhibited extensive MC degranulation in skin, which preceded neutrophil infiltration and subsequent subepidermal blistering. In the present study, we show that mast cells (MCs) play a crucial role in experimental BP. Passive transfer of antibodies to the murine BP180 (mBP180) ectodomain triggers a blistering skin disease in mice that depends on complement activation and neutrophil infiltration and closely mimics human BP. Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein BP180.
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