Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid

Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein BP 180. Passive transfer of antibodies to the murine BP180 (mBP180) ectodomain triggers a blistering skin disease in mice that depends on complement acti vation and neutrophil infiltration and closely mimics human BP. In the pres ent study, we show that mast cells (MCs) play a crucial role in experimenta l BP. Wild-type mice injected intradermally with pathogenic anti-mBP 180 Ig G exhibited extensive MC degranulation in skin,,which preceded neutrophil i nfiltration and subsequent subepidermal blistering. In contrast, mice genet ically deficient in MCs or MC-sufficient mice pretreated with an inhibitor of MC degranulation failed to develop BP. Further, MC-deficient mice recons tituted in skin with MCs became susceptible to experimental BP. Despite the activation of complement to yield C3a and C5a, in the absence of MCs, accu mulation of neutrophils at the injection site was blunted. The lack of resp onse due to MC deficiency was overcome by intradermal administration of a n eutrophil chemoattractant, IL-8, or by reconstitution of the injection site s with neutrophils. 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.