Role of eosinophils and MMP-9 in autoimmune blistering disease bullous pemphigoid

Abstract

Abstract Bullous pemphigoid (BP) is an autoimmune inflammatory subepidermal blistering disease associated with autoantibodies against two hemidesmosomal components, the BP230 and BP180 and an inflammatory infiltrate including eosinophils and neutrophils. BP180-specific IgG autoantibodies from BP patients induce BP-like skin lesions in BP180 humanized mice (hBP180 mice). Subepidermal blistering induced by anti-BP180 IgG depends on complement, mast cells, and neutrophils. Since mouse eosinophils lack IgE receptors for human IgE, we generated a humanized IgE receptor FceRI mouse strain (hFceRI) and crossed hFceRI mice onto hBP180 mice to generate hFceRI/hBP180 mice. Anti-BP180 IgE, when injected i.d. into hFceRI/hBP180 mice, trigger infiltration of dominant eosinophils and minor neutrophils and subsequent subepidermal blistering 48 h post IgE injection. In this study, we tested if anti-BP180 IgE-induced BP depends on eosinophils, neutrophils or both. We found that anti-BP180 IgE induce BP in hFceRI/hBP180 mice and neutrophil-deficient but not eosinophil-deficient hFceRI/hBP180 mice. Eosinophil-deficient hFceRI/hBP180 mice reconstituted with eosinophils but not neutrophils from hFceRI/hBP180 mice became susceptible to anti-BP180 IgE-induced BP. Increased MMP-9 was present in diseased mouse blister fluid. MMP-9-deficient and eosinophil-deficient hFceRI/hBP180 mice reconstituted with MMP-9-sufficient but not MMP-9-deficient eosinophils when injected with anti-BP180 IgE developed BP. These data suggest that eosinophils and MMP-9 are critical for BP and could be therapeutic targets for BP treatment.