Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease with itchy erythema and tense blisters developing over the whole body. Previous studies showed that pathogenic autoantibodies bind to type XVII collagen (COL17) and subsequent immune reactions result in the subepidermal blister formation. We previously reported that CD4+ T cells are essential for the pathogenesis of active BP mouse model. However, the pathogenic roles of CD4+ T cell subsets, cytokines and eosinophils in BP has been largely unclear. To investigate it, we made two different BP mouse models, a skin-grafting BP model and an active BP mouse model by using Stat6-/- mice, T-bet-/- mice and COL17-humanized mice. Th1- and Th2-skewed polarization was observed in both models using Stat6-/- mice and T-bet-/- mice, respectively, which was confirmed by the distribution of IgG subclass and cytokine levels. Interestingly, the frequency of subepidermal blister formation was significantly lower in models using Stat6-/- mice than that in models using wild-type mice and T-bet-/- mice. The expression levels of eotaxin-1 and eotaxin-2 and the number of eosinophils in the lesional skin were lower in Stat6-/- mice than that in T-bet-/- and wild-type mice. Notably, the expression levels of eosinophil granule proteins, major basic protein (MBP) and eosinophil derived neurotoxin (EDN), were upregulated in the lesional skin in T-bet-/- and wild-type mice but not in Stat6-/- mice, while eosinophil cationic protein (ECP) was upregulated in all mice. Furthermore, EDN levels in sera and in the lesional skin of BP patients were higher than those in healthy individuals. These findings strongly suggest that Stat6, eosinophils and possibly EDN play an important role in the subepidermal blister formation in BP.

Stat6 is a key molecule for subepidermal blister formation in bullous pemphigoid