178 Neutrophil elastase is critical in linear IgA bullous dermatosis in mice

Linear IgA bullous dermatosis (LABD) is a skin autoimmune disease characterized by the linear deposition of IgA autoantibodies at the basement membrane zone (BMZ), subepidermal blisters, and neutrophil infiltration. These IgA autoantibodies specifically recognize the hemidesmosomal component BP180 (also called type XVII collagen) and its processed 120 kDa and 97 kDa extracellular regions. The main epitopes recognized by LABD IgA autoantibodies are in the NC16A domain of BP180. Since there is a lack of immune cross-reactivity between mouse and human BP180 in the NC16A domain, we generated a humanized mouse strain expressing human BP180 NC16A domain (termed hNC16A mice). hNC16A mice, when reconstituted with purified human neutrophils and injected with purified anti-NC16A IgA from LABD patients’ sera, developed subepidermal blisters 48 h post IgA injection. The lesional skin showed IgA deposition at the BMZ, extensive neutrophilic infiltration, and significantly increased levels of neutrophil elastase (NE) and MMP-9.In vitro, anti-NC16A IgA in the presence of recombinant NC16A, activates human neutrophils to release NE and MMP-9. Blockade of NE but not MMP-9 significantly reduced the disease severity in the LABD mouse model. These findings suggest that NE plays a pivotal role in anti-NC16A IgA-induced LABD.