Emaciation, Congestive Heart Failure, and Systemic Amyloidosis in Severe Recessive Dystrophic Epidermolysis Bullosa: Possible Internal Complications Due to Skin-Derived Inflammatory Cytokines Derived from the Injured Skin

Abstract

Inherited epidermolysis bullosa (EB) is a rare genetic skin disorder characterized by epithelial tissue fragility. Recessive dystrophic epidermolysis bullosa (RDEB) is the most severe form, characterized by the presence of blisters, erosion, and ulcer formation, leading to scarring and contraction of the limbs. RDEB is also associated with extra-cutaneous complications, including emaciation, congestive heart failure, and systemic amyloidosis. The main cause of these clinical complications is unknown; however, we hypothesized that they are caused by elevated circulating inflammatory cytokines overproduced by injured keratinocytes. We addressed this phenomenon using keratin-14 driven, caspase-1 overexpressing, transgenic (KCASP1Tg) mice in which injured keratinocytes release high levels of IL-1α and β. KCASP1Tg showed severe spontaneous dermatitis, as well as systemic complications, including aberrant weight loss, cardiovascular disease, and extensive amyloid deposition with organ dysfunction, resembling the complications observed in severe EB. These morbid conditions were partially ameliorated by simultaneous administration of anti-IL-1α and β antibodies. The skin not only constitutes a physical barrier, but also functions as the largest immune organ. We suggest a novel role for IL-1 in the pathogenesis of EB and the use of anti-IL-1 antibodies as a potential therapy for EB complications.