Abstract
Epidermolysis bullosa acquisita (EBA) is a difficult-to-treat subepidermal autoimmune blistering skin disease (AIBD) with circulating and tissue-bound anti-type VII collagen antibodies. Different reports have indicated an increased concentration of tumor necrosis factor alpha (TNF) in the serum and blister fluid of patients with subepidermal AIBDs. Furthermore, successful anti-TNF treatment has been reported for individual patients with AIBDs. Here, we show that in mice, induction of experimental EBA by repeated injections of rabbit-anti mouse type VII collagen antibodies led to increased expression of TNF in skin, as determined by real-time PCR and immunohistochemistry. To investigate if the increased TNF expression is of functional relevance in experimental EBA, we inhibited TNF function using the soluble TNF receptor fusion protein etanercept (Enbrel®) or a monoclonal antibody to murine TNF. Interestingly, mice receiving either of these two treatments showed significantly milder disease progression than controls. In addition, immunohistochemical staining demonstrated reduced numbers of macrophages in lesional skin in mice treated with TNF inhibitors compared to controls. Furthermore, etanercept treatment significantly reduced the disease progression in immunization-induced EBA. In conclusion, the increased expression of TNF in experimental EBA is of functional relevance, as both the prophylactic blockade of TNF and the therapeutic use of etanercept impaired the induction and progression of experimental EBA. Thus, TNF is likely to serve as a new therapeutic target for EBA and AIBDs with a similar pathogenesis.
Highlights
Tumor necrosis factor α (TNF) was originally described as a circulating factor that can cause necrosis of tumors, but has since been identified as a key regulator of inflammatory responses [1]
Because of the role of TNF blockade in many inflammatory diseases, we evaluated its contribution to another immune-mediated inflammatory disease, epidermolysis bullosa acquisita (EBA), a prototypic antibody-dependent and organ-specific autoimmune blistering skin disease (AIBD) [14,15,16,17]
These data suggest that tissue-expressed TNF but not circulating TNF is increased in experimental Epidermolysis bullosa acquisita (EBA) and human AIBDs
Summary
Tumor necrosis factor α (TNF) was originally described as a circulating factor that can cause necrosis of tumors, but has since been identified as a key regulator of inflammatory responses [1]. High levels of TNF were detected in the wound fluid of chronic nonhealing wounds and induce cytotoxicity [9]. In many chronic inflammatory diseases, TNF inhibition results in the downregulation of abnormal and progressive inflammatory processes, induces rapid and sustained clinical remission, improves quality of life and prevents target organ damage [10]. It acts as a potent chemoattractant for neutrophils, induces microvascular leakage and promotes the expression of adhesion molecules on endothelial cells, helping neutrophils to migrate [11,12]. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases
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