PDF(Pubmed)
Abstract：
Epidermolysis bullosa acquisita (EBA) is a muco-cutaneous autoimmune disease characterized and caused by autoantibodies targeting type VII collagen (COL7). The treatment of EBA is notoriously difficult, with a median time to remission of 9 months. In preclinical EBA models, we previously discovered that depletion of regulatory T cells (Treg) enhances autoantibody-induced, neutrophil-mediated inflammation and blistering. Increased EBA severity in Treg-depleted mice was accompanied by an increased cutaneous expression of interferon gamma (IFN-γ). The functional relevance of IFN-γ in EBA pathogenesis had been unknown. Given that emapalumab, an anti-IFN-γ antibody, is approved for primary hemophagocytic lymphohistiocytosis patients, we sought to assess the therapeutic potential of IFN-γ inhibition in EBA. Specifically, we evaluated if IFN-γ inhibition has modulatory effects on skin inflammation in a pre-clinical EBA model, based on the transfer of COL7 antibodies into mice. Compared to isotype control antibody, anti-IFN-γ treatment significantly reduced clinical disease manifestation in experimental EBA. Clinical improvement was associated with a reduced dermal infiltrate, especially Ly6G+ neutrophils. On the molecular level, we noted few changes. Apart from reduced CXCL1 serum concentrations, which has been demonstrated to promote skin inflammation in EBA, the expression of cytokines was unaltered in the serum and skin following IFN-γ blockade. This validates IFN-γ as a potential therapeutic target in EBA, and possibly other diseases with a similar pathogenesis, such as bullous pemphigoid and mucous membrane pemphigoid.
摘要：
大疱性表皮松解症（EBA）是一种粘膜皮肤自身免疫性疾病，其特征是由靶向VII型胶原蛋白（COL7）的自身抗体引起。EBA的治疗是出了名的困难，中位缓解时间为9个月。在临床前EBA模型中，我们之前发现，调节性T细胞（Treg）的消耗增强了自身抗体诱导的，中性粒细胞介导的炎症和起泡。Treg耗竭小鼠中EBA严重程度的增加伴随着干扰素γ（IFN-γ）皮肤表达的增加。IFN-γ在EBA发病机制中的功能相关性尚不清楚。鉴于emapalumab，抗IFN-γ抗体，被批准用于原发性噬血细胞性淋巴组织细胞增生症患者，我们试图评估EBA中IFN-γ抑制的治疗潜力。具体来说,我们评估了IFN-γ抑制是否对临床前EBA模型中的皮肤炎症有调节作用，基于COL7抗体转移到小鼠体内。与同种型对照抗体相比，抗IFN-γ治疗可显着降低实验性EBA的临床疾病表现。临床改善与皮肤浸润减少有关，尤其是Ly6G+中性粒细胞.在分子水平上,我们注意到几乎没有变化。除了降低CXCL1血清浓度外，已被证明可以促进EBA的皮肤炎症，IFN-γ阻断后，血清和皮肤中细胞因子的表达没有改变。这证实了IFN-γ作为EBA的潜在治疗靶点，可能还有其他发病机制相似的疾病，如大疱性类天疱疮和粘膜类天疱疮。
