Matsushima Yoshiaki, Mizutani Kento, Goto Hiroyuki, Nakanishi Takehisa, Kondo Makoto, Habe Koji, Isoda Kenichi, Mizutani Hitoshi, Yamanaka Keiichi
Department of Dermatology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Dermatopathology (Basel). 2020 Sep 14;7(2):41-47. doi: 10.3390/dermatopathology7020007.
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.
遗传性大疱性表皮松解症（EB）是一种罕见的遗传性皮肤病，其特征为上皮组织脆弱。隐性营养不良型大疱性表皮松解症（RDEB）是最严重的一种类型，其特征为出现水疱、糜烂和溃疡形成，导致瘢痕形成和肢体挛缩。RDEB还与皮肤外并发症相关，包括消瘦、充血性心力衰竭和系统性淀粉样变性。这些临床并发症的主要原因尚不清楚；然而，我们推测它们是由受损角质形成细胞过度产生的循环炎症细胞因子升高所致。我们使用角蛋白-14驱动、半胱天冬酶-1过表达的转基因（KCASP1Tg）小鼠来研究这一现象，在这些小鼠中，受损角质形成细胞会释放高水平的IL-1α和β。KCASP1Tg小鼠表现出严重的自发性皮炎以及全身并发症，包括异常体重减轻、心血管疾病和伴有器官功能障碍的广泛淀粉样沉积，类似于在严重EB中观察到的并发症。同时给予抗IL-1α和β抗体可部分改善这些病态状况。皮肤不仅构成一个物理屏障，还作为最大的免疫器官发挥作用。我们提出IL-1在EB发病机制中的新作用，以及使用抗IL-1抗体作为EB并发症的潜在治疗方法。
