Hidradenitis Suppurativa as a Potential Subtype of Autoinflammatory Keratinization Disease
Hidradenitis Suppurativa as a Potential Subtype of Autoinflammatory Keratinization Disease
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DOI：
10.3389/fimmu.2020.00847
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发表时间：
2020-05
影响因子：
7.3
通讯作者：
T. Nomura
中科院分区：
文献类型：
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作者：
T. Nomura
化脓性汗腺炎 (HS) 是一种慢性炎症性皮肤病，临床特征为煮沸囊肿、粉刺、脓肿、肥厚性疤痕和/或窦道，通常发生在腋窝、腹股沟和/或臀部等顶浆腺丰富的区域。尽管其确切的致病机制仍不清楚，但我在此强调以下三个最新发现在 HS 发病机制中的重要性：首先，在一些 HS 患者中已发现编码 γ-分泌酶的基因（包括 NCSTN、PSENEN 和 PSEN1）杂合功能丧失突变。这种基因改变会导致角化过度、毛囊分化失调以及通过异常的 Notch 信号传导导致囊肿形成。此外，Psen1–/Psen2–、Psen1–、Ncstn+/– 和 Notch1–/Notch2– 小鼠具有人类 HS 的共同表型，表明异常角化在 HS 发展中的作用。其次，HS 样本中已证实白细胞介素 1β、白细胞介素 36、caspase-1 和 NLRP3 上调以及 Th17:Treg 细胞轴失调，表明自身炎症是该疾病病理生理学中的关键事件。值得注意的是，热射病可能与其他自身炎症性疾病并发，如炎症性肠病和坏疽性脓皮病，这再次凸显了自身炎症在热射病中的重要性。最后，据报道，阿达木单抗、英夫利昔单抗、阿那白滞素、乌特克单抗和苏金单抗等生物制剂对中度至重度 HS 有效。这些发现共同表明热射病与异常角化和自身炎症密切相关，从而提出了它是否代表自身炎症角化疾病（最近提出的一种疾病实体）的问题。在这篇小综述中，我介绍了自身炎症角化病的概念，并试图解决这个临床上重要的问题。
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition, clinically characterized by boiled cysts, comedones, abscesses, hypertrophic scars, and/or sinus tracts typically in the apocrine-gland-rich areas such as the axillae, groin, and/or buttocks. Although its precise pathogenic mechanisms remain unknown, I herein emphasize the importance of the following three recent discoveries in the pathogenesis of HS: First, heterozygous loss-of-function mutations in the genes encoding γ-secretase, including NCSTN, PSENEN, and PSEN1, have been identified in some patients with HS. Such genetic alterations result in hyperkeratosis, dysregulated hair follicle differentiation, and cyst formation via aberrant Notch signaling. Furthermore, Psen1–/Psen2–, Psen1–, Ncstn+/–, and Notch1–/Notch2– mice share common phenotypes of human HS, suggesting a role of aberrant keratinization in the development of HS. Second, upregulation of interleukin 1β, interleukin-36, caspase-1, and NLRP3 and dysregulation of the Th17:Treg cell axis have been demonstrated in HS samples, suggesting that autoinflammation is a key event in the pathophysiology of the disease. Notably, HS may be complicated with other autoinflammatory diseases such as inflammatory bowel diseases and pyoderma gangrenosum, again highlighting the importance of autoinflammation in HS. Last, biologics such as adalimumab, infliximab, anakinra, ustekinumab, and secukinumab are reportedly effective for moderate-to-severe HS. These findings collectively suggest that HS is closely linked with aberrant keratinization and autoinflammation, raising the question whether it represents an autoinflammatory keratinization disease, a recently proposed disease entity. In this mini review, I introduce the concept of autoinflammatory keratinization disease and attempt to address this clinically important question.