Chan Aegean, Godoy-Gijon Elena, Nuno-Gonzalez Almudena, Crumrine Debra, Hupe Melanie, Choi Eung-Ho, Gruber Robert, Williams Mary L, Choate Keith, Fleckman Philip H, Elias Peter M
Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
Department of Dermatology, Yonsei University, Wonju College of Medicine, Wonju, South Korea.
JAMA Dermatol. 2015 Mar;151(3):285-92. doi: 10.1001/jamadermatol.2014.3369.
Secondary infections and impaired desquamation complicate certain inherited ichthyoses, but their cellular basis remains unknown. In healthy human epidermis, the antimicrobial peptides cathelicidin (LL-37) and human β-defensin 2 (HBD2), as well as the desquamatory protease kallikrein-related peptidase 7 (KLK7), are delivered to the stratum corneum (SC) interstices by lamellar body (LB) exocytosis.
To assess whether abnormalities in the LB secretory system could account for increased risk of infections and impaired desquamation in inherited ichthyoses with known abnormalities in LB assembly (Harlequin ichthyosis [HI]), secretion (epidermolytic ichthyosis [EI]), or postsecretory proteolysis (Netherton syndrome [NS]).
DESIGN, SETTING, AND PARTICIPANTS: Samples from library material were taken from patients with HI, EI, NS, and other ichthyoses, but with a normal LB secretory system, and in healthy controls and were evaluated by electron microscopy and immunohistochemical analysis from July 1, 2010, through March 31, 2013.
Changes in LB secretion and in the fate of LB-derived enzymes and antimicrobial peptides in ichthyotic patients vs healthy controls.
In healthy controls and patients with X-linked ichthyosis, neutral lipid storage disease with ichthyosis, and Gaucher disease, LB secretion is normal, and delivery of LB-derived proteins and LL-37 immunostaining persists high into the SC. In contrast, proteins loaded into nascent LBs and their delivery to the SC interstices decrease markedly in patients with HI, paralleled by reduced immunostaining for LL-37, HBD2, and KLK7 in the SC. In patients with EI, the cytoskeletal abnormality impairs the exocytosis of LB contents and thus results in decreased LL-37, HBD2, and KLK7 secretion, causing substantial entombment of these proteins within the corneocyte cytosol. Finally, in patients with NS, although abundant enzyme proteins loaded in parallel with accelerated LB production, LL-37 disappears, whereas KLK7 levels increase markedly in the SC.
Together, these results suggest that diverse abnormalities in the LB secretory system account for the increased risk of secondary infections and impaired desquamation in patients with HI, EI, and NS.
继发性感染和脱屑受损使某些遗传性鱼鳞病病情复杂化，但其细胞基础仍不清楚。在健康人表皮中，抗菌肽cathelicidin（LL - 37）和人β - 防御素2（HBD2），以及脱屑蛋白酶激肽释放酶相关肽酶7（KLK7），通过板层小体（LB）胞吐作用输送到角质层（SC）间隙。
评估LB分泌系统异常是否可解释已知LB组装异常（丑角鱼鳞病[HI]）、分泌异常（表皮松解性鱼鳞病[EI]）或分泌后蛋白水解异常（Netherton综合征[NS]）的遗传性鱼鳞病患者感染风险增加和脱屑受损的情况。
设计、地点和参与者：2010年7月1日至2013年3月31日，从HI、EI、NS患者以及其他鱼鳞病患者（但LB分泌系统正常）和健康对照者的文库材料中取样，通过电子显微镜和免疫组织化学分析进行评估。
鱼鳞病患者与健康对照者相比，LB分泌以及LB衍生酶和抗菌肽命运的变化。
在健康对照者以及患有X连锁鱼鳞病、中性脂质贮积病伴鱼鳞病和戈谢病的患者中，LB分泌正常，LB衍生蛋白的输送以及LL - 37免疫染色在SC中一直保持较高水平。相比之下，HI患者中装载到新生LB中的蛋白质及其向SC间隙的输送显著减少，同时SC中LL - 37、HBD2和KLK7的免疫染色也减少。在EI患者中，细胞骨架异常损害了LB内容物的胞吐作用，从而导致LL - 37、HBD2和KLK7分泌减少，使这些蛋白质大量被困在角质形成细胞胞质溶胶中。最后，在NS患者中，尽管与LB产生加速同时装载了大量酶蛋白，但LL - 37消失，而KLK7水平在SC中显著增加。
总之，这些结果表明LB分泌系统的多种异常可解释HI、EI和NS患者继发性感染风险增加和脱屑受损的情况。
