美国国立卫生研究院Michael J. Lenardo等研究人员合作发现，先天性iRHOM2缺陷导致ADAM17功能障碍和环境相关的免疫失调疾病。该项研究成果于2021年12月22日在线发表在《自然—免疫学》杂志上。

研究人员报告了一种由RHBDF2（编码iRHOM2的基因）功能缺失突变引起的多态性疾病，该疾病在两个亲属中存在不同器官的反复感染。一位患者有复发性肺炎但没有结肠牵连，另一位有复发性传染性出血性结肠炎但没有肺部牵连，另外两位有复发性呼吸道感染。iRHOM2是调节ADAM17金属蛋白酶的超家族成员，它的缺失导致ADAM17依赖性切割和释放细胞因子的缺陷，包括肿瘤坏死因子和双调蛋白。

为了了解不同的临床表型，研究人员用铜绿假单胞菌对Rrbdf2^-/-小鼠进行鼻饲感染，并观察到更严重的肺炎，而与野生型小鼠相比，感染鼠柠檬酸杆菌引起更严重的炎症性结肠炎。结肠炎患者的粪便微生物群具有可导致结肠炎的特征性口腔物种。因此，由iRHOM2缺陷引起的人类免疫缺陷会导致不同的疾病表型，这可能涉及局部的微生物环境。

附：英文原文

Title: Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease

Author: Kubo, Satoshi, Fritz, Jill M., Raquer-McKay, Hayley M., Kataria, Rhea, Vujkovic-Cvijin, Ivan, Al-Shaibi, Ahmad, Yao, Yikun, Zheng, Lixin, Zou, Juan, Waldman, Alex D., Jing, Xinyi, Farley, Taylor K., Park, Ann Y., Oler, Andrew J., Charles, Adrian K., Makhlouf, Melanie, AbouMoussa, Eman H., Hasnah, Reem, Saraiva, Luis R., Ganesan, Sundar, Al-Subaiey, Abdulrahman Ahmed, Matthews, Helen, Flano, Emilio, Lee, Hyun Hee, Freeman, Alexandra F., Sefer, Asena Pnar, Sayar, Ersin, akr, Erkan, Karakoc-Aydiner, Elif, Baris, Safa, Belkaid, Yasmine, Ozen, Ahmet, Lo, Bernice, Lenardo, Michael J.

Issue&Volume: 2021-12-22

Abstract: We report a pleiotropic disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in two kindreds with recurrent infections in different organs. One patient had recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement and the other two experienced recurrent respiratory infections. Loss of iRHOM2, a rhomboid superfamily member that regulates the ADAM17 metalloproteinase, caused defective ADAM17-dependent cleavage and release of cytokines, including tumor-necrosis factor and amphiregulin. To understand the diverse clinical phenotypes, we challenged Rhbdf2/ mice with Pseudomonas aeruginosa by nasal gavage and observed more severe pneumonia, whereas infection with Citrobacter rodentium caused worse inflammatory colitis than in wild-type mice. The fecal microbiota in the colitis patient had characteristic oral species that can predispose to colitis. Thus, a human immunodeficiency arising from iRHOM2 deficiency causes divergent disease phenotypes that can involve the local microbial environment.

DOI: 10.1038/s41590-021-01093-y

Source: https://www.nature.com/articles/s41590-021-01093-y