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Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions.
Cell Reports ( IF 7.5 ) Pub Date : 2020-05-12 , DOI: 10.1016/j.celrep.2020.107633 Marta Martin-Fernandez 1 , María Bravo García-Morato 2 , Conor Gruber 1 , Sara Murias Loza 2 , Muhammad Nasir Hayat Malik 3 , Fahad Alsohime 4 , Abdullah Alakeel 5 , Rita Valdez 6 , Sofija Buta 1 , Guadalupe Buda 7 , Marcelo A Marti 7 , Margarita Larralde 8 , Bertrand Boisson 9 , Marta Feito Rodriguez 2 , Xueer Qiu 1 , Maya Chrabieh 10 , Mohammed Al Ayed 11 , Saleh Al Muhsen 4 , Jigar V Desai 12 , Elise M N Ferre 12 , Sergio D Rosenzweig 13 , Blanca Amador-Borrero 1 , Luz Yadira Bravo-Gallego 2 , Ruth Olmer 14 , Sylvia Merkert 14 , Montserrat Bret 2 , Amika K Sood 15 , Abdulkarim Al-Rabiaah 4 , Mohamad Hani Temsah 4 , Rabih Halwani 16 , Michelle Hernandez 15 , Frank Pessler 17 , Jean-Laurent Casanova 18 , Jacinta Bustamante 19 , Michail S Lionakis 12 , Dusan Bogunovic 1
Cell Reports ( IF 7.5 ) Pub Date : 2020-05-12 , DOI: 10.1016/j.celrep.2020.107633 Marta Martin-Fernandez 1 , María Bravo García-Morato 2 , Conor Gruber 1 , Sara Murias Loza 2 , Muhammad Nasir Hayat Malik 3 , Fahad Alsohime 4 , Abdullah Alakeel 5 , Rita Valdez 6 , Sofija Buta 1 , Guadalupe Buda 7 , Marcelo A Marti 7 , Margarita Larralde 8 , Bertrand Boisson 9 , Marta Feito Rodriguez 2 , Xueer Qiu 1 , Maya Chrabieh 10 , Mohammed Al Ayed 11 , Saleh Al Muhsen 4 , Jigar V Desai 12 , Elise M N Ferre 12 , Sergio D Rosenzweig 13 , Blanca Amador-Borrero 1 , Luz Yadira Bravo-Gallego 2 , Ruth Olmer 14 , Sylvia Merkert 14 , Montserrat Bret 2 , Amika K Sood 15 , Abdulkarim Al-Rabiaah 4 , Mohamad Hani Temsah 4 , Rabih Halwani 16 , Michelle Hernandez 15 , Frank Pessler 17 , Jean-Laurent Casanova 18 , Jacinta Bustamante 19 , Michail S Lionakis 12 , Dusan Bogunovic 1
Affiliation
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Most monogenic disorders have a primary clinical presentation. Inherited ISG15 deficiency, however, has manifested with two distinct presentations to date: susceptibility to mycobacterial disease and intracranial calcifications from hypomorphic interferon-II (IFN-II) production and excessive IFN-I response, respectively. Accordingly, these patients were managed for their infectious and neurologic complications. Herein, we describe five new patients with six novel ISG15 mutations presenting with skin lesions who were managed for dermatologic disease. Cellularly, we denote striking specificity to the IFN-I response, which was previously assumed to be universal. In peripheral blood, myeloid cells display the most robust IFN-I signatures. In the affected skin, IFN-I signaling is observed in the keratinocytes of the epidermis, endothelia, and the monocytes and macrophages of the dermis. These findings define the specific cells causing circulating and dermatologic inflammation and expand the clinical spectrum of ISG15 deficiency to dermatologic presentations as a third phenotype co-dominant to the infectious and neurologic manifestations.
中文翻译：
人类 ISG15 缺乏症中的系统性 I 型 IFN 炎症导致坏死性皮肤损伤。
大多数单基因疾病具有主要的临床表现。然而，遗传性 ISG15 缺陷迄今已表现出两种不同的表现：对分枝杆菌疾病的易感性和来自低形态干扰素-II (IFN-II) 产生的颅内钙化和过度的 IFN-I 反应，分别。因此，对这些患者的感染性和神经系统并发症进行了管理。在此，我们描述了 5 名新患者，这些患者有 6 种新的 ISG15 突变，表现为皮肤病变，他们因皮肤病而接受治疗。在细胞上，我们表示对 IFN-I 反应的显着特异性，这在以前被认为是普遍的。在外周血中，骨髓细胞显示出最强大的 IFN-I 特征。在受影响的皮肤中，在表皮、内皮细胞的角质形成细胞中观察到 IFN-I 信号，以及真皮的单核细胞和巨噬细胞。这些发现定义了引起循环和皮肤炎症的特定细胞，并将 ISG15 缺乏症的临床范围扩大到皮肤病学表现，作为传染性和神经系统表现的第三种表型。
更新日期：2020-05-12
中文翻译：
人类 ISG15 缺乏症中的系统性 I 型 IFN 炎症导致坏死性皮肤损伤。
大多数单基因疾病具有主要的临床表现。然而，遗传性 ISG15 缺陷迄今已表现出两种不同的表现：对分枝杆菌疾病的易感性和来自低形态干扰素-II (IFN-II) 产生的颅内钙化和过度的 IFN-I 反应，分别。因此，对这些患者的感染性和神经系统并发症进行了管理。在此，我们描述了 5 名新患者，这些患者有 6 种新的 ISG15 突变，表现为皮肤病变，他们因皮肤病而接受治疗。在细胞上，我们表示对 IFN-I 反应的显着特异性，这在以前被认为是普遍的。在外周血中，骨髓细胞显示出最强大的 IFN-I 特征。在受影响的皮肤中，在表皮、内皮细胞的角质形成细胞中观察到 IFN-I 信号，以及真皮的单核细胞和巨噬细胞。这些发现定义了引起循环和皮肤炎症的特定细胞，并将 ISG15 缺乏症的临床范围扩大到皮肤病学表现，作为传染性和神经系统表现的第三种表型。
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