Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions

• Published in: Cell reports (Cambridge) Vol. 31; no. 6; p. 107633
• Main Authors: Martin-Fernandez, Marta, Bravo García-Morato, María, Gruber, Conor, Murias Loza, Sara, Malik, Muhammad Nasir Hayat, Alsohime, Fahad, Alakeel, Abdullah, Valdez, Rita, Buta, Sofija, Buda, Guadalupe, Marti, Marcelo A., Larralde, Margarita, Boisson, Bertrand, Feito Rodriguez, Marta, Qiu, Xueer, Chrabieh, Maya, Al Ayed, Mohammed, Al Muhsen, Saleh, Desai, Jigar V., Ferre, Elise M.N., Rosenzweig, Sergio D., Amador-Borrero, Blanca, Bravo-Gallego, Luz Yadira, Olmer, Ruth, Merkert, Sylvia, Bret, Montserrat, Sood, Amika K., Al-rabiaah, Abdulkarim, Temsah, Mohamad Hani, Halwani, Rabih, Hernandez, Michelle, Pessler, Frank, Casanova, Jean-Laurent, Bustamante, Jacinta, Lionakis, Michail S., Bogunovic, Dusan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.05.2020
• Subjects: Alleles; Case-Control Studies; Child; Child, Preschool; Cytokines - deficiency; Cytokines - genetics; Cytokines - immunology; Dermatitis - genetics; Dermatitis - immunology; Dermatitis - pathology; endothelial cells; Female; HEK293 Cells; Humans; inborn errors of immunity; Infant; Interferon Type I - immunology; ISG15; keratinocytes; Male; Mendelian susceptibility to mycobacterial disease; Mutation; myeloid cells; Myeloid Cells - immunology; Myeloid Cells - pathology; Necrosis; Pedigree; Skin - pathology; skin inflammation; type I interferonopathy; Ubiquitins - deficiency; Ubiquitins - genetics; Ubiquitins - immunology; USP18; endothelial cells; myeloid cells; type I interferonopathy; ISG15; inborn errors of immunity; keratinocytes; USP18; Mendelian susceptibility to mycobacterial disease; skin inflammation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107633

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. [Display omitted] •ISG15 deficiency is identified in five new patients with six novel genetic lesions•All patients presented with dermatologic complications•ISG15 mutations lead to hyper-activated responses to type I interferon•Patient cells exhibit striking cell type specificity to the interferon response Martin-Fernandez et al. report on five patients with inherited ISG15 deficiency, a recently discovered syndrome of type I IFN autoinflammation and mycobacterial susceptibility. This study defines an expanded clinical spectrum that now includes dermatologic disease and pinpoints the specific cell types driving inflammation.