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

Marta Martin-Fernandez, María Bravo García-Morato, Conor Gruber, Sara Murias Loza, Muhammad Nasir Hayat Malik, Fahad Alsohime, Abdullah Alakeel, Rita Valdez, Sofija Buta, Guadalupe Buda, Marcelo A. Marti, Margarita Larralde, Bertrand Boisson, Marta Feito Rodriguez, Xueer Qiu, Maya Chrabieh, Mohammed Al Ayed, Saleh Al Muhsen, Jigar V. Desai, Elise M.N. FerreSergio D. Rosenzweig, Blanca Amador-Borrero, Luz Yadira Bravo-Gallego, Ruth Olmer, Sylvia Merkert, Montserrat Bret, Amika K. Sood, Abdulkarim Al-rabiaah, Mohamad Hani Temsah, Rabih Halwani, Michelle Hernandez, Frank Pessler, Jean Laurent Casanova, Jacinta Bustamante, Michail S. Lionakis, Dusan Bogunovic

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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.

Original languageEnglish
Article number107633
JournalCell Reports
Issue number6
StatePublished - 12 May 2020


  • ISG15
  • Mendelian susceptibility to mycobacterial disease
  • USP18
  • endothelial cells
  • inborn errors of immunity
  • keratinocytes
  • myeloid cells
  • skin inflammation
  • type I interferonopathy


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