TY - JOUR
T1 - Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions
AU - Martin-Fernandez, Marta
AU - Bravo García-Morato, María
AU - Gruber, Conor
AU - Murias Loza, Sara
AU - Malik, Muhammad Nasir Hayat
AU - Alsohime, Fahad
AU - Alakeel, Abdullah
AU - Valdez, Rita
AU - Buta, Sofija
AU - Buda, Guadalupe
AU - Marti, Marcelo A.
AU - Larralde, Margarita
AU - Boisson, Bertrand
AU - Feito Rodriguez, Marta
AU - Qiu, Xueer
AU - Chrabieh, Maya
AU - Al Ayed, Mohammed
AU - Al Muhsen, Saleh
AU - Desai, Jigar V.
AU - Ferre, Elise M.N.
AU - Rosenzweig, Sergio D.
AU - Amador-Borrero, Blanca
AU - Bravo-Gallego, Luz Yadira
AU - Olmer, Ruth
AU - Merkert, Sylvia
AU - Bret, Montserrat
AU - Sood, Amika K.
AU - Al-rabiaah, Abdulkarim
AU - Temsah, Mohamad Hani
AU - Halwani, Rabih
AU - Hernandez, Michelle
AU - Pessler, Frank
AU - Casanova, Jean Laurent
AU - Bustamante, Jacinta
AU - Lionakis, Michail S.
AU - Bogunovic, Dusan
N1 - Funding Information:
We would like to thank Ludovic Debure and Dr. Thomas Wisniewski of the New York State Center of Excellence for Alzheimer’s Disease for their technical assistance with the SiMoA assay. This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH). We would like to thank Rebeca Perez de Diego for her advice. This work was supported by National Institute of Allergy and Infectious Diseases / NIH grants R01AI127372 , R21AI134366 , and R21AI129827 , a grant from the March of Dimes to D.B., and The Helmholtz Association’s Cross-Program Initiative on Personalized Medicine, iMed. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the St. Giles Foundation , the Jeffrey Modell Foundation , The Rockefeller University Center for Clinical and Translational Science , grant UL1TR001866 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health , the National Institute of Allergy and Infectious Diseases ( 5R01AI089970-02 and 5R37AI095983 ), grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence ( ANR-10-LABX-62-IBEID ), the French Foundation for Medical Research ( Fondation pour la Recherche Médicale [FRM], EQU201903007798 ) and the French National Research Agency (ANR) under the “Investments for the Future” program ( ANR-10-IAHU-01 ), GENMSMD ( ANR-16-CE17-0005-01 ), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris University , and The Rockefeller University . C.G. was supported by T32 training grant 5T32HD075735-07 at the Icahn School of Medicine at Mount Sinai .
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/5/12
Y1 - 2020/5/12
N2 - 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.
AB - 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.
KW - ISG15
KW - Mendelian susceptibility to mycobacterial disease
KW - USP18
KW - endothelial cells
KW - inborn errors of immunity
KW - keratinocytes
KW - myeloid cells
KW - skin inflammation
KW - type I interferonopathy
UR - http://www.scopus.com/inward/record.url?scp=85084357696&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.107633
DO - 10.1016/j.celrep.2020.107633
M3 - Article
C2 - 32402279
AN - SCOPUS:85084357696
SN - 2211-1247
VL - 31
JO - Cell Reports
JF - Cell Reports
IS - 6
M1 - 107633
ER -