Frederik Staels1,2, Flaminia Lorenzetti1,2, Kerstin De Keukeleere1,2, Mathijs Willemsen1,3, Margaux Gerbaux1, Julika Neumann1,3, Thomas Tousseyn4, Emanuela Pasciuto1,3,5, Paul De Munter6, Xavier Bossuyt7, Rik Gijsbers8,9, Adrian Liston1,3,10, Stephanie Humblet-Baron1, Rik Schrijvers11,12. 1. Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium. 2. Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium. 3. VIB Center for Brain and Disease Research, Leuven, Belgium. 4. Department of Imaging and Pathology, Laboratory for Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium. 5. Department of Neurosciences, Laboratory for the Research of Neurodegenerative Diseases, KU Leuven, Leuven, Belgium. 6. Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium. 7. Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium. 8. Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Viral Vector Technology and Gene Therapy, KU Leuven, Leuven, Belgium. 9. Leuven Viral Vector Core, KU Leuven, Leuven, Belgium. 10. Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK. 11. Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium. rik.schrijvers@uzleuven.be. 12. Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium. rik.schrijvers@uzleuven.be.
Abstract
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. The most frequent genetic defects are found in IL12 or a subunit of its receptor. IL23R deficiency in MSMD has only been reported once, in two pediatric patients from the same kindred with isolated disseminated Bacille Calmette-Guérin disease. We evaluated the impact of a homozygous stop mutation in IL23R (R381X), identified by whole exome sequencing, in an adult patient with disseminated non-tuberculous mycobacterial disease. METHODS: We performed functional validation of the R381X mutation by evaluating IL23R expression and IL-23 signaling (STAT3 phosphorylation, IFN-γ production) in primary cells (PBMCs, EBV-B cells) and cell lines (HeLa) with or without back-complementation of wild-type IL23R. RESULTS: We report on a 48-year-old male with disseminated non-tuberculous mycobacterial disease. We identified and characterized a homozygous loss-of-function stop mutation underlying IL23R deficiency, resulting in near absent expression of membrane bound IL23R. IL23R deficiency was characterized by impaired IL-23-mediated IFN-γ secretion in CD4+, CD8+ T, and mucosal-associated invariant T (MAIT) cells, and low frequencies of circulating Th17 (CD3+CD45RA-CCR4+CXCR3-RORγT+), Th1* (CD45RA-CCR4-CXCR3+RORγT+), and MAIT (CD3+CD8+Vα7.2+CD161+) cells. Although the patient did not have a history of recurrent fungal infections, impaired Th17 differentiation and blunted IL-23-mediated IL-17 secretion in PBMCs were observed. CONCLUSION: We demonstrate that impaired IL-23 immunity caused by a homozygous R381X mutation in IL23R underlies MSMD, corroborating earlier findings with a homozygous p.C115Y IL23R mutation. Our report further supports a model of redundant contribution of IL-23- to IL-17-mediated anti-fungal immunity.1.
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. The most frequent genetic defects are found in IL12 or a subunit of its receptor. IL23R deficiency in MSMD has only been reported once, in two pediatric patients from the same kindred with isolated disseminated Bacille Calmette-Guérin disease. We evaluated the impact of a homozygous stop mutation in IL23R (R381X), identified by whole exome sequencing, in an adult patient with disseminated non-tuberculous mycobacterial disease. METHODS: We performed functional validation of the R381X mutation by evaluating IL23R expression and IL-23 signaling (STAT3 phosphorylation, IFN-γ production) in primary cells (PBMCs, EBV-B cells) and cell lines (HeLa) with or without back-complementation of wild-type IL23R. RESULTS: We report on a 48-year-old male with disseminated non-tuberculous mycobacterial disease. We identified and characterized a homozygous loss-of-function stop mutation underlying IL23R deficiency, resulting in near absent expression of membrane bound IL23R. IL23R deficiency was characterized by impaired IL-23-mediated IFN-γ secretion in CD4+, CD8+ T, and mucosal-associated invariant T (MAIT) cells, and low frequencies of circulating Th17 (CD3+CD45RA-CCR4+CXCR3-RORγT+), Th1* (CD45RA-CCR4-CXCR3+RORγT+), and MAIT (CD3+CD8+Vα7.2+CD161+) cells. Although the patient did not have a history of recurrent fungal infections, impaired Th17 differentiation and blunted IL-23-mediated IL-17 secretion in PBMCs were observed. CONCLUSION: We demonstrate that impaired IL-23 immunity caused by a homozygous R381X mutation in IL23R underlies MSMD, corroborating earlier findings with a homozygous p.C115Y IL23R mutation. Our report further supports a model of redundant contribution of IL-23- to IL-17-mediated anti-fungal immunity.1.
Authors: Rui Yang; Federico Mele; Lisa Worley; David Langlais; Jérémie Rosain; Ibithal Benhsaien; Houda Elarabi; Carys A Croft; Jean-Marc Doisne; Peng Zhang; Marc Weisshaar; David Jarrossay; Daniela Latorre; Yichao Shen; Jing Han; Masato Ogishi; Conor Gruber; Janet Markle; Fatima Al Ali; Mahbuba Rahman; Taushif Khan; Yoann Seeleuthner; Gaspard Kerner; Lucas T Husquin; Julia L Maclsaac; Mohamed Jeljeli; Abderrahmane Errami; Fatima Ailal; Michael S Kobor; Carmen Oleaga-Quintas; Manon Roynard; Mathieu Bourgey; Jamila El Baghdadi; Stéphanie Boisson-Dupuis; Anne Puel; Fréderic Batteux; Flore Rozenberg; Nico Marr; Qiang Pan-Hammarström; Dusan Bogunovic; Lluis Quintana-Murci; Thomas Carroll; Cindy S Ma; Laurent Abel; Aziz Bousfiha; James P Di Santo; Laurie H Glimcher; Philippe Gros; Stuart G Tangye; Federica Sallusto; Jacinta Bustamante; Jean-Laurent Casanova Journal: Cell Date: 2020-12-08 Impact factor: 41.582