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Humans homozygous for rare or common hypomorphic IL23R variants are prone to tuberculosis
Journal of Experimental Medicine · Ağustos 2026
Özet
Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-γ production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12Rβ1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-γ production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria.
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Journal of Experimental Medicine
Toplam Atıf
1 atıf
· Scopus
Yayın TarihiAğustos 2026
Cilt / Sayfa223
Scopus ID2-s2.0-105045150495
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Avignon Hospital
Avignon France
Center for Clinical Immunology
Buenos Aires Argentina
Centre Constitutif des Maladies respiratoires rares de l’enfant (RESPIRARE)
Bordeaux France
Centre de Compétence des Déficits immunitaires Héréditaires (CEREDIH)
Bordeaux France
Centre de Recherche Cardio-Thoracique de Bordeaux
Pessac France
Centre Hospitalier Universitaire de Bordeaux
Talence France
Centre of Membrane Proteins and Receptors
Birmingham United Kingdom
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Madrid Spain
CHU de Toulouse
Toulouse France
Departement Microbiologie, Immunologie en Transplantatie
Leuven Belgium
Dr. Shahrooei Lab
Tehran Iran
Facultad de Medicina
Medellin Colombia
Faculté de Médecine et de Pharmacie de Rabat
Rabat Morocco
Feinstein Institutes for Medical Research
Manhasset United States
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
Milan Italy
Garvan Institute of Medical Research
Sydney Australia
German Center for Child and Adolescent Health (DZKJ)
Munich Germany
GlaxoSmithKline plc.
Brentford United Kingdom
Groupe Hospitalier Pellegrin
Bordeaux France
Hopital Cochin AP-HP
Paris France
Hopital de Bicetre
Le Kremlin-Bicetre France
Hopital des Enfants
Toulouse France
Hôpital Necker Enfants Malades
Paris France
Hospital de Ninos Ricardo Gutierrez
Buenos Aires Argentina
Hospital Sant Joan de Déu Barcelona
Esplugues de Llobregat Spain
Hospital Universitario Reina Sofia
Cordoba Spain
Howard Hughes Medical Institute
Chevy Chase United States
Icahn School of Medicine at Mount Sinai
New York United States
Institut de Recerca Sant Joan de Déu (IRSJD)
Barcelona Spain
Instituto de Investigaciones Médicas
Medellin Colombia
İstanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine
Istanbul Turkey
Klinikum der Universität München
Munich Germany
KU Leuven– University Hospital Leuven
Leuven Belgium
Ludwig-Maximilians-Universität München
Munich Germany
Military Hospital Mohammed V
Agdal Rabat Morocco
Mofid Children's Hospital, Tehran
Tehran Iran
National Research Institute of Tuberculosis and Lung Disease Tehran
Tehran Iran
Necmettin Erbakan Üniversitesi
Meram Turkey
Research Center for Immunodeficiencies
Tehran Iran
Rockefeller University
New York United States
Saint George Hospital University Medical Center
Beirut Lebanon
SBUMS Clinical Tuberculosis and Epidemiology Research Center
Tehran Iran
School of Medicine
Medellin Colombia
School of Microbiology
Medellin Colombia
Selçuk Tip Fakültesi
Konya Turkey
Tehran University of Medical Sciences
Tehran Iran
Universal Scientific Education and Research Network (USERN)
Tehran Iran
Universidad de Antioquia
Medellin Colombia
Universitat de Barcelona
Barcelona Spain
Université de Montpellier
Montpellier France
Université Libanaise
Beirut Lebanon
Université Sorbonne Paris Cité
Paris France
University of Health Sciences
Istanbul Turkey
University of Nottingham
Nottingham United Kingdom
UNSW Sydney
Sydney Australia
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