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A Novel Homozygous Stop Mutation in IL23R Causes Mendelian Susceptibility to Mycobacterial Disease.
Staels, Frederik; Lorenzetti, Flaminia; De Keukeleere, Kerstin; Willemsen, Mathijs; Gerbaux, Margaux; Neumann, Julika; Tousseyn, Thomas; Pasciuto, Emanuela; De Munter, Paul; Bossuyt, Xavier; Gijsbers, Rik; Liston, Adrian; Humblet-Baron, Stephanie; Schrijvers, Rik.
Afiliación
  • Staels F; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.
  • Lorenzetti F; Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.
  • De Keukeleere K; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.
  • Willemsen M; Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.
  • Gerbaux M; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.
  • Neumann J; Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.
  • Tousseyn T; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.
  • Pasciuto E; VIB Center for Brain and Disease Research, Leuven, Belgium.
  • De Munter P; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.
  • Bossuyt X; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.
  • Gijsbers R; VIB Center for Brain and Disease Research, Leuven, Belgium.
  • Liston A; Department of Imaging and Pathology, Laboratory for Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.
  • Humblet-Baron S; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.
  • Schrijvers R; VIB Center for Brain and Disease Research, Leuven, Belgium.
J Clin Immunol ; 42(8): 1638-1652, 2022 11.
Article en En | MEDLINE | ID: mdl-35829840
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Infecciones por Mycobacterium / Infecciones por Mycobacterium no Tuberculosas Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Adult / Child / Humans / Male / Middle aged Idioma: En Revista: J Clin Immunol Año: 2022 Tipo del documento: Article País de afiliación: Bélgica

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Infecciones por Mycobacterium / Infecciones por Mycobacterium no Tuberculosas Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Adult / Child / Humans / Male / Middle aged Idioma: En Revista: J Clin Immunol Año: 2022 Tipo del documento: Article País de afiliación: Bélgica