A Novel Homozygous Stop Mutation in IL23R Causes Mendelian Susceptibility to Mycobacterial Disease

• Published in: Journal of clinical immunology Vol. 42; no. 8; pp. 1638 - 1652
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2022; Springer Nature B.V
• Subjects: Adult; Biomedical and Life Sciences; Biomedicine; CD3 antigen; CD4 antigen; CD45RA antigen; CD8 antigen; Cell lines; Child; Complementation; CXCR3 protein; Genetic Predisposition to Disease; Helper cells; Humans; Immunology; Infectious Diseases; Interleukin 12; Interleukin 17; Interleukin 23; Interleukin-17 - genetics; Internal Medicine; Lymphocytes B; Lymphocytes T; Male; Medical Microbiology; Middle Aged; Mutation; Mutation - genetics; Mycobacterium Infections - etiology; Mycobacterium Infections, Nontuberculous - complications; Mycobacterium Infections, Nontuberculous - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Original; Original Article; Patients; Pediatrics; Phosphorylation; Receptors, Interleukin - genetics; Stat3 protein; Tuberculosis; γ-Interferon; mendelian susceptibility to mycobacterial disease; non-tuberculous mycobacteria; IFN-γ; inborn errors of immunity; th17; IL23R
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-022-01320-7

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