The Journal of experimental medicine · 2026

Humans homozygous for rare or common hypomorphic IL23R variants are prone to tuberculosis.

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Olguín Calderón Diana, Kilpatrick Laura E, Conil Clément, Philippot Quentin, Ogishi Masato, Vellutini Joseph, Han Ji Eun, Keating Narelle, Li Hailun, Rao Geetha, Bohlen Jonathan, Lay Charles S, Platt Simon, Kerner Gaspard, Feredj Elsa, Peel Jessica N, Momenilandi Mana, Seeleuthner Yoann, Lainé Candice, Soudée Camille, Leloup Claire, Debuisson Cecile, Lanternier Fanny, Bitoun Samuel, Pavy Stephan, Mariette Xavier, Rafik Aniss, Skhoun Hanaa, El Ouazzani Hanane, Abderahmani-Ghorfi Ismael, El-Baghdadi Jamila, Baena Andrés, Tejada-Giraldo Manuela, Barrera Luis Fernando, Arias Andrés Augusto, Fabio Giovanna, Carrabba Maria, Emiroglu Melike, Bezrodnik Liliana, El Zein Loubna, Hammoud Hassan, Gregersen Peter K, Terrier Benjamin, Leon Lopez Rafael, Touzet Marion, Pestre Vincent, Pasquet Marlène, Rogge Lars, Fayon Michael, Galode François, Jeziorski Eric, Duffy Darragh, Quintana-Murci Lluis, Patin Etienne, Cunningham-Rundles Charlotte, Meyts Isabelle, Zhang Shen-Ying, Zhang Qian, Jouanguy Emmanuelle, Boisson Bertrand, Rosain Jérémie, Béziat Vivien, Shahrooei Mohammad, Mahdaviani Seyed Alireza, Rezaei Nima, Parvaneh Nima, Chavoshzadeh Zahra, Yazdanpanah Niloufar, Aladjidi Nathalie, Noguera-Julian Antoni, Esteve-Solé Ana, Alsina Laia, Mansouri Davood, Keles Sevgi, Ortakoylu Mediha Gonenc, Aygun Deniz, Yucel Esra, Kiykim Ayca, Camcioglu Yildiz, Ma Cindy S, Tangye Stuart G, Zhang Peng, Abel Laurent, Craggs Peter D, Casanova Jean-Laurent, Cobat Aurélie, Puel Anne, Bustamante Jacinta, Hill Stephen J, Boisson-Dupuis Stéphanie

Аннотация

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.

Предметные рубрики MeSH

Humans Receptors, Interleukin Interferon-gamma Homozygote Interleukin-23 Tuberculosis Killer Cells, Natural Genetic Predisposition to Disease Gene Frequency T-Lymphocytes

Humans homozygous for rare or common hypomorphic IL23R variants are prone to tuberculosis.

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH