Tuberculosis in otherwise healthy adults with inherited TNF deficiency
Authors: Arias Andrés A. , Neehus Anna-Lena , Ogishi Masato , Meynier Vincent , Krebs Adam , Lazarov Tomi , Lee Angela M. , Arango-Franco Carlos A. , Yang Rui , Orrego Julio , Corcini Berndt Melissa , Rojas Julian , Li Hailun , Rinchai Darawan , Erazo-Borrás Lucia , Han Ji Eun , Pillay Bethany , Ponsin Khoren , Chaldebas Matthieu , Philippot Quentin , Bohlen Jonathan , Rosain Jérémie , Le Voyer Tom , Janotte Till , Amarajeeva Krishnajina , Soudée Camille , Brollo Marion , Wiegmann Katja , Marquant Quentin , Seeleuthner Yoann , Lee Danyel , Lainé Candice , Kloos Doreen , Bailey Rasheed , Bastard Paul , Keating Narelle , Rapaport Franck , Khan Taushif , Moncada-Vélez Marcela , Carmona María Camila , Obando Catalina , Alvarez Jesús , Cataño Juan Carlos , Martínez-Rosado Larry Luber , Sanchez Juan P. , Tejada-Giraldo Manuela , L’Honneur Anne-Sophie , Agudelo María L. , Perez-Zapata Lizet J. , Arboleda Diana M. , Alzate Juan Fernando , Cabarcas Felipe , Zuluaga Alejandra , Pelham Simon J. , Ensser Armin , Schmidt Monika , Velásquez-Lopera Margarita M. , Jouanguy Emmanuelle , Puel Anne , Krönke Martin , Ghirardello Stefano , Borghesi Alessandro , Pahari Susanta , Boisson Bertrand , Pittaluga Stefania , Ma Cindy S. , Emile Jean-François , Notarangelo Luigi D. , Tangye Stuart G. , Marr Nico , Lachmann Nico , Salvator Hélène , Schlesinger Larry S. , Zhang Peng , Glickman Michael S. , Nathan Carl F. , Geissmann Frédéric , Abel Laurent , Franco José Luis , Bustamante Jacinta , Casanova Jean-Laurent , Boisson-Dupuis Stéphanie 
Published: August 2024

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette–Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte–macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette–Guérin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.