Tuberculosis in otherwise healthy adults with inherited TNF deficiency

• Published in: Nature (London) Vol. 633; no. 8029; pp. 417 - 425
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2024; Nature Publishing Group
• Subjects: 13/109; 13/21; 13/31; 38/23; 38/70; 38/91; 631/250/127/1220; 631/250/2504/342; 631/250/255/1856; 96/34; Adult; Adults; Alveoli; Bacillus; Bacillus Calmette-Guerin vaccine; BCG; Cell differentiation; Colony-stimulating factor; Defects; Female; Genomes; Genotype & phenotype; Granulocyte-macrophage colony stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - deficiency; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Homozygote; Humanities and Social Sciences; Humans; Immunity; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - immunology; Induced Pluripotent Stem Cells - metabolism; Infections; Interferon-gamma - immunology; Leukocytes; Lung diseases; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Macrophages, Alveolar - immunology; Macrophages, Alveolar - microbiology; Male; Monocytes; multidisciplinary; Mycobacterium tuberculosis - immunology; Pathogens; Patients; Phagocytes; Phenotypes; Pluripotency; Receptors, Tumor Necrosis Factor, Type I - deficiency; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Remission (Medicine); Respiratory Burst; Science; Science (multidisciplinary); Stimulation; TNF inhibitors; Tuberculosis; Tuberculosis, Pulmonary - genetics; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - microbiology; Tumor Necrosis Factor Inhibitors - pharmacology; Tumor Necrosis Factor Inhibitors - therapeutic use; Tumor necrosis factor receptors; Tumor Necrosis Factor-alpha - metabolism; Virulence; γ-Interferon
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07866-3

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette–Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis 1 . 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) cells 2 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 tuberculosis 3 . 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. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.