1. Tuberculosis in otherwise healthy adults with inherited TNF deficiency.
- Author
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Arias AA, Neehus AL, Ogishi M, Meynier V, Krebs A, Lazarov T, Lee AM, Arango-Franco CA, Yang R, Orrego J, Corcini Berndt M, Rojas J, Li H, Rinchai D, Erazo-Borrás L, Han JE, Pillay B, Ponsin K, Chaldebas M, Philippot Q, Bohlen J, Rosain J, Le Voyer T, Janotte T, Amarajeeva K, Soudée C, Brollo M, Wiegmann K, Marquant Q, Seeleuthner Y, Lee D, Lainé C, Kloos D, Bailey R, Bastard P, Keating N, Rapaport F, Khan T, Moncada-Vélez M, Carmona MC, Obando C, Alvarez J, Cataño JC, Martínez-Rosado LL, Sanchez JP, Tejada-Giraldo M, L'Honneur AS, Agudelo ML, Perez-Zapata LJ, Arboleda DM, Alzate JF, Cabarcas F, Zuluaga A, Pelham SJ, Ensser A, Schmidt M, Velásquez-Lopera MM, Jouanguy E, Puel A, Krönke M, Ghirardello S, Borghesi A, Pahari S, Boisson B, Pittaluga S, Ma CS, Emile JF, Notarangelo LD, Tangye SG, Marr N, Lachmann N, Salvator H, Schlesinger LS, Zhang P, Glickman MS, Nathan CF, Geissmann F, Abel L, Franco JL, Bustamante J, Casanova JL, and Boisson-Dupuis S
- Subjects
- Adult, Female, Humans, Male, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Homozygote, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells immunology, Induced Pluripotent Stem Cells cytology, Inflammation immunology, Interferon-gamma immunology, Loss of Function Mutation, Lung cytology, Lung drug effects, Macrophages, Alveolar cytology, Macrophages, Alveolar drug effects, Macrophages, Alveolar immunology, Macrophages, Alveolar microbiology, Macrophages, Alveolar pathology, Mycobacterium tuberculosis immunology, Phenotype, Reactive Oxygen Species metabolism, Receptors, Tumor Necrosis Factor, Type I deficiency, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I metabolism, Respiratory Burst, Tumor Necrosis Factor Inhibitors pharmacology, Adolescent, Young Adult, Macrophages cytology, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Macrophages pathology, Tuberculosis, Pulmonary immunology, Tuberculosis, Pulmonary microbiology, Tuberculosis, Pulmonary genetics, Tumor Necrosis Factors deficiency, Tumor Necrosis Factors genetics
- Abstract
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) 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., (© 2024. The Author(s).)- Published
- 2024
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