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Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function <jats:italic>TNF<\/jats:italic> 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 IFN\u03b3. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte\u2013macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells<jats:sup>2<\/jats:sup> 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\u2013Gu\u00e9rin disease and tuberculosis<jats:sup>3<\/jats:sup>. Human TNF is required for respiratory-burst-dependent immunity to <jats:italic>Mycobacterium tuberculosis<\/jats:italic> in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents.<\/jats:p>","DOI":"10.1038\/s41586-024-07866-3","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T16:02:48Z","timestamp":1724860968000},"page":"417-425","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Tuberculosis in otherwise healthy adults with inherited TNF deficiency"],"prefix":"10.1038","volume":"633","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9478-8403","authenticated-orcid":false,"given":"Andr\u00e9s 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