美国洛克菲勒大学Jean-Laurent Casanova、哥伦比亚安蒂奥基亚大学José Luis Franco和法国人类传染病遗传学实验室Anna-Lena Neehus研究团队合作，揭示了其他功能正常的遗传性TNF缺失结核病患者的特征。2024年8月28日出版的《自然》杂志发表了这项成果。

研究人员观察了两名患有复发性肺结核的成年人，他们是TNF功能缺失变体的同卵双生患者。他们都没有其他临床表型，临床和生物炎症反应正常。他们的白细胞，包括单核细胞和单核细胞衍生的巨噬细胞（MDMs），即使在IFNγ的刺激下也不产生TNF。这些患者的血液白细胞亚群发育正常。

然而，在粒细胞-巨噬细胞集落刺激因子(GM-CSF)成熟的MDMs和肺泡巨噬细胞样(AML)细胞中，无论是TNF缺乏症患者，TNF-或tnfr1缺乏症诱导多能干细胞(iPS)衍生的GM-CSF成熟巨噬细胞，还是体外用TNF阻滞剂分化的健康对照MDMs和AML细胞，以及体外用TNF阻滞剂治疗的肺巨噬细胞，都观察到呼吸爆发损伤。

用TNF刺激TNF缺失的iPS衍生巨噬细胞可挽救呼吸爆发。这些发现与在遗传性所有吞噬细胞呼吸爆发功能完全缺乏患者中的发现形成鲜明对比，后者易患多种感染，包括卡介苗-桂林杆菌病和肺结核。巨噬细胞对结核分枝杆菌的呼吸爆发依赖性免疫需要人TNF，但令人惊讶的是，人TNF在包括炎症和对弱毒性分枝杆菌及其他许多感染性病原体的免疫等方面是多余的。

研究人员表示，严重的人IFNγ免疫系统缺陷导致个体易患卡介苗-桂林杆菌病和肺结核，而轻微缺陷只导致个体易患肺结核。

附：英文原文

Title: Tuberculosis in otherwise healthy adults with inherited TNF deficiency

Author: Arias, Andrs 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-Borrs, Lucia, Han, Ji Eun, Pillay, Bethany, Ponsin, Khoren, Chaldebas, Matthieu, Philippot, Quentin, Bohlen, Jonathan, Rosain, Jrmie, Le Voyer, Tom, Janotte, Till, Amarajeeva, Krishnajina, Soude, Camille, Brollo, Marion, Wiegmann, Katja, Marquant, Quentin, Seeleuthner, Yoann, Lee, Danyel, Lain, Candice, Kloos, Doreen, Bailey, Rasheed, Bastard, Paul, Keating, Narelle, Rapaport, Franck, Khan, Taushif, Moncada-Vlez, Marcela, Carmona, Mara Camila, Obando, Catalina, Alvarez, Jess, Catao, Juan Carlos, Martnez-Rosado, Larry Luber, Sanchez, Juan P., Tejada-Giraldo, Manuela, LHonneur, Anne-Sophie, Agudelo, Mara L., Perez-Zapata, Lizet J., Arboleda, Diana M., Alzate, Juan Fernando, Cabarcas, Felipe, Zuluaga, Alejandra, Pelham, Simon J., Ensser, Armin, Schmidt, Monika, Velsquez-Lopera, Margarita M.

Issue&Volume: 2024-08-28

Abstract: 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.

DOI: 10.1038/s41586-024-07866-3

Source: https://www.nature.com/articles/s41586-024-07866-3