Jacobs M, Marino M W, Brown N, Abel B, Bekker L G, Quesniaux V J, Fick L, Ryffel B
Department of Immunology, University of Cape Town, South Africa.
Lab Invest. 2000 Jun;80(6):901-14. doi: 10.1038/labinvest.3780094.
Tumour necrosis factor-alpha (TNF) plays a central role in the recruitment and activation of mononuclear cells in mycobacterial infection. In the absence of type 1 TNF receptor, Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection of mice is not contained, leading to fatal disease. Because type 1 TNF receptor binds both TNF and lymphotoxin-a, we used TNF-deficient mice to determine the specific role of TNF in the host resistance to BCG infection. The bacterial burden of the lungs of TNF-deficient mice was substantially increased and the mice succumbed to pneumonia between 8 and 12 weeks with a defective granuloma response. Atypical granulomas developed by 4 weeks expressing low levels of MHC class II, intracellular adhesion molecule (ICAM-1), CD11b and CD11c. Macrophages showed little signs of activation and had low levels of acid phosphatase activity and inducible nitric oxide synthase (INOS) expression. Despite the defective cellular recruitment, the chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1alpha), were increased in broncho-alveolar lavage fluid of TNF-deficient mice. The defective host response was corrected by the transplantation of normal bone marrow cells into irradiated TNF-deficient mice. These results demonstrate that TNF derived from hemopoietic cells rather than from mesenchymal origin are essential for a normal host response to BCG infection. Furthermore, TNF dependent expression of adhesion molecules may be essential for the recruitment of mononuclear cells for the formation of bactericidal BCG granulomas.
肿瘤坏死因子-α（TNF）在分枝杆菌感染中单核细胞的募集和激活过程中起核心作用。在缺乏1型TNF受体的情况下，小鼠对卡介苗（BCG）感染无法控制，导致致命疾病。由于1型TNF受体可结合TNF和淋巴毒素-α，我们使用TNF缺陷小鼠来确定TNF在宿主抵抗BCG感染中的具体作用。TNF缺陷小鼠肺部的细菌负荷显著增加，小鼠在8至12周时死于肺炎，肉芽肿反应存在缺陷。4周时形成非典型肉芽肿，其主要组织相容性复合体II类分子（MHC class II）、细胞间黏附分子（ICAM-1）、CD11b和CD11c表达水平较低。巨噬细胞几乎没有激活迹象，酸性磷酸酶活性和诱导型一氧化氮合酶（INOS）表达水平较低。尽管细胞募集存在缺陷，但TNF缺陷小鼠支气管肺泡灌洗液中的趋化因子，即单核细胞趋化蛋白-1（MCP-1）和巨噬细胞炎性蛋白-1α（MIP-1α）却有所增加。将正常骨髓细胞移植到经辐射的TNF缺陷小鼠体内可纠正宿主反应缺陷。这些结果表明，造血细胞而非间充质来源产生的TNF对于宿主对BCG感染的正常反应至关重要。此外，TNF依赖的黏附分子表达对于募集单核细胞形成杀菌性BCG肉芽肿可能至关重要。
