X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.
X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.
复制标题
X连锁对分枝杆菌的敏感性是由NEMO中的突变损害CD40依赖性IL-12产生引起的。
DOI：
10.1084/jem.20060085
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发表时间：
2006-07-10
影响因子：
15.3
通讯作者：
Casanova, Jean-Laurent
中科院分区：
文献类型：
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作者：
Filipe-Santos, Orchidee;Bustamante, Jacinta;Haverkamp, Margje H;Vinolo, Emilie;Ku, Cheng-Lung;Puel, Anne;Frucht, David M;Christel, Karin;von Bernuth, Horst;Jouanguy, Emmanuelle;Feinberg, Jacqueline;Durandy, Anne;Senechal, Brigitte;Chapgier, Ariane;Vogt, Guillaume;de Beaucoudrey, Ludovic;Fieschi, Claire;Picard, Capucine;Garfa, Meriem;Chemli, Jalel;Bejaoui, Mohamed;Tsolia, Maria N;Kutukculer, Necil;Plebani, Alessandro;Notarangelo, Luigi;Bodemer, Christine;Geissmann, Frederic;Israel, Alain;Veron, Michel;Knackstedt, Maike;Barbouche, Ridha;Abel, Laurent;Magdorf, Klaus;Gendrel, Dominique;Agou, Fabrice;Holland, Steven M;Casanova, Jean-Laurent
涉及白细胞介素 (IL)-12 依赖性、干扰素 (IFN)-γ 介导免疫的 5 个常染色体基因的种系突变导致孟德尔对分枝杆菌疾病 (MSMD) 的易感性。 X 连锁隐性遗传 (XR)–MSMD 的分子基础仍然未知。我们在这里报告了三个与 XR-MSMD 无关的亲属中 NF-κB 必需调节剂 (NEMO) 基因的亮氨酸拉链 (LZ) 结构域的突变。血液和成纤维细胞中产生正常量的突变蛋白。然而，患者的单核细胞在 T 细胞依赖性 IL-12 产生方面存在固有缺陷，导致 T 细胞分泌 IFN-γ 存在缺陷。在表达 CD40L 的 T 细胞和成纤维细胞分别刺激单核细胞和树突状细胞后，由于 NEMO 和 NF-κB/c-Rel 介导的 CD40 信号传导存在特定缺陷，IL-12 的产生也受到损害。然而，树突状细胞共刺激分子的CD40依赖性上调以及B细胞的增殖和免疫球蛋白类别转换均正常。此外，患者的血液和成纤维细胞对其他 NF-κB 激活剂（如肿瘤坏死因子-α、IL-1β 和脂多糖）也有反应。 NEMO LZ 结构域中的这两个突变提供了 XR-MSMD 的第一个遗传病因。他们还证明了 T 细胞和 CD40L 触发、CD40 和 NEMO/NF-κB/c-Rel 介导的单核细胞衍生细胞诱导 IL-12 对于人类分枝杆菌的保护性免疫的重要性。
Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon (IFN)-γ–mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)–MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-κB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell–dependent IL-12 production, resulting in defective IFN-γ secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-κB/c-Rel–mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-κB activators, such as tumor necrosis factor-α, IL-1β, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell– and CD40L-triggered, CD40-, and NEMO/NF-κB/c-Rel–mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.