Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency.
Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency.
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DOI：
10.1016/j.clim.2016.01.010
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Rohr JC
中科院分区：
文献类型：
--
作者：
Klemann C;Pannicke U;Morris-Rosendahl DJ;Vlantis K;Rizzi M;Uhlig H;Vraetz T;Speckmann C;Strahm B;Pasparakis M;Schwarz K;Ehl S;Rohr JC
NF-κB必需调节因子（NEMO）缺陷导致男性外胚层发育不良伴免疫缺陷，而杂合子女性表现为色素失禁。我们报告了一个NEMO缺乏症的家族，其中一名女性携带者表现出偏向的X-失活，有利于与白塞病症状相关的突变NEMO等位基因。受影响的男孩从这个供体造血干细胞移植重建的免疫系统保留偏X失活。移植后没有发生更严重的感染，表明只有10%的免疫细胞中的活性野生型NEMO等位基因恢复宿主防御。然而，他患上了炎症性肠病（IBD）。虽然肠浸润免疫细胞对核p65染色强烈，表明NEMO功能恢复，但肠上皮细胞的情况并非如此-与来自常规IBD患者的细胞相反。这些结果扩展了上皮NEMO缺陷足以引起IBD的小鼠观察。高剂量的抗TNF可控制肠道炎症和白塞病的症状。
NF-κB essential modulator (NEMO) deficiency causes ectodermal dysplasia with immunodeficiency in males, while manifesting as incontinentia pigmenti in heterozygous females. We report a family with NEMO deficiency, in which a female carrier displayed skewed X-inactivation favoring the mutant NEMO allele associated with symptoms of Behçet’s disease. Haematopoietic stem cell transplantation of an affected boy from this donor reconstituted an immune system with retained skewed X-inactivation. After transplantation no more severe infections occurred, indicating that an active wild-type NEMO allele in only 10% of immune cells restores host defense. Yet he developed inflammatory bowel disease (IBD). While gut infiltrating immune cells stained strongly for nuclear p65 indicating restored NEMO function, this was not the case in intestinal epithelial cells – in contrast to cells from conventional IBD patients. These results extend murine observations that epithelial NEMO-deficiency suffices to cause IBD. High anti-TNF doses controlled the intestinal inflammation and symptoms of Behçet’s disease.
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