慢性粘膜皮肤溃疡:RELA基因异常

JOURNAL OF EXPERIMENTAL MEDICINE

2017-06-09Article

11.991

影响因子

原标题:人类RELA基因单倍剂量 (haploinsufficiency) 不足导致常染色体显性慢性粘膜皮肤溃疡(CMU)

① 抗TNF治剂有疗效的染色体显性CMU家庭中,发现可导致基因单倍剂量的RELA突变;② RELA编码NF-κB亚基RelA,TNF激活caspase-8介导的凋亡和NF-κB依赖的细胞存活;③ TNF处理患者成纤维细胞和RELA杂合子小鼠,NF-κB活化受损,细胞凋亡增加,小鼠有溃疡和TNF抑制剂可改善的较严重DSD诱导结肠炎;④ 移植正常小鼠骨髓到RELA杂合子,注射TNF长溃疡,反之不会,表明RELA杂合子鼠上皮和间质细胞RelA单倍体不足导致粘膜溃疡,与骨髓造血细胞无关。

RELA 基因单倍剂量 慢性粘膜皮肤溃疡

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Title:
Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration

DOI:
10.1084/jem.20160724

Abstract & Authors展开

Abstract:
The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor κB (NF-κB)-dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA, encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients' fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-κB activation, and defective expression of NF-κB-dependent antiapoptotic genes. Rela(+/-) mice have similarly impaired NF-κB activation, develop cutaneous ulceration from TNF exposure, and exhibit severe dextran sodium sulfate-induced colitis, ameliorated by TNF inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF inhibition in this disease.

All Authors:
Yousef R Badran,Fatma Dedeoglu,Juan Manuel Leyva Castillo,Wayne Bainter,Toshiro K Ohsumi,Athos Bousvaros,Jeffrey D Goldsmith,Raif S Geha,Janet Chou

First Authors:
Yousef R Badran,Fatma Dedeoglu

Correspondence:
Janet Chou

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