Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration
| Autor: | Raif S. Geha, Juan Manuel Leyva Castillo, Janet Chou, Fatma Dedeoglu, Jeff Goldsmith, Wayne Bainter, Yousef R. Badran, Athos Bousvaros, Toshiro K. Ohsumi |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proband Male Programmed cell death Stromal cell Immunology Haploinsufficiency Caspase 8 03 medical and health sciences 0302 clinical medicine Skin Ulcer Immunology and Allergy Medicine Animals Humans Exome Colitis Oral Ulcer Research Articles Cells Cultured Genes Dominant Mice Knockout Base Sequence business.industry Tumor Necrosis Factor-alpha Gene Expression Profiling Dextran Sulfate Brief Definitive Report NF-kappa B Transcription Factor RelA Sequence Analysis DNA Fibroblasts medicine.disease 3. Good health Pedigree 030104 developmental biology Apoptosis Chronic Disease Cancer research Tumor necrosis factor alpha Female business 030215 immunology |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Badran et al. demonstrate an essential contribution of biallelic RELA expression in protecting stromal and epithelial cells from TNF-mediated cell death in patients with chronic mucocutaneous ulceration. 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. |
| Databáze: | OpenAIRE |
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