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J Exp Med. 2017 Jul 3;214(7):1937-1947. doi: 10.1084/jem.20160724. Epub 2017 Jun 9.

Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration.

Author information

1
Division of Immunology, Boston Children's Hospital, Boston, MA.
2
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA.
3
Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA.
4
Department of Pathology, Boston Children's Hospital, Boston, MA.
5
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA.
6
Division of Immunology, Boston Children's Hospital, Boston, MA janet.chou@childrens.harvard.edu.

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.

PMID:
28600438
PMCID:
PMC5502421
DOI:
10.1084/jem.20160724
[Indexed for MEDLINE]
Free PMC Article

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