Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.
Delphine Cuchet-LourençoDavide ElettoChangxin WuVincent PlagnolOlivier PapapietroJames CurtisLourdes Ceron-GutierrezChris M BaconScott HackettBadr M Rasheed AlsaleemMailis MaesMiguel GasparAli AlisaacEmma GossEman AlIdrissiDaniela SiegmundHarald WajantDinakantha KumararatneMofareh S AlZahraniPeter D ArkwrightMario AbinunRainer DoffingerSergey NejentsevPublished in: Science (New York, N.Y.) (2018)
RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.
Keyphrases
- early onset
- end stage renal disease
- cell death
- newly diagnosed
- ejection fraction
- chronic kidney disease
- oxidative stress
- signaling pathway
- induced apoptosis
- late onset
- rheumatoid arthritis
- multiple sclerosis
- prognostic factors
- endothelial cells
- transcription factor
- case report
- cell proliferation
- high throughput
- physical activity
- patient reported
- endoplasmic reticulum stress
- induced pluripotent stem cells
- replacement therapy
- electronic health record
- drug induced
- pluripotent stem cells