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Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Cuchet-Lourenço, Delphine  ORCID logo  https://orcid.org/0000-0002-9501-6122
Wu, Changxin 
Papapietro, Olivier  ORCID logo  https://orcid.org/0000-0001-5072-5235

Abstract

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.

Description

Keywords

Alleles, Arthritis, Cytokines, Female, Fibroblasts, Humans, Inflammatory Bowel Diseases, Lymphopenia, Male, Mitogen-Activated Protein Kinases, Pedigree, Receptor-Interacting Protein Serine-Threonine Kinases, Severe Combined Immunodeficiency

Journal Title

Science

Conference Name

Journal ISSN

0036-8075
1095-9203

Volume Title

361

Publisher

American Association for the Advancement of Science (AAAS)
Sponsorship
Medical Research Council (MR/M012328/1)
Wellcome Trust (095198/Z/10/Z)
European Research Council (260477)