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

Delphine Cuchet-Lourenço; Davide Eletto; Changxin Wu; Vincent Plagnol; Olivier Papapietro; James Curtis; Lourdes Ceron-Gutierrez; Chris M Bacon; Scott Hackett; Badr Alsaleem; Mailis Maes; Miguel Gaspar; Ali Alisaac; Emma Goss; Eman AlIdrissi; Daniela Siegmund; Harald Wajant; Dinakantha Kumararatne; Mofareh S AlZahrani; Peter D Arkwright; Mario Abinun; Rainer Doffinger; Sergey Nejentsev

doi:10.1126/science.aar2641

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

Delphine Cuchet-Lourenço
, Davide Eletto
, Changxin Wu
, Vincent Plagnol
, Olivier Papapietro
, James Curtis
, Lourdes Ceron-Gutierrez
, Chris M Bacon
, Scott Hackett
, Badr Alsaleem
, Mailis Maes
, Miguel Gaspar
, Ali Alisaac
, Emma Goss
, Eman AlIdrissi
, Daniela Siegmund
, Harald Wajant
, Dinakantha Kumararatne
, Mofareh S AlZahrani
, Peter D Arkwright

Mario Abinun, Rainer Doffinger, Sergey Nejentsev

British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
Genetics Institute, University College London, WC1E 6BT, London, United Kingdom.
Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK.
Department of Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Paediatric Immunology Department, Birmingham Heartland Hospital, Birmingham, UK.
Children's Hospital, King Fahad Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.
Faculty of Applied Medical Sciences, Albaha University, Albaha, Kingdom of Saudi Arabia.
Children's Hospital, University of King Saud for Health Sciences, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia.
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	810-813
Number of pages	4
Journal	Science
Volume	361
Issue number	6404
DOIs	https://doi.org/10.1126/science.aar2641
Publication status	Published - 24 Aug 2018
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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10.1126/science.aar2641

Biallelic-ripk1-mutations-in-humans-cause-severe-immunodeficiency-arthritis-and-intestinal-inflammation.pdfFinal published version, 594 KBLicence: CC BY

Cite this

Cuchet-Lourenço, D., Eletto, D., Wu, C., Plagnol, V., Papapietro, O., Curtis, J., Ceron-Gutierrez, L., Bacon, C. M., Hackett, S., Alsaleem, B., Maes, M., Gaspar, M., Alisaac, A., Goss, E., AlIdrissi, E., Siegmund, D., Wajant, H., Kumararatne, D., AlZahrani, M. S., ... Nejentsev, S. (2018). Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science, 361(6404), 810-813. https://doi.org/10.1126/science.aar2641

@article{b27753d012934cc0b78f1734ac7620bd,

title = "Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation",

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.",

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

author = "Delphine Cuchet-Louren{\c c}o and Davide Eletto and Changxin Wu and Vincent Plagnol and Olivier Papapietro and James Curtis and Lourdes Ceron-Gutierrez and Bacon, \{Chris M\} and Scott Hackett and Badr Alsaleem and Mailis Maes and Miguel Gaspar and Ali Alisaac and Emma Goss and Eman AlIdrissi and Daniela Siegmund and Harald Wajant and Dinakantha Kumararatne and AlZahrani, \{Mofareh S\} and Arkwright, \{Peter D\} and Mario Abinun and Rainer Doffinger and Sergey Nejentsev",

year = "2018",

month = aug,

day = "24",

doi = "10.1126/science.aar2641",

language = "English",

volume = "361",

pages = "810--813",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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}

Cuchet-Lourenço, D, Eletto, D, Wu, C, Plagnol, V, Papapietro, O, Curtis, J, Ceron-Gutierrez, L, Bacon, CM, Hackett, S, Alsaleem, B, Maes, M, Gaspar, M, Alisaac, A, Goss, E, AlIdrissi, E, Siegmund, D, Wajant, H, Kumararatne, D, AlZahrani, MS, Arkwright, PD, Abinun, M, Doffinger, R & Nejentsev, S 2018, 'Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation', Science, vol. 361, no. 6404, pp. 810-813. https://doi.org/10.1126/science.aar2641

TY - JOUR

T1 - Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation

AU - Cuchet-Lourenço, Delphine

AU - Eletto, Davide

AU - Wu, Changxin

AU - Plagnol, Vincent

AU - Papapietro, Olivier

AU - Curtis, James

AU - Ceron-Gutierrez, Lourdes

AU - Bacon, Chris M

AU - Hackett, Scott

AU - Alsaleem, Badr

AU - Maes, Mailis

AU - Gaspar, Miguel

AU - Alisaac, Ali

AU - Goss, Emma

AU - AlIdrissi, Eman

AU - Siegmund, Daniela

AU - Wajant, Harald

AU - Kumararatne, Dinakantha

AU - AlZahrani, Mofareh S

AU - Arkwright, Peter D

AU - Abinun, Mario

AU - Doffinger, Rainer

AU - Nejentsev, Sergey

PY - 2018/8/24

Y1 - 2018/8/24

N2 - 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.

AB - 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.

KW - Alleles

KW - Arthritis/genetics

KW - Cytokines/metabolism

KW - Female

KW - Fibroblasts/metabolism

KW - Humans

KW - Inflammatory Bowel Diseases/genetics

KW - Lymphopenia/genetics

KW - Male

KW - Mitogen-Activated Protein Kinases/metabolism

KW - Pedigree

KW - Receptor-Interacting Protein Serine-Threonine Kinases/genetics

KW - Severe Combined Immunodeficiency/genetics

U2 - 10.1126/science.aar2641

DO - 10.1126/science.aar2641

M3 - Article

SN - 0036-8075

VL - 361

SP - 810

EP - 813

JO - Science

JF - Science

IS - 6404

ER -

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

Abstract

UN SDGs

Keywords

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