Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

Yue Li; Marita Führer; Ehsan Bahrami; Piotr Socha; Maja Klaudel-Dreszler; Amira Bouzidi; Yanshan Liu; Anna S. Lehle; Thomas Magg; Sebastian Hollizeck; Meino Rohlfs; Raffaele Conca; Michael Field; Neil Warner; Slae Mordechai; Eyal Shteyer; Dan Turner; Rachida Boukari; Reda Belbouab; Christoph Walz; Moritz M. Gaidt; Veit Hornung; Bernd Baumann; Ulrich Pannicke; Eman Al Idrissi; Hamza Ali Alghamdi; Fernando E. Sepulveda; Marine Gil; Geneviève De Saint Basile; Manfred Hönig; Sibylle Koletzko; Aleixo M. Muise; Scott B. Snapper; Klaus Schwarz; Christoph Klein; Daniel Kotlarz

doi:10.1073/pnas.1813582116

Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

Yue Li, Marita Führer, Ehsan Bahrami, Piotr Socha, Maja Klaudel-Dreszler, Amira Bouzidi, Yanshan Liu, Anna S. Lehle, Thomas Magg, Sebastian Hollizeck, Meino Rohlfs, Raffaele Conca, Michael Field, Neil Warner, Slae Mordechai, Eyal Shteyer, Dan Turner, Rachida Boukari, Reda Belbouab, Christoph WalzMoritz M. Gaidt, Veit Hornung, Bernd Baumann, Ulrich Pannicke, Eman Al Idrissi, Hamza Ali Alghamdi, Fernando E. Sepulveda, Marine Gil, Geneviève De Saint Basile, Manfred Hönig, Sibylle Koletzko, Aleixo M. Muise, Scott B. Snapper, Klaus Schwarz, Christoph Klein, Daniel Kotlarz^*

^*Corresponding author for this work

Faculty of Medicine

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

104 Scopus citations

Abstract

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/ or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

Original language	American English
Pages (from-to)	970-975
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	3
DOIs	https://doi.org/10.1073/pnas.1813582116
State	Published - 15 Jan 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We are grateful to the interdisciplinary medical staff. We acknowledge the assistance of the Flow Cytometry and Care-for-Rare Genomics Core Facility at the Dr. von Hauner Children’s Hospital, as well as the FACS facility of the Department of Pediatrics and Department of Molecular Diagnostics of the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm and the Genomics and Bioinformatics Core Facility at the Imagine Institute and UFR Necker. We thank Dr. T. Graf (Center for Genomic Regulation, Barcelona) for providing BLaER1 cells, and Genentech for supplying BV6. Further, we acknowledge bioinformatics support by Dr. Jacek Puchalka. The work has been supported by The Leona M. and Harry B. Helmsley Charitable Trust, DFG (Gottfried-Wilhelm-Leibniz Program, Collaborative Research Consortium SFB1054 project A05), PID-NET (BMBF), BioSysNet, the Care-for-Rare Foundation, and INSERM. Y. Li has been supported by the China Scholarship Council, E.B. received a scholarship from the Care-for-Rare Foundation, and M. Führer received a scholarship from the “Landesgraduiertenförderungsgesetz.” D.K. has been a scholar funded by the Daimler und Benz Stiftung, Reinhard-Frank Stiftung, and Else-Kröner-Fresenius Stiftung.

Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.

Keywords

Inflammatory bowel diseases |
Primary immunodeficiency |
Rare diseases

UN SDGs

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

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10.1073/pnas.1813582116

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Li, Y., Führer, M., Bahrami, E., Socha, P., Klaudel-Dreszler, M., Bouzidi, A., Liu, Y., Lehle, A. S., Magg, T., Hollizeck, S., Rohlfs, M., Conca, R., Field, M., Warner, N., Mordechai, S., Shteyer, E., Turner, D., Boukari, R., Belbouab, R., ... Kotlarz, D. (2019). Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proceedings of the National Academy of Sciences of the United States of America, 116(3), 970-975. https://doi.org/10.1073/pnas.1813582116

@article{c527c1be5b1d43d6aebca622b2158221,

title = "Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases",

abstract = "Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/ or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.",

keywords = "Inflammatory bowel diseases |, Primary immunodeficiency |, Rare diseases",

author = "Yue Li and Marita F{\"u}hrer and Ehsan Bahrami and Piotr Socha and Maja Klaudel-Dreszler and Amira Bouzidi and Yanshan Liu and Lehle, {Anna S.} and Thomas Magg and Sebastian Hollizeck and Meino Rohlfs and Raffaele Conca and Michael Field and Neil Warner and Slae Mordechai and Eyal Shteyer and Dan Turner and Rachida Boukari and Reda Belbouab and Christoph Walz and Gaidt, {Moritz M.} and Veit Hornung and Bernd Baumann and Ulrich Pannicke and Idrissi, {Eman Al} and Alghamdi, {Hamza Ali} and Sepulveda, {Fernando E.} and Marine Gil and {De Saint Basile}, Genevi{\`e}ve and Manfred H{\"o}nig and Sibylle Koletzko and Muise, {Aleixo M.} and Snapper, {Scott B.} and Klaus Schwarz and Christoph Klein and Daniel Kotlarz",

note = "Funding Information: ACKNOWLEDGMENTS. We are grateful to the interdisciplinary medical staff. We acknowledge the assistance of the Flow Cytometry and Care-for-Rare Genomics Core Facility at the Dr. von Hauner Children{\textquoteright}s Hospital, as well as the FACS facility of the Department of Pediatrics and Department of Molecular Diagnostics of the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm and the Genomics and Bioinformatics Core Facility at the Imagine Institute and UFR Necker. We thank Dr. T. Graf (Center for Genomic Regulation, Barcelona) for providing BLaER1 cells, and Genentech for supplying BV6. Further, we acknowledge bioinformatics support by Dr. Jacek Puchalka. The work has been supported by The Leona M. and Harry B. Helmsley Charitable Trust, DFG (Gottfried-Wilhelm-Leibniz Program, Collaborative Research Consortium SFB1054 project A05), PID-NET (BMBF), BioSysNet, the Care-for-Rare Foundation, and INSERM. Y. Li has been supported by the China Scholarship Council, E.B. received a scholarship from the Care-for-Rare Foundation, and M. F{\"u}hrer received a scholarship from the “Landesgraduiertenf{\"o}rderungsgesetz.” D.K. has been a scholar funded by the Daimler und Benz Stiftung, Reinhard-Frank Stiftung, and Else-Kr{\"o}ner-Fresenius Stiftung. Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All Rights Reserved.",

year = "2019",

month = jan,

day = "15",

doi = "10.1073/pnas.1813582116",

language = "American English",

volume = "116",

pages = "970--975",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "3",

}

Li, Y, Führer, M, Bahrami, E, Socha, P, Klaudel-Dreszler, M, Bouzidi, A, Liu, Y, Lehle, AS, Magg, T, Hollizeck, S, Rohlfs, M, Conca, R, Field, M, Warner, N, Mordechai, S, Shteyer, E, Turner, D, Boukari, R, Belbouab, R, Walz, C, Gaidt, MM, Hornung, V, Baumann, B, Pannicke, U, Idrissi, EA, Alghamdi, HA, Sepulveda, FE, Gil, M, De Saint Basile, G, Hönig, M, Koletzko, S, Muise, AM, Snapper, SB, Schwarz, K, Klein, C & Kotlarz, D 2019, 'Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 3, pp. 970-975. https://doi.org/10.1073/pnas.1813582116

TY - JOUR

T1 - Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

AU - Li, Yue

AU - Führer, Marita

AU - Bahrami, Ehsan

AU - Socha, Piotr

AU - Klaudel-Dreszler, Maja

AU - Bouzidi, Amira

AU - Liu, Yanshan

AU - Lehle, Anna S.

AU - Magg, Thomas

AU - Hollizeck, Sebastian

AU - Rohlfs, Meino

AU - Conca, Raffaele

AU - Field, Michael

AU - Warner, Neil

AU - Mordechai, Slae

AU - Shteyer, Eyal

AU - Turner, Dan

AU - Boukari, Rachida

AU - Belbouab, Reda

AU - Walz, Christoph

AU - Gaidt, Moritz M.

AU - Hornung, Veit

AU - Baumann, Bernd

AU - Pannicke, Ulrich

AU - Idrissi, Eman Al

AU - Alghamdi, Hamza Ali

AU - Sepulveda, Fernando E.

AU - Gil, Marine

AU - De Saint Basile, Geneviève

AU - Hönig, Manfred

AU - Koletzko, Sibylle

AU - Muise, Aleixo M.

AU - Snapper, Scott B.

AU - Schwarz, Klaus

AU - Klein, Christoph

AU - Kotlarz, Daniel

N1 - Funding Information: ACKNOWLEDGMENTS. We are grateful to the interdisciplinary medical staff. We acknowledge the assistance of the Flow Cytometry and Care-for-Rare Genomics Core Facility at the Dr. von Hauner Children’s Hospital, as well as the FACS facility of the Department of Pediatrics and Department of Molecular Diagnostics of the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm and the Genomics and Bioinformatics Core Facility at the Imagine Institute and UFR Necker. We thank Dr. T. Graf (Center for Genomic Regulation, Barcelona) for providing BLaER1 cells, and Genentech for supplying BV6. Further, we acknowledge bioinformatics support by Dr. Jacek Puchalka. The work has been supported by The Leona M. and Harry B. Helmsley Charitable Trust, DFG (Gottfried-Wilhelm-Leibniz Program, Collaborative Research Consortium SFB1054 project A05), PID-NET (BMBF), BioSysNet, the Care-for-Rare Foundation, and INSERM. Y. Li has been supported by the China Scholarship Council, E.B. received a scholarship from the Care-for-Rare Foundation, and M. Führer received a scholarship from the “Landesgraduiertenförderungsgesetz.” D.K. has been a scholar funded by the Daimler und Benz Stiftung, Reinhard-Frank Stiftung, and Else-Kröner-Fresenius Stiftung. Publisher Copyright: © 2019 National Academy of Sciences. All Rights Reserved.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/ or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

AB - Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/ or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.

KW - Inflammatory bowel diseases |

KW - Primary immunodeficiency |

KW - Rare diseases

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U2 - 10.1073/pnas.1813582116

DO - 10.1073/pnas.1813582116

M3 - Article

C2 - 30591564

AN - SCOPUS:85060065060

SN - 0027-8424

VL - 116

SP - 970

EP - 975

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 3

ER -

Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

Abstract

Bibliographical note

Keywords

UN SDGs

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