CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Ido Somekh; Marini Thian; David Medgyesi; Nesrin Gülez; Thomas Magg; Alejandro Gallón Duque; Tali Stauber; Atar Lev; Ferah Genel; Ekrem Unal; Amos J. Simon; Yu Nee Lee; Artem Kalinichenko; Jasmin Dmytrus; Michael J. Kraakman; Ginette Schiby; Meino Rohlfs; Jeffrey M. Jacobson; Erdener Özer; Ömer Akcal; Raffaele Conca; Türkan Patiroglu; Musa Karakukcu; Alper Ozcan; Tala Shahin; Eliana Appella; Megumi Tatematsu; Catalina Martinez-Jaramillo; Ivan K. Chinn; Jordan S. Orange; Claudia Milena Trujillo-Vargas; José Luis Franco; Fabian Hauck; Raz Somech; Christoph Klein; Kaan Boztug

doi:10.1182/blood.2019000644

CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Ido Somekh, Marini Thian, David Medgyesi, Nesrin Gülez, Thomas Magg, Alejandro Gallón Duque, Tali Stauber, Atar Lev, Ferah Genel, Ekrem Unal, Amos J. Simon, Yu Nee Lee, Artem Kalinichenko, Jasmin Dmytrus, Michael J. Kraakman, Ginette Schiby, Meino Rohlfs, Jeffrey M. Jacobson, Erdener Özer, Ömer AkcalRaffaele Conca, Türkan Patiroglu, Musa Karakukcu, Alper Ozcan, Tala Shahin, Eliana Appella, Megumi Tatematsu, Catalina Martinez-Jaramillo, Ivan K. Chinn, Jordan S. Orange, Claudia Milena Trujillo-Vargas, José Luis Franco, Fabian Hauck, Raz Somech^*, Christoph Klein, Kaan Boztug

^*Corresponding author for this work

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

56 Scopus citations

Abstract

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)- associated lymphoma.Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.

Original language	English
Pages (from-to)	1510-1516
Number of pages	7
Journal	Blood
Volume	134
Issue number	18
DOIs	https://doi.org/10.1182/blood.2019000644
State	Published - 31 Oct 2019

Funding

Funders	Funder number
CCHD
Else Kröner-Fresenius-Stiftung
Jeffrey Modell Foundation
Stiftung
ERC Advanced grant
Care for Rare Foundation
Baylor-Hopkins
National Institutes of Health
C.K.
Forschungskolleg Rare Diseases of the Immune System
ERC advanced
National Heart, Lung, and Blood Institute
Österreichischen Akademie der Wissenschaften
German-Israeli Foundation for Scientific Research and Development
European Research Council
Medizinische Universität Wien
Deutscher Akademischer Austauschdienst/German Academic Exchange Service	Therapies
Deutsche Forschungsgemeinschaft	CRC1054
National Human Genome Research Institute	UM1HG006542
California Department of Conservation	25225
Horizon 2020 Framework Programme	820074

UN SDGs

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

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10.1182/blood.2019000644

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Somekh, I., Thian, M., Medgyesi, D., Gülez, N., Magg, T., Duque, A. G., Stauber, T., Lev, A., Genel, F., Unal, E., Simon, A. J., Lee, Y. N., Kalinichenko, A., Dmytrus, J., Kraakman, M. J., Schiby, G., Rohlfs, M., Jacobson, J. M., Özer, E., ... Boztug, K. (2019). CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis. Blood, 134(18), 1510-1516. https://doi.org/10.1182/blood.2019000644

@article{e3b6b5ef5e03449dbbfb673449ec5dd6,

title = "CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis",

abstract = "Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)- associated lymphoma.Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.",

author = "Ido Somekh and Marini Thian and David Medgyesi and Nesrin G{\"u}lez and Thomas Magg and Duque, {Alejandro Gall{\'o}n} and Tali Stauber and Atar Lev and Ferah Genel and Ekrem Unal and Simon, {Amos J.} and Lee, {Yu Nee} and Artem Kalinichenko and Jasmin Dmytrus and Kraakman, {Michael J.} and Ginette Schiby and Meino Rohlfs and Jacobson, {Jeffrey M.} and Erdener {\"O}zer and {\"O}mer Akcal and Raffaele Conca and T{\"u}rkan Patiroglu and Musa Karakukcu and Alper Ozcan and Tala Shahin and Eliana Appella and Megumi Tatematsu and Catalina Martinez-Jaramillo and Chinn, {Ivan K.} and Orange, {Jordan S.} and Trujillo-Vargas, {Claudia Milena} and Franco, {Jos{\'e} Luis} and Fabian Hauck and Raz Somech and Christoph Klein and Kaan Boztug",

note = "Publisher Copyright: {\textcopyright} 2019 by The American Society of Hematology.",

year = "2019",

month = oct,

day = "31",

doi = "10.1182/blood.2019000644",

language = "אנגלית",

volume = "134",

pages = "1510--1516",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "18",

}

Somekh, I, Thian, M, Medgyesi, D, Gülez, N, Magg, T, Duque, AG, Stauber, T, Lev, A, Genel, F, Unal, E, Simon, AJ, Lee, YN, Kalinichenko, A, Dmytrus, J, Kraakman, MJ, Schiby, G, Rohlfs, M, Jacobson, JM, Özer, E, Akcal, Ö, Conca, R, Patiroglu, T, Karakukcu, M, Ozcan, A, Shahin, T, Appella, E, Tatematsu, M, Martinez-Jaramillo, C, Chinn, IK, Orange, JS, Trujillo-Vargas, CM, Franco, JL, Hauck, F, Somech, R, Klein, C & Boztug, K 2019, 'CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis', Blood, vol. 134, no. 18, pp. 1510-1516. https://doi.org/10.1182/blood.2019000644

TY - JOUR

T1 - CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

AU - Somekh, Ido

AU - Thian, Marini

AU - Medgyesi, David

AU - Gülez, Nesrin

AU - Magg, Thomas

AU - Duque, Alejandro Gallón

AU - Stauber, Tali

AU - Lev, Atar

AU - Genel, Ferah

AU - Unal, Ekrem

AU - Simon, Amos J.

AU - Lee, Yu Nee

AU - Kalinichenko, Artem

AU - Dmytrus, Jasmin

AU - Kraakman, Michael J.

AU - Schiby, Ginette

AU - Rohlfs, Meino

AU - Jacobson, Jeffrey M.

AU - Özer, Erdener

AU - Akcal, Ömer

AU - Conca, Raffaele

AU - Patiroglu, Türkan

AU - Karakukcu, Musa

AU - Ozcan, Alper

AU - Shahin, Tala

AU - Appella, Eliana

AU - Tatematsu, Megumi

AU - Martinez-Jaramillo, Catalina

AU - Chinn, Ivan K.

AU - Orange, Jordan S.

AU - Trujillo-Vargas, Claudia Milena

AU - Franco, José Luis

AU - Hauck, Fabian

AU - Somech, Raz

AU - Klein, Christoph

AU - Boztug, Kaan

PY - 2019/10/31

Y1 - 2019/10/31

N2 - Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)- associated lymphoma.Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.

AB - Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)- associated lymphoma.Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.

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U2 - 10.1182/blood.2019000644

DO - 10.1182/blood.2019000644

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C2 - 31501153

AN - SCOPUS:85074507331

SN - 0006-4971

VL - 134

SP - 1510

EP - 1516

JO - Blood

JF - Blood

IS - 18

ER -

CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Abstract

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