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 |
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Pages (from-to) | 1510-1516 |
Number of pages | 7 |
Journal | Blood |
Volume | 134 |
Issue number | 18 |
DOIs | |
State | Published - 31 Oct 2019 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2019 by The American Society of Hematology.
Funding
This work was supported by the European Research Council (ERC; Consolidator grant 820074 “iDysChart” [K.B.] and an ERC Advanced grant [C.K.]), the Jeffrey Modell Foundation (JMF; R.S.), the Care for Rare Foundation, the German Research Foundation (Gottfried-Wilhelm-Leibniz Program, CRC1054 [C.K.]), and the Else Kröner-Fresenius-Stiftung (Forschungskolleg Rare Diseases of the Immune System [C.K.]). I.S. was supported by the Care for Rare Foundation and has been a scholar of the Else Kröner-Fresenius-Stiftung. M. Thian was supported by a Cell Communication in Health and Disease (CCHD; Medical University of Vienna) doctoral fellowship and a DOC fellowship (25225) of the Austrian Academy of Sciences. A.G.D. was supported by a Deutscher Akademischer Austauschdienst/German Academic Exchange Service (DAAD) Fellowship (Thematic Program on Rare Diseases and Personalized Therapies). The Baylor-Hopkins Center for Mendelian Genomics was supported by the National Institutes of Health, National Human Genome Research Institute/ National Heart, Lung, and Blood Institute grant UM1HG006542. This work was supported by the European Research Council (ERC; Consolidator grant 820074 "iDysChart" [K.B.] and an ERC Advanced grant [C.K.]), the Jeffrey Modell Foundation (JMF; R.S.), the Care for Rare Foundation, the German Research Foundation (Gottfried-Wilhelm- Leibniz Program, CRC1054 [C.K.]), and the Else Kr?ner-Fresenius- Stiftung (Forschungskolleg Rare Diseases of the Immune System [C.K.]). I.S. was supported by the Care for Rare Foundation and has been a scholar of the Else Kr?ner-Fresenius-Stiftung. M. Thian was supported by a Cell Communication in Health and Disease (CCHD; Medical University of Vienna) doctoral fellowship and a DOC fellowship (25225) of the Austrian Academy of Sciences. A.G.D. was supported by a Deutscher Akademischer Austauschdienst/German Academic Exchange Service (DAAD) Fellowship (Thematic Program on Rare Diseases and Personalized Therapies). The Baylor-Hopkins Center for Mendelian Genomics was supported by the National Institutes of Health, National Human Genome Research Institute/ National Heart, Lung, and Blood Institute grant UM1HG006542.
Funders | Funder number |
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Baylor-Hopkins | |
C.K. | |
CCHD | |
Care for Rare Foundation | |
Deutscher Akademischer Austauschdienst/German Academic Exchange Service | Therapies |
ERC advanced | |
Forschungskolleg Rare Diseases of the Immune System | |
Stiftung | |
National Institutes of Health | |
National Heart, Lung, and Blood Institute | |
National Human Genome Research Institute | UM1HG006542 |
Jeffrey Modell Foundation | |
California Department of Conservation | 25225 |
European Commission | 820074 |
Deutsche Forschungsgemeinschaft | CRC1054 |
German-Israeli Foundation for Scientific Research and Development | |
Österreichischen Akademie der Wissenschaften | |
Else Kröner-Fresenius-Stiftung | |
Medizinische Universität Wien |