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Blood. 2019 Sep 9. pii: blood.2019000644. doi: 10.1182/blood.2019000644. [Epub ahead of print]

CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis.

Author information

1
Dr Von Hauner Children's Hospital, Germany.
2
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Austria.
3
Pediatric Immunology Allergy, S.B.U. Dr.Behçet Uz Children's Education And Research Hospital, Turkey.
4
Ludwig Maximilian University, Germany.
5
Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University, Munich, Germany, Germany.
6
Sheba Medical Center.
7
Tel Aviv Univesity, Israel.
8
Pediatric Immunology and Allergy, S.B.U. Dr. Behcet Uz Children's Education and Research Hospital, Izmir, Turkey.
9
Department of Pediatric Hematology, Erciyes University, Faculty of Medicine, Turkey.
10
Sheba Cancer Reserach Center and Institute of Hematology, Sheba Medical Center, Israel.
11
Sheba Medical Center and Tel Aviv University Institute for Pediatric Research, Israel.
12
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases.
13
Pathology, Chaim Sheba Medical Center, Israel.
14
Dr. von Hauner Childrens Hospital, Department of Pediatrics, University Hospital, LMU Munich.
15
Radiology, Sheba Medical Center, Israel.
16
Dokuz Eylul University School of Medicine, Turkey.
17
S.B.U. Dr.Behçet Uz Children's Education And Research Hospital, Turkey.
18
Department of Pediatrics, Erciyes Univesity, Faculty of Medicine, Turkey.
19
Pediatric Hematology Oncology and Stem Cell Transplantation Center, Erciyes University, Turkey.
20
Erciyes Univesity, Faculty of Medicine, Turkey.
21
Immunology, Argentina.
22
Group of Primary Immunodeficiencies, School of Medicine, University of Antioquia UdeA, Colombia.
23
Baylor College of Medicine, United States.
24
Department of Pediatrics, Columbia University, United States.
25
Departamento de Microbiología y Parasitología, Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia UdeA, Colombia.
26
MICROBIOLOGY AND PARASITOLOGY, UNIVERSIDAD DE ANTIOQUIA, Colombia.
27
Pediatric Immunology and Rheumatology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Germany.
28
Pediatric, Immunology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, affiliated to Tel Aviv University, Israel.
29
Pediatrics, Ludwig Maximilians University Munich, Germany.
30
Pediatrics and Adolescent Medicine, St. Anna Children's Cancer Research Institute (CCRI), Austria kaan.boztug@ccri.at.

Abstract

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity and immunodeficiency. We here investigated four patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified four distinct homozygous mutations in TNFRSF9 encoding the Tumor Necrosis Factor 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.

PMID:
31501153
DOI:
10.1182/blood.2019000644

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