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J Allergy Clin Immunol. 2018 Dec;142(6):1932-1946. doi: 10.1016/j.jaci.2018.02.055. Epub 2018 May 4.

Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

Author information

1
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2
Sección de Infectología e Inmunopatología, Unidad de Pediatría, Hospital Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain.
3
Immunology Team, American Insurance, Montevideo, Uruguay.
4
Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
5
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
6
Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
7
Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
8
Department of Hematology, Oslo University Hospital, Oslo, Norway.
9
Department of Radiology, Royal Free Hospital, University College London, London, United Kingdom.
10
UCL Institute of Immunity and Transplantation, Royal Free Hospital, London, United Kingdom.
11
Unidad de Inmunología, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain.
12
Center for Chronic Immunodeficiency and Molecular Pathology, Department of Pathology, University Medical Center, University of Freiburg, Freiburg, Germany.
13
Department of Pathology, University Medical Center, University of Freiburg, Freiburg, Germany.
14
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
15
Institute for Transfusion Medicine and Gene Therapy, University Medical Center Freiburg, Freiburg, Germany.
16
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Freiburg University, Freiburg, Germany.
17
Department of Immunology and Histocompatibility, Centre for Primary Immunodeficiencies, "Aghia Sophia" Children's Hospital, Athens, Greece.
18
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati, Children's Hospital Medical Center, Cincinnati, Ohio.
19
Department of Medicine, Clinical Immunology and Allergy Division, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal, Montreal, Quebec, Canada.
20
Department of Pediatrics, University Hospital Motol and 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
21
Department of Immunology, University Hospital Motol and 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
22
Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
23
University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom.
24
Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
25
Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany.
26
Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili of Brescia, Brescia, Italy.
27
Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, Conn.
28
Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
29
Department of Infectious Diseases and General Internal Medicine, University Hospital of Liège, Liege, Belgium.
30
Department of Clinical Immunology and Allergology, Medical Faculty, Masaryk University, Brno, Czech Republic; Department of Clinical Immunology and Allergology, St Anne's University Hospital, Brno, Czech Republic.
31
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic; Medical Genomics RG, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
32
Department of Internal Medicine, Radboudumc Center for Infectious Diseases (RCI), Nijmegen, The Netherlands.
33
Immunodeficiency Clinic, Medical Outpatient Unit and Immunodeficiency Lab, Department Biomedicine, University Hospital, Basel, Switzerland.
34
Department of Pediatric Immunology and Stem Cell Transplantation, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
35
Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom.
36
Division of Immunology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
37
Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
38
Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Melbourne, Australia.
39
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany; Center of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
40
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Pediatrics, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
41
Division of Gastroenterology and Department of Pediatrics, Harvard Medical School, Boston, Mass.
42
Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
43
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
44
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children's Hospital Boston, Mass.
45
Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Medicine I, University Medical Center Dresden, Technical University Dresden, Dresden, Germany; Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
46
Mount Sinai Hospital, Mount Sinai St Luke's and Mount Sinai West, Department of Medicine-Allergy & Immunology, New York, NY.
47
Department of Pediatrics, Division of Pediatric Hematology/Oncology, Weill Cornell Medicine, New York, NY.
48
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY.
49
HELIOS Children's Hospital, Krefeld, Germany.
50
CLIP, Department of Paediatric Haematology/Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
51
Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
52
Clinical Immunology and Allergy Unit, Nottingham University Hospitals, Nottingham, United Kingdom.
53
Department of Paediatric Gastroenterology, Great North Children's Hospital, Newcastle, United Kingdom.
54
Department of Pediatrics, University Hospital Jena, Jena, Germany.
55
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
56
Allergy and Clinical Immunology Department, Functional Unit of Immunology SJD-Clinic, Hospital Sant Joan de Déu, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
57
Servei de Genòmica, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
58
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Institute for Cancer Research, University Hospital Oslo, Oslo, Norway.
59
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom. Electronic address: bodo.grimbacher@uniklinik-freiburg.de.

Abstract

BACKGROUND:

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects.

OBJECTIVE:

We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers.

METHODS:

Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers.

RESULTS:

We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression.

CONCLUSIONS:

Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

KEYWORDS:

Cytotoxic T-lymphocyte antigen 4; abatacept; autoimmunity; common variable immunodeficiency; hematopoietic stem cell transplantation; hypogammaglobulinemia; immune dysregulation; primary immunodeficiency; sirolimus

PMID:
29729943
PMCID:
PMC6215742
[Available on 2019-12-01]
DOI:
10.1016/j.jaci.2018.02.055

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