[en] BACKGROUND: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness.
OBJECTIVE: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level.
METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated.
RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed.
CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
Disciplines :
Immunology & infectious disease
Author, co-author :
Egg, David ; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Rump, Ina Caroline; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Mitsuiki, Noriko; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Rojas-Restrepo, Jessica; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Maccari, Maria-Elena; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany, Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Schwab, Charlotte; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Gabrysch, Annemarie; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Warnatz, Klaus; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany, Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Goldacker, Sigune; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany, Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Patiño, Virginia; Immunology Team, American Insurance, Montevideo, Uruguay
Wolff, Daniel; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
Okada, Satoshi; Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
Hayakawa, Seiichi; Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
Shikama, Yoshiaki; Division of Infection, Immunology and Infection, Kanagawa Children's Medical Center, Yokohama, Japan
Kanda, Kenji; Department of Pediatrics, Hikone Municipal Hospital, Shiga, Japan
Imai, Kohsuke; Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan
Sotomatsu, Manabu; Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan
Kuwashima, Makoto; Department of Pediatrics, Kiryu Kosei General Hospital, Kiryū, Japan
Kamiya, Takahiro; Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan
Morio, Tomohiro; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
Matsumoto, Kazuaki; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
Mori, Takeshi; Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
Yoshimoto, Yuri; Department of Pediatrics, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan
Dybedal, Ingunn; Department of Hematology, Oslo University Hospital, Oslo, Norway
Kanariou, Maria; Department of Immunology and Histocompatibility, Center for Primary Immunodeficiencies-Paediatric Immunology, Aghia Sophia Children's Hospital, Athens, Greece
Kucuk, Zeynep Yesim; Division of Bone Marrow Transplantation and Immune Deficiency, Children's Hospital Medical Center, Cincinnati, Ohio
Chapdelaine, Hugo; Division of Clinical Immunology, Montreal Clinical Research Institute, Montreal, Quebec, Canada
Petruzelkova, Lenka; Department of Paediatrics, Motol University Hospital, Second Medical Faculty in Prague, Charles University, Prague, Czech Republic
Lorenz, Hanns-Martin; Division of Rheumatology, Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
Sullivan, Kathleen E; The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania
Heimall, Jennifer; The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania
Moutschen, Michel ; Centre Hospitalier Universitaire de Liège - CHU > > Service des maladies infectieuses - médecine interne
Litzman, Jiri; 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
Recher, Mike; Immunodeficiency Clinic, Medical Outpatient Unit and Immunodeficiency Lab, Department Biomedicine, University Hospital, Basel, Switzerland
Albert, Michael H; Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilians Universität München, Munich, Germany
Hauck, Fabian; Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, Ludwig Maximilians Universität München, Munich, Germany
Seneviratne, Suranjith; Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom
Pachlopnik Schmid, Jana; Division of Immunology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
Kolios, Antonios; Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
Unglik, Gary; Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Melbourne, Australia
Klemann, Christian; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany, Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Snapper, Scott; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
Giulino-Roth, Lisa; Department of Pediatrics, Division of Pediatric Hematology/Oncology, Weill Cornell Medicine, New York, NY
Svaton, Michael; Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Platt, Craig D; Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
Hambleton, Sophie; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom
Neth, Olaf; Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, RECLIP, Spain
Gosse, Geraldine; Montreal Clinical Research Institute, Université de Montréal, Montreal, Quebec, Canada
Reinsch, Steffen; Jena University Hospital, Pediatric Gastroenterology, Jena, Germany
Holzinger, Dirk; Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
Kim, Yae-Jean; Division of Infectious Diseases and Immunodeficiency, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Bakhtiar, Shahrzad; Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany
Atschekzei, Faranaz; Department for Clinical Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
Schmidt, Reinhold; Department for Clinical Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
Sogkas, Georgios; Department for Clinical Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
Chandrakasan, Shanmuganathan; Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
Rae, William; Department of Immunology, University Hospital Southampton NHSFT, Southampton, United Kingdom, Southampton National Institute for Health Research Clinical Research Facility, University Hospital Southampton NHSFT, Southampton, United Kingdom
Derfalvi, Beata; Division of Immunology, IWK Health Centre and Dalhousie University, Department of Pediatrics, Halifax, Nova Scotia, Canada
Marquart, Hanne Vibeke; Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Ozen, Ahmet; Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey
Kiykim, Ayca; Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey
Karakoc-Aydiner, Elif; Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey
Králíčková, Pavlína; Institute of Clinical Immunology and Allergy, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic
de Bree, Godelieve; Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Kiritsi, Dimitra; Department of Dermatology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany
Seidel, Markus G; Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hemato-Oncology, Department of Pediatric and Adolescent Medicine, Medical University Graz, Graz, Austria
Kobbe, Robin; Division of Infectious Diseases, First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Dantzer, Jennifer; Division of Pediatric Allergy and Immunology, and Rheumatology, Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, Md
Alsina, Laia; Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Clinical Immunology Unit Hospital Sant Joan de Déu-Hospital Clínic Barcelona, Universitat de Barcelona, Barcelona, Spain
Armangue, Thais; Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
Lougaris, Vassilios; Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona, Barcelona, Spain
Agyeman, Philipp; 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
Nyström, Sofia; Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Buchbinder, David; Department of Clinical Immunology and Transfusion Medicine, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
Arkwright, Peter D; Division of Pediatric Hematology, Children's Hospital of Orange County, Orange, Calif
Grimbacher, Bodo ; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany, Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany, Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom, Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom, German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany, Centre for Integrative Biological Signaling Studies, Albert Ludwig University of Freiburg, Freiburg, Germany, RESIST-Cluster of Excellence 2155 to Hannover Medical School, Satellite Center Freiburg, Freiburg, Germany. Electronic address: bodo.grimbacher@uniklinik-freiburg.de
Supported by the Deutsche Forschungsgemeinschaft (grant SFB1160/2_B5 ), under Germany's Excellence Strategy (CIBSS–EXC-2189 [project identifier 390939984] and RESIST–EXC 2155 [project identifier 39087428] [to B.D.]); the E-Rare Program of the European Union, managed by the Deutsche Forschungsgemeinschaft (grant code GR1617/14-1/iPAD [to B.D.]); the Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research (grant code GAIN 01GM1910A [to B.D.]); the Ministry of Health of the Czech Republic (grant code NV19-05-00332 [to M.S.]); the Torrons Vicens Foundation (grant code PFNR0144 [to L.A. and T.A.]); the Else Kröner-Fresenius-Stiftung (EKFS, 2017_A110 [to F.H.]), and the German Federal Ministry of Education and Research (BMBF, 01GM1910C [to F.H.]); and the Cancer Research Center Funding Program (CRC, C3Z) of the University of Zurich, Zurich, Switzerland (to J.P.S.).
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