Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Autor:	Schuetz C; Department of Paediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Gerke J; Department of Paediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany., Ege M; Dr. von Hauner Children's Hospital at Ludwig-Maximilians-Universität, München, Germany.; Helmholtz Zentrum München, Neuherberg, Germany., Walter J; Division of Allergy and Immunology, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL.; Division of Allergy and Immunology, Department of Medicine, Johns Hopkins All Children's Hospital, St. Petersburg, FL., Kusters M; Department of Immunology and Gene therapy, Great Ormond Street Hospital, NHS Foundation trust, London, United Kingdom., Worth A; Department of Immunology and Gene therapy, Great Ormond Street Hospital, NHS Foundation trust, London, United Kingdom., Kanakry JA; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Dimitrova D; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Wolska-Kuśnierz B; Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland., Chen K; Division of Allergy and Immunology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT., Unal E; Division of Pediatric Hematology and Oncology, Department of Pediatrics, Erciyes University, Kayseri, Turkey., Karakukcu M; Division of Pediatric Hematology and Oncology, Department of Pediatrics, Erciyes University, Kayseri, Turkey., Pashchenko O; Department of Immunology, Pirogov Russian National Research Medical University, Moscow, Russia., Leiding J; Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Orlando Health Arnold Pamer Hospital for Children, Orlando, FL., Kawai T; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Amrolia PJ; Bone Marrow Transplant Unit, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom., Berghuis D; Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands., Buechner J; Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway., Buchbinder D; Division of Hematology, Children's Hospital of Orange County, Orange, CA., Cowan MJ; Division of Allergy, Immunology, and Blood and Marrow Transplant, Department of Pediatrics, University of California San Francisco, San Francisco, CA., Gennery AR; Translational and Clinical Research Institute, Newcastle University, Paediatric Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom., Güngör T; Department of Hematology/Oncology/Immunology, Gene-therapy, and Stem Cell Transplantation, University Children's Hospital Zurich-Eleonore Foundation & Children's Research Center, Zürich, Switzerland., Heimall J; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA.; Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA., Miano M; IRCCS Istituto Giannina Gaslini, Genova, Italy., Meyts I; Department of Pediatrics, Department of Microbiology and Immunology, University Hospitals Leuven, Leuven, Belgium., Morris EC; UCL Institute of Immunity & Transplantation, University College London Hospitals NHS Foundation Trust, Royal Free London Hospital NHS Foundation Trust, London, United Kingdom., Rivière J; Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain., Sharapova SO; Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus., Shaw PJ; Blood Transplant and Cell Therapies, Children's Hospital at Westmead, Sydney, Australia., Slatter M; Paediatric Immunology & HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom., Honig M; Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany., Veys P; Bone Marrow Transplant Unit, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom., Fischer A; Paediatric Immunology, Department of Immunology, Haematology and Rheumatology, Necker-Enfants Malades, Paris, France.; Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, Paris, France.; Collège de France, Paris, France., Cavazzana M; Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, Paris, France.; Département de Biothérapie, Hôpital Universitaire Necker-Enfants Malades, Groupe Hospitalier Paris Centre, Assistance Publique-Hopitaux de Paris, Paris, France.; Centre d'Investigation Clinique Biothérapie, Groupe hospitalier Universitaire paris centre, Assistance Publique-Hôpitaux de Paris, INSERM CIC 1416, Paris, France., Moshous D; Paediatric Immunology, Department of Immunology, Haematology and Rheumatology, Necker-Enfants Malades, Paris, France.; Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, Paris, France., Schulz A; Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany., Albert MH; Pediatric SCT Program, Dr. von Hauner University Children's Hospital, Ludwig-Maximilians Universität, München, Germany., Puck JM; Division of Allergy, Immunology, and Blood and Marrow Transplant, Department of Pediatrics, University of California San Francisco, San Francisco, CA., Lankester AC; Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands., Notarangelo LD; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Neven B; Paediatric Immunology, Department of Immunology, Haematology and Rheumatology, Necker-Enfants Malades, Paris, France.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Feb 16; Vol. 141 (7), pp. 713-724.
DOI:	10.1182/blood.2022017667
Abstrakt:	Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation. (© 2023 by The American Society of Hematology.)
Databáze:	MEDLINE
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