Patients with T+/low NK+ IL‐2 receptor γ chain deficiency have differentially‐impaired cytokine signaling resulting in severe combined immunodeficiency |
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| Authors: | Sebastian Fuchs Anne Rensing‐Ehl Miriam Erlacher Thomas Vraetz Lara Hartjes Ales Janda Marta Rizzi Myriam R. Lorenz Kimberly Gilmour Geneviève de Saint‐Basile Chaim M. Roifman Steven Cheuk Andrew Gennery Adrian J. Thrasher Ilka Fuchs Klaus Schwarz Carsten Speckmann Stephan Ehl |
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| Affiliation: | 1. Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany;2. Faculty of Biology, University of Freiburg, Freiburg, Germany;3. Center of Pediatric and Adolescent Medicine, University Medical Center, Freiburg, Germany;4. Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;5. Molecular Immunology Unit, Institute of Child Health (ICH), University College London (UCL), London, UK;6. INSEM UMR 1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France;7. Paris Descartes‐Sorbonne Paris Cité University, Imagine Institute, Paris, France;8. Centre d'Etudes des Déficits Immunitaires, Assistance Publique‐H?pitaux de Paris, H?pital Necker, Paris, France;9. The Canadian Centre for Primary Immunodeficiency, Division of Immunology and Allergy and Department of Pediatrics, the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, the Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada;10. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK;11. Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Ulm, Germany |
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| Abstract: | X‐linked severe combined immunodeficiency (X‐SCID) leads to a T?NK?B+ immunophenotype and is caused by mutations in the gene encoding the IL‐2 receptor γ‐chain (IL2RG). IL2RGR222C leads to atypical SCID with a severe early onset phenotype despite largely normal NK‐ and T‐cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL‐2, IL‐4, IL‐15, and IL‐21 in a patient with the IL2RGR222C mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T‐cell development was variably affected, but led to borderline T‐cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL‐2. While NK‐cell development was normal, IL‐2 enhancement of NK‐cell degranulation and IL‐15‐induced cytokine production were absent. IL‐2 or IL‐21 failed to enhance B‐cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RGR222C on cytokine signal transduction, with a gradient IL‐4R222C causes a consistently severe clinical phenotype that is not predicted by the variable and moderate impairment of T‐cell immunity or TREC analysis. |
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| Keywords: | Atypical SCID Common gamma chain Cytokine signaling Leaky SCID Severe combined immunodeficiency |
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