Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.
| Autor: | Narula M; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Lakshmanan U; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Borna S; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Schulze JJ; Epimune GmbH, Berlin, Germany., Holmes TH; Human Immune Monitoring Center, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, Calif., Harre N; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Kirkey M; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Ramachandran A; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Tagi VM; San Raffaele Telethon Institute for Gene Therapy, Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute Milan, Milan, Italy., Barzaghi F; San Raffaele Telethon Institute for Gene Therapy, Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute Milan, Milan, Italy., Grunebaum E; Division of Immunology and Allergy, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada., Upton JEM; Division of Immunology and Allergy, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada., Hong-Diep Kim V; Division of Immunology and Allergy, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada., Wysocki C; Department of Internal Medicine, Pediatrics, Allergy and Immunology, UT Southwestern Medical Center, Dallas, Tex., Dimitriades VR; Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, UC Davis Health Medical Center, Sacramento, Calif., Weinberg K; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Weinacht KG; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif., Gernez Y; Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, Stanford University School of Medicine, Stanford, Calif., Sathi BK; Valley Children's Healthcare, Madera, Calif., Schelotto M; Hemato - Immunology, Hospital Británico, Montevideo, Uruguay., Johnson M; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom., Olek S; Ivana Turbachova Laboratory of Epigenetics, Precision for Medicine GmbH, Berlin, Germany., Sachsenmaier C; Epimune GmbH, Berlin, Germany., Roncarolo MG; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif; Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, Calif., Bacchetta R; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif; Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, Calif. Electronic address: rosab@stanford.edu. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2023 Jan; Vol. 151 (1), pp. 233-246.e10. Date of Electronic Publication: 2022 Sep 21. |
| DOI: | 10.1016/j.jaci.2022.09.013 |
| Abstrakt: | Background: Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4 + CD25 hi CD127 lo regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution, and treatment choice. Objective: We sought to study the type and extent of immunologic abnormalities that remain ill-defined in IPEX, across genetic and clinical heterogeneity. Methods: We performed Treg-cell-specific epigenetic quantification and immunologic characterization of severe "typical" (n = 6) and "atypical" or asymptomatic (n = 9) patients with IPEX. Results: Increased number of cells with Treg-cell-Specific Demethylated Region demethylation in FOXP3 is a consistent feature in patients with IPEX, with (1) highest values in those with typical IPEX, (2) increased values in subjects with pathogenic FOXP3 but still no symptoms, and (3) gradual increase over the course of disease progression. Large-scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and T Conclusions: Elevated TSDR-demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized type 2 inflammatory immune response, extends our understanding of IPEX diagnosis and heterogeneity. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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