Early bone marrow alterations in patients with adenosine deaminase 2 deficiency across disease phenotypes and severities.

Autor:	Bulté D; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Barzaghi F; Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Mesa-Nuñez C; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Rigamonti C; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Basso-Ricci L; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Visconti C; Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Crippa S; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Pettinato E; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Gilioli D; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Milani R; Immunohematology and Transfusion Medicine Unit, IRCCS Ospedale San Raffaele, Milan, Italy., Quaranta P; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Caorsi R; UOC Rheumatology and Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Cafaro A; Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Cangemi G; Chromatography and Mass Spectrometry Section, Central Laboratory of Analysis, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Lupia M; Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Schena F; UOC Rheumatology and Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Grossi A; Laboratorio Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Di Colo G; Vita-Salute San Raffaele University, Milan, Italy; Immunology, Rheumatology, Allergy and Rare Disease Unit, IRCCS San Raffaele Hospital, Milan, Italy., Federici S; Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Insalaco A; Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., De Benedetti F; Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Marktel S; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy., Di Micco R; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Bernardo ME; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Scala S; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Cicalese MP; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Conti F; Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy., Miano M; Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Gattorno M; UOC Rheumatology and Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Dufour C; Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Aiuti A; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Mortellaro A; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: mortellaro.alessandra@hsr.it.
Jazyk:	angličtina
Zdroj:	The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2024 Sep 14. Date of Electronic Publication: 2024 Sep 14.
DOI:	10.1016/j.jaci.2024.09.007
Abstrakt:	Background: Deficiency of adenosine deaminase 2 (DADA2) is a complex monogenic disease caused by recessive mutations in the ADA2 gene. DADA2 exhibits a broad clinical spectrum encompassing vasculitis, immunodeficiency, and hematologic abnormalities. Yet, the impact of DADA2 on the bone marrow (BM) microenvironment is largely unexplored. Objective: This study comprehensively examined the BM and peripheral blood of pediatric and adult patients with DADA2 presenting with rheumatologic/immunologic symptoms or severe hematologic manifestations. Methods: Immunophenotyping of hematopoietic stem cells (HSCs), progenitor cells, and mature cell populations was performed for 18 patients with DADA2. We also conducted a characterization of mesenchymal stromal cells. Results: Our study revealed a significant decrease in primitive HSCs and progenitor cells, alongside their reduced clonogenic capacity and multilineage differentiation potential. These BM defects were evident in patients with both severe and nonsevere hematologic manifestations, including pediatric patients, demonstrating that BM disruption can emerge silently and early on, even in patients who do not show obvious hematologic symptoms. Beyond stem cells, there was a reduction in mature cell populations in the BM and peripheral blood, affecting myeloid, erythroid, and lymphoid populations. Furthermore, BM mesenchymal stromal cells in patients with DADA2 exhibited reduced clonogenic and proliferation capabilities and were more prone to undergo cellular senescence marked by elevated DNA damage. Conclusions: Our exploration into the BM landscape of patients with DADA2 sheds light on the critical hematologic dimension of the disease and emphasizes the importance of vigilant monitoring, even in the case of subclinical presentation. Competing Interests: Disclosure statement This work received support from Fondazione Telethon (SR-Tiget Core Grant, Tele21-A5 and Tele21-E5) to A.M. and R.D.M., the Italian Ministry of Health (Progetto Ricerca Finalizzata 2019, RF-2019-12370600) to M.G., C.D., A.A., and A.M., PNRR 2022 (PNRR-MR1-2022-12376594) to F.B. and A.A., and the Else Kröner-Fresenius-Stiftung (EKFS) prize for Medical Research 2020 to A.A. R.D.M. is a New York Stem Cell FoundationRobertson Investigator. IRCCS San Raffaele Scientific Institute, IRCCS Istituto Giannina Gaslini, and IRCCS Bambino Gesù Children’s Hospital are part of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases, ERN-RITA (Project ID 739543). The centers involved are part of the Italian Pediatric Onco-Hematology Association (AIEOP). IRCCS San Raffaele Scientific Institute is part of the Inborn Error Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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