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Lookup NU author(s): Professor Andrew GenneryORCiD
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Copyright © 2025 The Authors, some rights reserved.Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of RAG-mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic RAG variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (TH2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.
Author(s): Bosticardo M, Dobbs K, Delmonte OM, Martins AJ, Pala F, Kawai T, Kenney H, Magro G, Rosen LB, Yamazaki Y, Yu H-H, Calzoni E, Lee YN, Liu C, Stoddard J, Niemela J, Fink D, Castagnoli R, Ramba M, Cheng A, Riley D, Oikonomou V, Shaw E, Belaid B, Keles S, Al-Herz W, Cancrini C, Cifaldi C, Baris S, Sharapova S, Schuetz C, Gennery AR, Freeman AF, Somech R, Choo S, Giliani SC, Gungor T, Drozdov D, Meyts I, Moshous D, Neven B, Abraham RS, El-Marsafy A, Kanariou M, King A, Licciardi F, Cruz-Munoz ME, Palma P, Poli C, Adeli M, Algeri M, Alroqi FJ, Bastard P, Bergerson JRE, Booth C, Brett A, Burns SO, Butte MJ, Padem N, de la Morena MT, Dbaibo G, de Ravin SS, Dimitrova D, Djidjik R, Dorna MB, Dutmer CM, Elfeky R, Facchetti F, Fuleihan RL, Geha RS, Gonzalez-Granado LI, Haljasmagi L, Ale H, Hayward A, Hifanova AM, Ip W, Kaplan B, Kapoor N, Karakoc-Aydiner E, Karner J, Keller MD, Davila Saldana BJ, Kiykim A, Kuijpers TW, Kuznetsova EE, Latysheva EA, Leiding JW, Locatelli F, Alva-Lozada G, McCusker C, Celmeli F, Morsheimer M, Ozen A, Parvaneh N, Pasic S, Plebani A, Preece K, Prockop S, Sakovich IS, Starkova EE, Torgerson T, Verbsky J, Walter JE, Ward B, Wisner EL, Draper D, Myint-Hpu K, Truong PM, Lionakis MS, Similuk MB, Walkiewicz MA, Klion A, Holland SM, Oguz C, Bogunovic D, Kisand K, Su HC, Tsang JS, Kuhns D, Villa A, Rosenzweig SD, Pittaluga S, Notarangelo LD
Publication type: Article
Publication status: Published
Journal: Science Immunology
Year: 2025
Volume: 10
Issue: 103
Print publication date: 01/01/2025
Online publication date: 10/01/2025
Acceptance date: 12/12/2024
ISSN (electronic): 2470-9468
Publisher: American Association for the Advancement of Science
URL: https://doi.org/10.1126/sciimmunol.adq1697
DOI: 10.1126/sciimmunol.adq1697
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