Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of <i>RAG</i>-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 <i>RAG</i> 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 (T<sub>H</sub>2) 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.

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Publication Details

Journal
Science Immunology
Published
2025-01-10
DOI
https://doi.org/10.1126/sciimmunol.adq1697
Citations
11
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
8.77

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article

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature

Deanna Riley, Vasileios Oikonomou, Stefania Pittaluga, Winnie Ip et al.
11 citations
Science Immunology
Immune Cell Function and Interaction
8.77
article

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature

Deanna Riley, Vasileios Oikonomou, Stefania Pittaluga, Winnie Ip, Claire Booth, Bénédicte Neven, Daniel Drozdov, Mayra de Barros Dorna, Elizabeth Wisner, Paul Bastard, Safa Barış, Taco W. Kuijpers, Siobhan O. Burns, Andrew R. Gennery, Waleed Al–Herz, Helen C. Su, Francesco Licciardi, Andrew J. Martins, Silvia Clara Giliani, Michael D. Keller, Mattia Algeri, Alessandro Plebani, Douglas B. Kuhns, Tomoki Kawai, Amy D. Klion, Marita Bosticardo, James Verbsky, Franco Locatelli, Michail S. Lionakis, Nadjalisse Reynolds‐Lallement, Maite de la Morena, Liis Haljasmägi, Mehdi Adeli, Katherine Myint‐Hpu, Heather Kenney, Despina Moshous, Aisha Elmarsafy, Elif Karakoç-Aydıner, Luigi Daniele Notarangelo, Brahim Belaid, John S. Tsang, Rajarshi Ghosh, Yan Jia, Mario Ernesto Cruz‐Muñoz, Jolán E. Walter, Nima Parvaneh, Jaanika Kärner, Ayça Aslan Kıykım, Elena Kuznetsova, M. Cecilia Poli, Ottavia M. Delmonte, Svetlana Sharapova, Roshini S. Abraham, Kerry Dobbs, Cihan Oguz, Beate Ward, Dimana Dimitrova, Isabelle Meyts, Ana Brett, Phi Truong, Sarah A. Bannon, Elana Shaw, Inga Sakovich, Blanka Kaplan, Danielle Fink, Megan Morsheimer, Anthony Hayward, Manish J. Butte, Riccardo Castagnoli, Sergio D. Rosenzweig, Blachy J. Dávila Saldaña, Enrica Calzoni, Caterina Cancrini, Adrienne Borges, Susan E. Prockop, Hsin‐Hui Yu, Anna Hilfanova, Mari Tokita, Steven M. Holland, Guisela Alva‐Lozada, Réda Djidjik, Lindsey B. Rosen, Gloria Magro, Kahn Preece, Yu Nee Lee, Reem Elfeky, Srdjan Pašić, Julie E. Niemela, Nurcicek Padem, Alexandra F. Freeman, Fatih Çelmeli, Magdalena Walkiewicz, Dusan Bogunovic, Maria Kanariou, Elena A. Latysheva, Francesca Pala, Cullen M. Dutmer, Troy R. Torgerson, Hanadys Ale, Colleen Jodarski, Cristina Cifaldi, Raz Somech, Luis Ignacio González‐Granado, Aristine Cheng, Fabio Facchetti, Jenna Bergerson, Anna Villa, Katie Lewis, Morgan N. Similuk, Ramsay Fuleihan, Alejandra King, Rachel Gore Moses, Kai Kisand, Ghassan Dbaibo, Suk See De Ravin, Sevgi Keleş, Jennifer W. Leiding, Fayhan Alroqi, Meredith Ramba, Can Liu, Neena Kapoor, Yasuhiro Yamazaki, Deborah Draper, Jennifer Stoddard, Tayfun Güngör, Catharina Schuetz, Nicole Gentile, Sharon Choo, Ahmet Özen, Christine McCusker, R S Geha, Elena E. Starkova, Bryce Siefert, Mike Kamen
article en
11 citations

Abstract

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of <i>RAG</i>-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 <i>RAG</i> 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 (T<sub>H</sub>2) 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.

Science ImmunologyVol. 10(103)
Università Cattolica del Sacro Cuore (IT), Leidos (United States) (US), University of Rome Tor Vergata (IT), Universidad Complutense de Madrid (ES), Children's Hospital of Wisconsin (US), Hôpital Necker-Enfants Malades (FR), Boston Children's Hospital (US), National Institutes of Health (US), Qatar Airways (Qatar) (QA), Nationwide Children's Hospital (US), Royal Children's Hospital (AU), Universidad del Desarrollo (CL), Children's National (US), Children's Hospital of Los Angeles (US), Johns Hopkins University (US), Cairo University (EG), Inserm (FR), University of California, Los Angeles (US), Royal Free London NHS Foundation Trust (GB), Virginia Commonwealth University (US), King Saud bin Abdulaziz University for Health Sciences (SA), University of Algiers Benyoucef Benkhedda (DZ), Florida International University (US), Université Paris Cité (FR), University of South Florida (US), Columbia University Irving Medical Center (US), Johns Hopkins Medicine (US), Montreal Children's Hospital (CA), Shupyk National Healthcare University of Ukraine (UA), Great Ormond Street Hospital (GB), Rhode Island Hospital (US), The Royal Free Hospital (GB), McGill University Health Centre (CA), Hospitais da Universidade de Coimbra (PT), Riley Hospital for Children (US), Pirogov Russian National Research Medical University (RU), Kuwait University (KW), University of Belgrade (RS), Research Institute Hospital 12 de Octubre (ES), Hospital Nacional Cayetano Heredia (PE), King Abdullah International Medical Research Center (SA), Children's Hospital Colorado (US), Los Angeles Medical Center (US), Assistance Publique – Hôpitaux de Paris (FR), Grade Medical (Czechia) (CZ), Memorial Healthcare System (US), Johns Hopkins All Children's Hospital (US), Antalya Bilim University (TR), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Allen Institute for Immunology (US), American University of Beirut Medical Center (LB), Donald & Barbara Zucker School of Medicine at Hofstra/Northwell (US), Necmettin Erbakan University (TR), Amsterdam Neuroscience (NL), Seattle Children's Hospital (US), Hospital Luis Calvo Mackenna (CL), Istanbul University-Cerrahpaşa (TR), Institute of Genetic and Biomedical Research (IT), Cohen Children's Medical Center (US), Children's Hospital Agia Sophia (GR), Bambino Gesù Children's Hospital (IT), University Children's Hospital Zurich (CH), Al-Sabah Hospital (KW), National Taiwan University Hospital (TW), Children’s Foundation (GB), National Institute of Allergy and Infectious Diseases (US), Institute of Public Health of Serbia (RS), Ospedale Regina Margherita (IT), John Hunter Children's Hospital (AU), National Cancer Institute (US), The San Raffaele Telethon Institute for Gene Therapy (IT), Edmond and Lily Safra Children's Hospital (IL), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Belarusian Research Center For Pediatric Oncology and Hematology (BY), National Institutes of Health Clinical Center (US), St Martins Hospital (GB), Jeffrey Modell Foundation (AU), Joe DiMaggio Children's Hospital (US), Orenburg Regional Clinical Hospital №2 (RU), Kantonsspital Aarau (CH), University Hospital Carl Gustav Carus (DE), Institut des Maladies Génétiques Imagine (FR), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), University College London (GB), Indiana University – Purdue University Indianapolis (US), University of Tartu (EE), Tehran University of Medical Sciences (IR), Marmara University (TR), Louisiana State University Health Sciences Center New Orleans (US), Technische Universität Dresden (DE), University of Pennsylvania (US), University of Brescia (IT), Newcastle University (GB), Universidad Autónoma del Estado de Morelos (MX), University of Amsterdam (NL), University of Colorado Denver (US), American University of Beirut (LB), Icahn School of Medicine at Mount Sinai (US), KU Leuven (BE)
Bill and Melinda Gates Foundation, Amgen, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Memorial Sloan-Kettering Cancer Center, Regeneron Pharmaceuticals, Les Laboratories Pierre Fabre, Atara Biotherapeutics, Eesti Teadusagentuur, Swedish Orphan Biovitrum, Grifols, National Institutes of Health, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
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Immune Cell Function and Interaction
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