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

Authors

Marita Bosticardo, National Institute of Allergy and Infectious Diseases (NIAID)
Kerry Dobbs, National Institute of Allergy and Infectious Diseases (NIAID)
Ottavia M. Delmonte, National Institute of Allergy and Infectious Diseases (NIAID)
Andrew J. Martins, National Institute of Allergy and Infectious Diseases (NIAID)
Francesca Pala, National Institute of Allergy and Infectious Diseases (NIAID)
Tomoki Kawai, National Institute of Allergy and Infectious Diseases (NIAID)
Heather Kenney, National Institute of Allergy and Infectious Diseases (NIAID)
Gloria Magro, National Institute of Allergy and Infectious Diseases (NIAID)
Lindsey B. Rosen, National Institute of Allergy and Infectious Diseases (NIAID)
Yasuhiro Yamazaki, National Institute of Allergy and Infectious Diseases (NIAID)
Hsin Hui Yu, National Institute of Allergy and Infectious Diseases (NIAID)
Enrica Calzoni, National Institute of Allergy and Infectious Diseases (NIAID)
Yu Nee Lee, Chaim Sheba Medical Center Israel
Can Liu, National Institute of Allergy and Infectious Diseases (NIAID)
Jennifer Stoddard, NIH Clinical Center (CC)
Julie Niemela, NIH Clinical Center (CC)
Danielle Fink, Leidos Inc.
Riccardo Castagnoli, National Institute of Allergy and Infectious Diseases (NIAID)
Meredith Ramba, Icahn School of Medicine at Mount Sinai
Aristine Cheng, National Institute of Allergy and Infectious Diseases (NIAID)
Deanna Riley, National Cancer Institute (NCI)
Vasileios Oikonomou, National Institute of Allergy and Infectious Diseases (NIAID)
Elana Shaw, National Institute of Allergy and Infectious Diseases (NIAID)
Brahim Belaid, Centre Hospitalier et Universitaire de Béni-Messous, Algiers
Sevgi Keles, Necmettin Erbakan Üniversitesi
Waleed Al-Herz, Kuwait University
Caterina Cancrini, Università degli Studi di Roma "Tor Vergata"
Cristina Cifaldi, Università degli Studi di Roma "Tor Vergata"
Elizabeth Wisner, LSU Health Sciences Center - New OrleansFollow
et al

Document Type

Article

Publication Date

1-10-2025

Publication Title

Science Immunology

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 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.

PubMed ID

39792639

Volume

10

Issue

103

Comments

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