Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
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
Recommended Citation
Bosticardo, Marita; Dobbs, Kerry; Delmonte, Ottavia M.; Martins, Andrew J.; Pala, Francesca; Kawai, Tomoki; Kenney, Heather; Magro, Gloria; Rosen, Lindsey B.; Yamazaki, Yasuhiro; Yu, Hsin Hui; Calzoni, Enrica; Lee, Yu Nee; Liu, Can; Stoddard, Jennifer; Niemela, Julie; Fink, Danielle; Castagnoli, Riccardo; Ramba, Meredith; Cheng, Aristine; Riley, Deanna; Oikonomou, Vasileios; Shaw, Elana; Belaid, Brahim; Keles, Sevgi; Al-Herz, Waleed; Cancrini, Caterina; Cifaldi, Cristina; Wisner, Elizabeth; and al, et, "Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature" (2025). School of Medicine Faculty Publications. 3406.
https://digitalscholar.lsuhsc.edu/som_facpubs/3406
10.1126/sciimmunol.adq1697
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