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Multi-omics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature

Bosticardo, Marita1; Dobbs, Adam1; Delmonte, Ottavia1; Martins, Andrew2; Liu, Can2; Tsang, John2; Notarangelo, Luigi1

Research facility: National Institute of Allergy and Infectious Diseases
Published Feb 24, 2025 on Dryad. https://doi.org/10.5061/dryad.cfxpnvxg3

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Feb 24, 2025 version files 196.91 KB

Abstract

Human RAG deficiency may manifest with distinct clinical and immunological phenotypes. By applying a multi-omics approach to a large group of RAG-mutant patients, we aimed to characterize the immunopathology associated with various forms of RAG deficiency. Defective T and B cell development has been observed in all phenotypes; however, patients with RAG deficiency due to hypomorphic mutations can generate T and B cells with signatures of immune dysregulation and production of autoantibodies to a broad range of self-antigens, including type I interferons. TH2 skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas leaky forms of RAG deficiency are associated with a TH1 profile both in blood and in tissues. CITE-seq analysis helped define the cell lineage-specific contribution to the distinct immunopathology associated with human RAG deficiency phenotypes, opening perspectives for targeted pharmacological interventions. Our results show that all RAG-mutant patients share common immunopathological mechanisms, while some abnormalities are typical of the different clinical phenotypes and could help improve the diagnosis and clinical management of RAG patients. Please see GEO accession GSE274284 for the associated CITEseq data. In the deposited dataset, SOMAscan (SomaLogic) was used to measure 1,305 human protein analytes in plasma from 20 RAG patients (5 each for the CID, LS, OS, and SCID groups) and 12 HD.