Multiomics Dissection of Human Rag Deficiency Reveals Distinctive Patterns of Immune Dysregulation But a Common Inflammatory Signature Publisher Pubmed

Summary: Can gene defects vary wildly? Study uses multiomics on RAG-mutated patients—reveals TH2 skewing in Omenn syndrome, type 1 in hypomorphic. Suggests better diagnosis, management. #Immunodeficiency #Genetics

Bosticardo M¹ ; Dobbs K¹ ; Delmonte OM¹ ; Martins AJ² ; Pala F¹ ; Kawai T¹ ; Kenney H¹ ; Magro G¹ ; Rosen LB¹ ; Yamazaki Y¹ ; Yu HH^{1, 3} ; Calzoni E¹ ; Lee YN⁴ ; Liu C² Show All Authors
Source: Science Immunology Published:2025

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. Copyright © 2025 The Authors, some rights reserved.