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

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.