Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
Authors: 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 , Baris Safa , Sharapova Svetlana , Schuetz Catharina , Gennery Andrew R. , Freeman Alexandra F. , Somech Raz , Choo Sharon , Giliani Silvia C. , Güngör Tayfun , Drozdov Daniel , Meyts Isabelle , Moshous Despina , Neven Benedicte , Abraham Roshini S. , El-Marsafy Aisha , Kanariou Maria , King Alejandra , Licciardi Francesco , Cruz-Muñoz Mario E. , Palma Paolo , Poli Cecilia , Adeli Mehdi , Algeri Mattia , Alroqi Fayhan J. , Bastard Paul , Bergerson Jenna R. E. , Booth Claire , Brett Ana , Burns Siobhan O. , Butte Manish J. , Padem Nurcicek , de la Morena M. , Dbaibo Ghassan , de Ravin Suk See , Dimitrova Dimana , Djidjik Reda , Dorna Mayra B. , Dutmer Cullen M. , Elfeky Reem , Facchetti Fabio , Fuleihan Ramsay L. , Geha Raif S. , Gonzalez-Granado Luis I. , Haljasmägi Liis , Ale Hanadys , Hayward Anthony , Hifanova Anna M. , Ip Winnie , Kaplan Blanka , Kapoor Neena , Karakoc-Aydiner Elif , Kärner Jaanika , Keller Michael D. , Dávila Saldaña Blachy J. , Kiykim Ayça , Kuijpers Taco W. , Kuznetsova Elena E. , Latysheva Elena A. , Leiding Jennifer W. , Locatelli Franco , Alva-Lozada Guisela , McCusker Christine , Celmeli Fatih , Morsheimer Megan , Ozen Ahmet , Parvaneh Nima , Pasic Srdjan , Plebani Alessandro , Preece Kahn , Prockop Susan , Sakovich Inga S. , Starkova Elena E. , Torgerson Troy , Verbsky James , Walter Jolan E. , Ward Brant , Wisner Elizabeth L. , Draper Deborah , Myint-Hpu Katherine , Truong Pooi M. , Lionakis Michail S. , Similuk Morgan B. ,   Centralized Sequencing Program Group§§, Walkiewicz Magdalena A. , Klion Amy , Holland Steven M. , Oguz Cihan , Bogunovic Dusan , Kisand Kai , Su Helen C. , Tsang John S. , Kuhns Douglas , Villa Anna , Rosenzweig Sergio D. , Pittaluga Stefania , Notarangelo Luigi D. , Ghosh Rajarshi , Siefert Bryce , Tokita Mari , Yan Jia , Jodarski Colleen , Kamen Mike , Gore Rachel , Reynolds-Lallement Nadjalisse , Lewis Katie , Bannon Sarah , Borges Adrienne , Gentile Nicole 
Published: January 2025

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 (T
H
2) 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.