Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
Journal
Science Immunology
Journal Volume
10
Journal Issue
103
Start Page
Article number eadq1697
ISSN
2470-9468
Date Issued
2025-01-10
Author(s)
Marita Bosticardo
Kerry Dobbs
Ottavia M. Delmonte
Andrew J. Martins
Francesca Pala
Tomoki Kawai
Heather Kenney
Gloria Magro
Lindsey B. Rosen
Yasuhiro Yamazaki
Enrica Calzoni
Yu Nee Lee
Can Liu
Jennifer Stoddard
Julie Niemela
Danielle Fink
Riccardo Castagnoli
Meredith Ramba
Deanna Riley
Vasileios Oikonomou
Elana Shaw
Brahim Belaid
Sevgi Keles
Waleed Al-Herz
Caterina Cancrini
Cristina Cifaldi
Safa Baris
Svetlana Sharapova
Catharina Schuetz
Andrew R. Gennery
Alexandra F. Freeman
Raz Somech
Sharon Choo
Silvia C. Giliani
Tayfun Güngör
Daniel Drozdov
Isabelle Meyts
Despina Moshous
Benedicte Neven
Roshini S. Abraham
Aisha El-Marsafy
Maria Kanariou
Alejandra King
Francesco Licciardi
Mario E. Cruz-Muñoz
Paolo Palma
Cecilia Poli
Mehdi Adeli
Mattia Algeri
Fayhan J. Alroqi
Paul Bastard
Jenna R. E. Bergerson
Claire Booth
Ana Brett
Siobhan O. Burns
Manish J. Butte
Nurcicek Padem
M. de la Morena
Ghassan Dbaibo
Suk See de Ravin
Dimana Dimitrova
Reda Djidjik
Mayra B. Dorna
Cullen M. Dutmer
Reem Elfeky
Fabio Facchetti
Ramsay L. Fuleihan
Raif S. Geha
Luis I. Gonzalez-Granado
Liis Haljasmägi
Hanadys Ale
Anthony Hayward
Anna M. Hifanova
Winnie Ip
Blanka Kaplan
Neena Kapoor
Elif Karakoc-Aydiner
Jaanika Kärner
Michael D. Keller
Blachy J. Dávila Saldaña
Ayça Kiykim
Taco W. Kuijpers
Elena E. Kuznetsova
Elena A. Latysheva
Jennifer W. Leiding
Franco Locatelli
Guisela Alva-Lozada
Christine McCusker
Fatih Celmeli
Megan Morsheimer
Ahmet Ozen
Nima Parvaneh
Srdjan Pasic
Alessandro Plebani
Kahn Preece
Susan Prockop
Inga S. Sakovich
Elena E. Starkova
Troy Torgerson
James Verbsky
Jolan E. Walter
Brant Ward
Elizabeth L. Wisner
Deborah Draper
Katherine Myint-Hpu
Pooi M. Truong
Michail S. Lionakis
Morgan B. Similuk
Magdalena A. Walkiewicz
Amy Klion
Steven M. Holland
Cihan Oguz
Dusan Bogunovic
Kai Kisand
Helen C. Su
John S. Tsang
Douglas Kuhns
Anna Villa
Sergio D. Rosenzweig
Stefania Pittaluga
Luigi D. Notarangelo
Rajarshi Ghosh
Bryce Siefert
Mari Tokita
Jia Yan
Colleen Jodarski
Mike Kamen
Rachel Gore
Nadjalisse Reynolds-Lallement
Katie Lewis
Sarah Bannon
Adrienne Borges
Nicole Gentile
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.
Publisher
American Association for the Advancement of Science (AAAS)
Type
journal article