Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
Authors: Marita Bosticardo, Kerry Dobbs, Ottavia M. Delmonte, Andrew J. Martins, Francesca Pala, Tomoki Kawai, Heather Kenney, Gloria Magro, Lindsey B. Rosen, Yasuhiro Yamazaki, Hsin-Hui Yu, Enrica Calzoni, Yu Nee Lee, Can Liu, Jennifer Stoddard, Julie Niemela, Danielle Fink, Riccardo Castagnoli, Meredith Ramba, Aristine Cheng, 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
Journal: Science Immunology (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 (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.