Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature
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 E. Niemela, Danielle Fink, Riccardo Castagnoli, Meredith Ramba, Aristine Cheng, Deanna Riley, Vasileios Oikonomou, Elana Shaw, Brahim Belaid, Sevgi Keleş, Waleed Al–Herz, Caterina Cancrini, Cristina Cifaldi, Safa Barış, Svetlana Sharapova, Catharina Schuetz, Andrew R. Gennery, Alexandra F. Freeman, Raz Somech, Sharon Choo, Silvia Giliani, Tayfun Güngör, Daniel Drozdov, Isabelle Meyts, Despina Moshous, Bénédicte Neven, Roshini S. Abraham, Aisha Elmarsafy, Maria Kanariou, Alejandra King, Francesco Licciardi, Mario Ernesto Cruz‐Muñoz, Paolo Palma, M. Cecilia Poli, Mehdi Adeli, Mattia Algeri, Fayhan Alroqi, Paul Bastard, Jenna Bergerson, Claire Booth, Ana Brett, Siobhan O. Burns, Manish J. Butte, Nurcicek Padem, Maite de la Morena, Ghassan Dbaibo, Suk See De Ravin, Dimana Dimitrova, Réda Djidjik, Mayra de Barros Dorna, Cullen M. Dutmer, Reem Elfeky, Fabio Facchetti, Ramsay Fuleihan, Raif S. Geha, Luis Ignacio González‐Granado, Liis Haljasmägi, Hanadys Ale, Anthony Hayward, Anna Hilfanova, Winnie Ip, Blanka Kaplan, Neena Kapoor, Elif Karakoç-Aydıner, Jaanika Kärner, Michael D. Keller, Blachy J. Dávila Saldaña, Ayça Kıykım, Taco W. Kuijpers, Elena Kuznetsova, Elena A. Latysheva, Jennifer W. Leiding, Franco Locatelli, Guisela Alva‐Lozada, Christine McCusker, Fatih Çelmeli, Megan Morsheimer, Ahmet Özen, Nima Parvaneh, Srdjan Pašić, Alessandro Plebani, Kahn Preece, Susan E. Prockop, Inga Sakovich, Elena E. Starkova
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 (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.