| Title: |
A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency |
| Authors: |
Fornes, Oriol; Jia, Alicia; Kuehn, Hye Sun; Min, Qing; Pannicke, Ulrich; Schleussner, Nikolai; Thouenon, Romane; Yu, Zhijia; de los Angeles Astbury, María; Biggs, Catherine, M; Galicchio, Miguel; Garcia-Campos, Jorge Alberto; Gismondi, Silvina; Gonzalez Villarreal, Guadalupe; Hildebrand, Kyla, J; Hönig, Manfred; Hou, Jia; Moshous, Despina; Pittaluga, Stefania; Qian, Xiaowen; Rozmus, Jacob; Schulz, Ansgar, S; Staines-Boone, Aidé Tamara; Sun, Bijun; Sun, Jinqiao; Uwe, Schauer; Venegas-Montoya, Edna; Wang, Wenjie; Wang, Xiaochuan; Ying, Wenjing; Zhai, Xiaowen; Zhou, Qinhua; Akalin, Altuna; André, Isabelle; Barth, Thomas, F E; Baumann, Bernd; Brüstle, Anne; Burgio, Gaetan; Bustamante, Jacinta, C; Casanova, Jean-Laurent; Casarotto, Marco, G; Cavazzana, Marina; Chentout, Loïc; Cockburn, Ian, A; Costanza, Mariantonia; Cui, Chaoqun; Daumke, Oliver; del Bel, Kate, L; Eibel, Hermann; Feng, Xiaoqian; Franke, Vedran; Gebhardt, J. Christof M.; Götz, Andrea; Grunwald, Stephan; Hoareau, Bénédicte; Hughes, Timothy, R; Jacobsen, Eva-Maria; Janz, Martin; Jolma, Arttu; Lagresle-Peyrou, Chantal; Lai, Nannan; Li, Yaxuan; Lin, Susan; Lu, Henry, Y; Lugo-Reyes, Saul, O; Meng, Xin; Möller, Peter; Moreno-Corona, Nidia; Niemela, Julie, E; Novakovsky, Gherman; Perez-Caraballo, Jareb, J; Picard, Capucine; Poggi, Lucie; Puig-Lombardi, Maria-Emilia; Randall, Katrina, L; Reisser, Anja; Schmitt, Yohann; Seneviratne, Sandali; Sharma, Mehul; Stoddard, Jennifer; Sundararaj, Srinivasan; Sutton, Harry; Tran, Linh, Q; Wang, Ying; Wasserman, Wyeth, W; Wen, Zichao; Winkler, Wiebke; Xiong, Ermeng; Yang, Ally, W H; Yu, Meiping; Zhang, Lumin; Zhang, Hai; Zhao, Qian; Zhen, Xin; Enders, Anselm; Kracker, Sven; Martinez-Barricarte, Ruben; Mathas, Stephan; Rosenzweig, Sergio, D; Schwarz, Klaus; Turvey, Stuart, E; Wang, Ji-Yang |
| Contributors: |
BC Children's Hospital Research Institute Vancouver, BC, Canada (BCCHR); University of British Columbia Canada (UBC); Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland; Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Childrens Hosp Victor J Vilela Rosario Santa Fé; Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Service d'immuno-hématologie pédiatrique CHU Necker; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP; National Cancer Institute Bethesda (NCI-NIH); National Institutes of Health Bethesda, MD, USA (NIH); ANR-19-CE17-0012,AID,déficits immunitaires héréditaires humoraux: génétique et mécanismes pathologiques(2019) |
| Source: |
ISSN: 2470-9468 ; Science Immunology ; https://hal.science/hal-03952946 ; Science Immunology, 2023, 8 (79), ⟨10.1126/sciimmunol.ade7953⟩. |
| Publisher Information: |
CCSD; American Association for the Advancement of Science (AAAS) |
| Publication Year: |
2023 |
| Subject Terms: |
IRF4 International Consortium 1; [SDV]Life Sciences [q-bio] |
| Description: |
International audience ; Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii , and presented with agammaglobulinemia. Patients’ B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced T H 17 and T FH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4 T95R variant maps to the TF’s DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4 T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4 WT . Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4 T95R . Simultaneously, IRF4 T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4 T95R but not by IRF4 WT . This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1126/sciimmunol.ade7953 |
| Availability: |
https://hal.science/hal-03952946; https://hal.science/hal-03952946v1/document; https://hal.science/hal-03952946v1/file/ade7953_ArticleContent_v10_SK_2301%20with%20figures%20and%20supplemental%20information%20figures.pdf; https://doi.org/10.1126/sciimmunol.ade7953 |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.43938445 |
| Database: |
BASE |