A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

• DOI: 10.1126/sciimmunol.ade7953
• Publication Date: 2023-01-20T13:58:33Z
• Authors: Oriol Fornes; Alicia Jia; Hye Sun Kuehn; Qing Min; Ulrich Pannicke; Nikolai Schleussner; Romane Thouenon; Zhijia Yu; María de los Ange...; Catherine M. Biggs; Miguel Galicchio; Jorge Alberto Gar...; Silvina Gismondi; Guadalupe Gonzale...; Kyla J. Hildebrand; Manfred Hönig; Jia Hou; Despina Moshous; Stefania Pittaluga; Xiaowen Qian; Jacob Rozmus; Ansgar S. Schulz; Aidé Tamara Stain...; Bijun Sun; Jinqiao Sun; Schauer Uwe; Edna Venegas-Montoya; Wenjie Wang; Xiaochuan Wang; Wenjing Ying; Xiaowen Zhai; Qinhua Zhou; Altuna Akalin; Isabelle André; Thomas F. E. Barth; Bernd Baumann; Anne Brüstle; Gaetan Burgio; Jacinta C. Bustam...; Jean-Laurent Casa...; Marco G. Casarotto; Marina Cavazzana; Loïc Chentout; Ian A. Cockburn; Mariantonia Costanza; Chaoqun Cui; Oliver Daumke; Kate L. Del Bel; Hermann Eibel; Xiaoqian Feng; Vedran Franke; J. Christof M. Ge...; Andrea Götz; Stephan Grunwald; Bénédicte Hoareau; Timothy R. Hughes; Eva-Maria Jacobsen; Martin Janz; Arttu Jolma; Chantal Lagresle-...; Nannan Lai; Yaxuan Li; Susan Lin; Henry Y. Lu; Saul O. Lugo-Reyes; Xin Meng; Peter Möller; Nidia Moreno-Corona; Julie E. Niemela; Gherman Novakovsky; Jareb J. Perez-Ca...; Capucine Picard; Lucie Poggi; Maria-Emilia Puig...; Katrina L. Randall; Anja Reisser; Yohann Schmitt; Sandali Seneviratne; Mehul Sharma; Jennifer Stoddard; Srinivasan Sundar...; Harry Sutton; Linh Q. Tran; Ying Wang; Wyeth W. Wasserman; Zichao Wen; Wiebke Winkler; Ermeng Xiong; Ally W. H. Yang; Meiping Yu; Lumin Zhang; Hai Zhang; Qian Zhao; Xin Zhen; Anselm Enders; Sven Kracker; Ruben Martinez-Ba...; Stephan Mathas; Sergio D. Rosenzweig; Klaus Schwarz; Stuart E. Turvey; Ji-Yang Wang
• Keywords: IRF4

Interferon regulatory factor 4 (IRF4) is a transcription (TF) and key regulator of immune cell development function. We report recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) seven patients from six unrelated families. The exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii , presented with agammaglobulinemia. Patients’ B cells showed impaired maturation, decreased immunoglobulin isotype switching, defective plasma differentiation, whereas their T contained reduced H 17 FH populations cytokine production. A knock-in mouse model T95R severe defect antibody production both at the steady state after immunization different types antigens, consistent CID observed these patients. IRF4 variant maps TF’s DNA binding domain, alters its canonical specificities, results simultaneous multimorphic combination loss, gain, new functions for IRF4. behaved as gain-of-function hypermorph by higher affinity than WT . Despite this increased DNA, transcriptional activity on genes was reduced, showcasing hypomorphic Simultaneously, neomorph noncanonical sites alter gene expression profile, including exclusively induced but not This previously undescribed pathophysiology disrupts normal lymphocyte biology, human disease.