1. Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation
- Author
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Akihiro Hoshino, David Boutboul, Yuan Zhang, Hye Sun Kuehn, Jerôme Hadjadj, Nihal Özdemir, Tiraje Celkan, Christoph Walz, Capucine Picard, Christelle Lenoir, Nizar Mahlaoui, Christoph Klein, Xiao Peng, Antoine Azar, Erin Reigh, Morgane Cheminant, Alain Fischer, Frédéric Rieux-Laucat, Isabelle Callebaut, Fabian Hauck, Joshua Milner, Sergio D. Rosenzweig, Sylvain Latour, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-18-CE15-0025,ImmunoBioCTPS1,Comprendre la biologie et la physiopathologie de CTPS1, une nouvelle cible pour le développement d'immunosuppresseurs.(2018), ANR-18-CE17-0001,ACTION,Cytopénies Auto-immunes: génétique et mécanismes physiopathologiques du syndrome d'Evans pédaitrique(2018), and ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018)
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[SDV]Life Sciences [q-bio] ,Immunology ,General Medicine - Abstract
IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline IKZF1 haploinsufficient ( IKZF1 HI ) and dominant-negative ( IKZF1 DN ) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous IKZF1 variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T H ) skewing toward T H 2, low numbers of regulatory T cells (T reg ), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1 HI and IKZF1 DN , IKZF1 R183H/C proteins showed increased DNA binding associated with increased gene expression of T H 2 and PC differentiation, thus demonstrating that IKZF1 R183H/C behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T H 2 and PC abnormalities caused by IKZF1 R183H/C . These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.
- Published
- 2022
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