Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

doi:10.1126/sciimmunol.abi7160

. 2022 Mar 25;7(69):eabi7160.

doi: 10.1126/sciimmunol.abi7160. Epub 2022 Mar 25.

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Akihiro Hoshino¹, David Boutboul¹, Yuan Zhang², Hye Sun Kuehn³, Jerôme Hadjadj^{4

5}, Nihal Özdemir⁶, Tiraje Celkan⁷, Christoph Walz⁸, Capucine Picard^{1

5

9}, Christelle Lenoir¹, Nizar Mahlaoui¹⁰, Christoph Klein¹¹, Xiao Peng¹², Antoine Azar¹², Erin Reigh¹³, Morgane Cheminant¹⁴, Alain Fischer^{10

15

16}, Frédéric Rieux-Laucat^{4

5}, Isabelle Callebaut¹⁷, Fabian Hauck¹¹, Joshua Milner², Sergio D Rosenzweig³, Sylvain Latour^{1

5}

Affiliations

¹ Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France.
² Department of Pediatrics, Irving Medical Center, Columbia University, New York, NY, USA.
³ Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, NIH, Bethesda, MD, USA.
⁴ Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Paris, France.
⁵ Université de Paris, Paris, France.
⁶ Kanuni Sultan Süleyman Training and Research Hospital, Pediatric Hematology Oncology Department, Istanbul, Turkey.
⁷ Cerrahpasa Medical University, Pediatric Hematology Oncology Department, Istanbul, Turkey.
⁸ Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
⁹ Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.
¹⁰ Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris, France.
¹¹ Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
¹² Laboratory of Clinical Immunology and Microbiology and the Immune Deficiency Genetics Section, NIH, Bethesda, MD, USA.
¹³ Dartmouth-Hitchcock Medical Center, Boston, MA, USA.
¹⁴ Department of Adult Hematology, Necker-Enfants Malades Hospital, APHP, Paris, France.
¹⁵ Imagine Institute, Paris, France.
¹⁶ Collège de France, Paris, France.
¹⁷ Sorbonne Université, Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, Paris, France.

PMID: 35333544
DOI: 10.1126/sciimmunol.abi7160

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Akihiro Hoshino et al. Sci Immunol. 2022.

. 2022 Mar 25;7(69):eabi7160.

doi: 10.1126/sciimmunol.abi7160. Epub 2022 Mar 25.

Authors

Affiliations

¹ Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France.
² Department of Pediatrics, Irving Medical Center, Columbia University, New York, NY, USA.
³ Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, NIH, Bethesda, MD, USA.
⁴ Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Imagine Institute, Paris, France.
⁵ Université de Paris, Paris, France.
⁶ Kanuni Sultan Süleyman Training and Research Hospital, Pediatric Hematology Oncology Department, Istanbul, Turkey.
⁷ Cerrahpasa Medical University, Pediatric Hematology Oncology Department, Istanbul, Turkey.
⁸ Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
⁹ Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.
¹⁰ Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris, France.
¹¹ Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
¹² Laboratory of Clinical Immunology and Microbiology and the Immune Deficiency Genetics Section, NIH, Bethesda, MD, USA.
¹³ Dartmouth-Hitchcock Medical Center, Boston, MA, USA.
¹⁴ Department of Adult Hematology, Necker-Enfants Malades Hospital, APHP, Paris, France.
¹⁵ Imagine Institute, Paris, France.
¹⁶ Collège de France, Paris, France.
¹⁷ Sorbonne Université, Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, Paris, France.

PMID: 35333544
DOI: 10.1126/sciimmunol.abi7160

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_H2, 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_H2 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_H2 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.

PubMed Disclaimer

Cited by

Inborn errors of human IKAROS: LOF and GOF variants associated with primary immunodeficiency.
Kuehn HS, Boast B, Rosenzweig SD. Kuehn HS, et al. Clin Exp Immunol. 2023 Apr 25;212(2):129-136. doi: 10.1093/cei/uxac109. Clin Exp Immunol. 2023. PMID: 36433803 Free PMC article. Review.
Atopic manifestations of inborn errors of immunity.
Sams L, Wijetilleka S, Ponsford M, Gennery A, Jolles S. Sams L, et al. Curr Opin Allergy Clin Immunol. 2023 Dec 1;23(6):478-490. doi: 10.1097/ACI.0000000000000943. Epub 2023 Sep 26. Curr Opin Allergy Clin Immunol. 2023. PMID: 37755421 Free PMC article. Review.
IKAROS-how many feathers have you lost: mild and severe phenotypes in IKZF1 deficiency.
Strauss T, Körholz J, Kuehn HS, Gil Silva AA, Taube F, Trautmann-Grill K, Stittrich A, Pietzsch L, Wiedemuth R, Wahn V, von Bernuth H, Rosenzweig SD, Fasshauer M, Krüger R, Schuetz C. Strauss T, et al. Front Pediatr. 2024 May 9;12:1345730. doi: 10.3389/fped.2024.1345730. eCollection 2024. Front Pediatr. 2024. PMID: 38813543 Free PMC article.
A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development.
Okuyama K, Yamashita M, Koumoundourou A, Wiegreffe C, Ohno-Oishi M, Murphy SJH, Zhao X, Yoshida H, Ebihara T, Satoh-Takayama N, Kojo S, Ohno H, Morio T, Wu Y, Puck J, Xue HH, Britsch S, Taniuchi I. Okuyama K, et al. Nat Immunol. 2024 Dec;25(12):2284-2296. doi: 10.1038/s41590-024-01997-5. Epub 2024 Nov 1. Nat Immunol. 2024. PMID: 39487351
IKAROS Family Transcription Factors in Lymphocyte Differentiation and Function.
Kastner P, Chan S. Kastner P, et al. Adv Exp Med Biol. 2024;1459:33-52. doi: 10.1007/978-3-031-62731-6_2. Adv Exp Med Biol. 2024. PMID: 39017838 Review.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Atypon
- Ovid Technologies, Inc.
Other Literature Sources
- H1 Connect

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Affiliations

Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Authors

Affiliations

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources