Journal of Clinical Immunology

, Volume 39, Issue 4, pp 353–357 | Cite as

IKZF1 Loss-of-Function Variant Causes Autoimmunity and Severe Familial Antiphospholipid Syndrome

  • Yannick Dieudonné
  • Aurélien Guffroy
  • Olivier Vollmer
  • Raphael Carapito
  • Anne-Sophie KorganowEmail author
Letter to the Editor

To the Editor,

Ikaros is a transcription factor with key roles in lymphocyte development and homeostasis. It is encoded by the IKAROS family zinc finger protein 1 (IKZF1) gene, which contains highly conserved N-terminal and C-terminal zinc finger domains and is highly expressed in hematopoietic cells. The functions of Ikaros were first illustrated in different sets of IKZF1-deficient mice. In humans, IKZF1 loss-of-function (LOF) somatic variants are associated with leukemogenesis in B cell acute lymphoblastic leukemia (B-ALL) [1]. More recently, different germline heterozygous variants, acting either by haploinsufficiency or by a dominant negative effect in IKZF1, were identified in autosomal dominant forms of common variable immunodeficiencies (CVID) or combined immunodeficiencies (CID) [2, 3, 4]. A series of families showed a progressive loss of B cells and hypogammaglobulinemia, but the absence of symptoms in several mutated patients suggests an incomplete penetrance. Additional...



We thank C. Bole and S. Hanein (Institut Imagine) for exome sequencing. We thank JL Pasquali and P Kieffer for clinical data. We thank S. Bahram for critical reading. We thank S Jung for her helpful comments.

Funding Information

A.S.K., A. G, and Y. D are supported by grants from the French Ministry of Health (PHRC IR 2011), from the Société Nationale Française de Médecine Interne (SNFMI), from the Hôpitaux Universitaires de Strasbourg (HUS), and from the EU-funded (ERDF) project INTERREG V “RARENET.” R.C. is supported by the Agence Nationale de la Recherche (ANR) (ANR-11-LABX-0070_TRANSPLANTEX), MSD Avenir, and the INTERREG V European regional development fund (European Union) program (project 3.2 TRIDIAG).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

10875_2019_643_MOESM1_ESM.docx (537 kb)
ESM 1 (DOCX 537 kb)


  1. 1.
    Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–4.CrossRefPubMedGoogle Scholar
  2. 2.
    Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, et al. Loss of B cells in patients with heterozygous mutations in IKAROS. N Engl J Med. 2016;374:1032–43.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Boutboul D, Kuehn HS, Van de Wyngaert Z, Niemela JE, Callebaut I, Stoddard J, et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest. 2018;128:3071–87.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bogaert DJ, Kuehn HS, Bonroy C, Calvo KR, Dehoorne J, Vanlander AV, et al. A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects. J Allergy Clin Immunol. 2018;141:432–5 e7.CrossRefPubMedGoogle Scholar
  5. 5.
    Van Nieuwenhove E, Garcia-Perez JE, Helsen C, Rodriguez PD, van Schouwenburg PA, Dooley J, et al. A kindred with mutant IKAROS and autoimmunity. J Allergy Clin Immunol. 2018;142:699–702 e12.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hoshino A, Okada S, Yoshida K, Nishida N, Okuno Y, Ueno H, et al. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J Allergy Clin Immunol. 2017;140:223–31.CrossRefPubMedGoogle Scholar
  7. 7.
    Eskandarian Z, Fliegauf M, Bulashevska A, Proietti M, Hague R, Smulski CR, et al. Assessing the functional relevance of variants in the IKAROS family zinc finger protein 1 (IKZF1) in a cohort of patients with primary immunodeficiency. Front Immunol. 2019;10:568.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Turpin D, Furudoi A, Parrens M, Blanco P, Viallard J-F, Duluc D. Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications. Clin Immunol. 2018;197:130–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Fischer A, Provot J, Jais J-P, Alcais A, Mahlaoui N, Adoue D, et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140:1388–93 e8.CrossRefPubMedGoogle Scholar
  10. 10.
    Kirstetter P, Thomas M, Dierich A, Kastner P, Chan S. Ikaros is critical for B cell differentiation and function. Eur J Immunol. 2002;32:720–30.CrossRefPubMedGoogle Scholar
  11. 11.
    Macias-Garcia A, Heizmann B, Sellars M, Marchal P, Dali H, Pasquali J-L, et al. Ikaros is a negative regulator of B1 cell development and function. J Biol Chem. 2016;291:9073–86.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wojcik H, Griffiths E, Staggs S, Hagman J, Winandy S. Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis. Eur J Immunol. 2007;37:1022–32.CrossRefPubMedGoogle Scholar
  13. 13.
    Unger S, Seidl M, van Schouwenburg P, Rakhmanov M, Bulashevska A, Frede N, et al. The T H 1 phenotype of follicular helper T cells indicates an IFN-γ–associated immune dysregulation in patients with CD21low common variable immunodeficiency. J Allergy Clin Immunol. 2018;141:730–40.CrossRefPubMedGoogle Scholar
  14. 14.
    He C-F, Liu Y-S, Cheng Y-L, Gao J-P, Pan T-M, Han J-W, et al. TNIP1, SLC15A4, ETS1, RasGRP3 and IKZF1 are associated with clinical features of systemic lupus erythematosus in a Chinese Han population. Lupus. 2010;19:1181–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Wang C, Ahlford A, Järvinen TM, Nordmark G, Eloranta M-L, Gunnarsson I, et al. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J Hum Genet. 2013;21:994–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Legault K, Schunemann H, Hillis C, Yeung C, Akl EA, Carrier M, et al. McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome. J Thromb Haemost JTH. 2018;16:1656–64.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.CNRS UPR 3572, Immunopathology and Therapeutic Chemistry, Laboratory of Excellence MedalisInstitute of Molecular and Cellular Biology (IBMC)Strasbourg CedexFrance
  2. 2.Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune DiseasesHôpitaux Universitaires de StrasbourgStrasbourgFrance
  3. 3.UFR MédecineUniversité de StrasbourgStrasbourgFrance
  4. 4.Laboratoire d’ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEXUniversité de StrasbourgStrasbourgFrance
  5. 5.Service d’Immunologie Biologique, Plateau Technique de Biologie, Pôle de BiologieNouvel Hôpital CivilStrasbourgFrance

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