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Enhanced CD19 activity in B cells contributes to immunodeficiency in mice deficient in the ICF syndrome gene Zbtb24

Cellular & Molecular Immunology volume 20, pages 1487–1498 (2023)Cite this article

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A Correction to this article was published on 20 December 2023

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Abstract

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM, IgG1, and IgA. Zbtb24-deficient mice are hyper and hypo-responsive to T-dependent and T-independent type 2 antigens, respectively, and marginal zone B-cell activation is impaired. Mechanistically, Zbtb24-deficient B cells show severe loss of DNA methylation in the promoter region of Il5ra (interleukin-5 receptor subunit alpha), and Il5ra derepression leads to elevated CD19 phosphorylation. Heterozygous disruption of Cd19 can revert the hypogammaglobulinemia phenotype of Zbtb24-deficient mice. Our results suggest the potential role of enhanced CD19 activity in immunodeficiency in ICF syndrome.

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Acknowledgements

We thank Drs. Margarida Albuquerque Almeida Santos and Momoko Yoshimoto-Kobayashi for discussions and Ms. Zaowen Chen for technical assistance. The work was supported by grants (1R01AI12140301A1 to TC; CA16672 to CCSG Cores at MD Anderson Cancer Center) from National Institutes of Health (NIH), Core Facility Support Award (RP170002 to JS) from Cancer Prevention and Research Institute of Texas (CPRIT), and next-generation sequencing (NGS) allowances from the Center for Cancer Epigenetics (CCE) at MD Anderson Cancer Center. ZY received a fellowship from the Sam and Freda Davis Fund. TH received a CCE Scholarship.

Funding

This study was supported by a grant (1R01AI12140301A1) from the National Institutes of Health (NIH) in the USA.

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  1. Zhengzhou Ying

    Present address: The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China

Authors and Affiliations

  1. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Zhengzhou Ying, Swanand Hardikar, Joshua B. Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M. McBride & Taiping Chen

  2. Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA

    Bin Liu, Jianjun Shen, Kevin M. McBride & Taiping Chen

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Contributions

ZY, KMM, and TC designed the research and wrote the manuscript; ZY, SH, JBP, TH, and YM performed the experiments; YC and JS performed the RNA-Seq; BL performed the bioinformatics analysis; ZY, YM, KMM, and TC analyzed the data.

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Correspondence to Kevin M. McBride or Taiping Chen.

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The original online version of this article was revised: In the sentence beginning ‘To trace cell proliferation, FO and MZ B cells’ and the sentence beginning ‘For cell activation, naïve B cells or CH12F3 cells’ in this article, the [10 ng/ml] ‘F(ab’)2 fragment goat anti-mouse IgM’ should have read ‘10 μg/ml F(ab’)2 fragment goat anti-mouse IgM’. The original article has been corrected.

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Ying, Z., Hardikar, S., Plummer, J.B. et al. Enhanced CD19 activity in B cells contributes to immunodeficiency in mice deficient in the ICF syndrome gene Zbtb24. Cell Mol Immunol 20, 1487–1498 (2023). https://doi.org/10.1038/s41423-023-01106-w

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