Enhanced CD19 Activity in B Cells Contributes to Immunodeficiency in Mice Deficient in the ICF Syndrome Gene Zbtb24

Authors

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

Publication Date

12-1-2023

Journal

Cellular & Molecular Immunology

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.

Keywords

Agammaglobulinemia, Nuclear Proteins, Mice, Mutation, DNA Methylation, Face, Humans, Primary Immunodeficiency Diseases, Immunologic Deficiency Syndromes, Animals, Repressor Proteins, ICF syndrome, ZBTB24, CD19, IL-5Ra, hypogammaglobulinemia, Immunology, Immunological deficiency syndromes

Comments

This article has been corrected. See Cell Mol Immunol. 2023 Dec 20;21(1):100.

DOI

10.1038/s41423-023-01106-w

PMID

37990035

PMCID

PMC10687020

PubMedCentral® Posted Date

11-22-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes