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

I mmunodeficiency, c entromeric instability, and f acial 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.