Characterization of a mouse model of ICF syndrome reveals enhanced CD19 activation in inducing hypogammaglobulinemia.

Unlabelled: 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 or . 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 for in the hematopoietic lineage recapitulate major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of does not affect lymphocyte development but results in reduced plasma cells and low levels of IgM, IgG1 and IgA. -deficient mice are hyper- and hypo-responsive to T-dependent and Tindependent type 2 antigens, respectively, and marginal zone B cell activation is impaired. B cells from -deficient mice display elevated CD19 phosphorylation. Heterozygous disruption of can revert the hypogammaglobulinemia phenotype in these mice. Mechanistically, (interleukin-5 receptor subunit alpha) is derepressed in -deficient B cells, and elevated IL-5 signaling enhances CD19 phosphorylation. Our results reveal a novel link between IL-5 signaling and CD19 activation and suggest that abnormal CD19 activity contributes to immunodeficiency in ICF syndrome.

Significance Statement: ICF syndrome is a rare immunodeficiency disorder first reported in the 1970s. The lack of appropriate animal models has hindered the investigation of the pathogenesis of antibody deficiency, the major cause of death in ICF syndrome. Here we show that, in mice, disruption of , one of the ICF-related genes, in the hematopoietic lineage results in low levels of immunoglobulins. Characterization of these mice reveals abnormal B cell activation due to elevated CD19 phosphorylation. Mechanistically, (interleukin-5 receptor subunit alpha) is derepressed in -deficient B cells, and increased IL-5 signaling enhances CD19 phosphorylation.