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

作者全名："Ying, Zhengzhou; Hardikar, Swanand; Plummer, Joshua B.; Hamidi, Tewfik; Liu, Bin; Chen, Yueping; Shen, Jianjun; Mu, Yunxiang; McBride, Kevin M.; Chen, Taiping"

作者地址："[Ying, Zhengzhou; Hardikar, Swanand; Plummer, Joshua B.; Hamidi, Tewfik; Liu, Bin; Chen, Yueping; Shen, Jianjun; Mu, Yunxiang; McBride, Kevin M.; Chen, Taiping] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA; [Liu, Bin; Shen, Jianjun; McBride, Kevin M.; Chen, Taiping] Univ Texas MD Anderson Canc Ctr, UTHealth Grad Sch Biomed Sci, Program Genet & Epigenet, Houston, TX 77030 USA; [Ying, Zhengzhou] Chongqing Med Univ, Coll Lab Med, Key Lab Lab Med Diagnost, Minist Educ, Chongqing 400016, Peoples R China"

通信作者："McBride, KM; Chen, TP (通讯作者)，Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA.; McBride, KM; Chen, TP (通讯作者)，Univ Texas MD Anderson Canc Ctr, UTHealth Grad Sch Biomed Sci, Program Genet & Epigenet, Houston, TX 77030 USA."

来源：CELLULAR & MOLECULAR IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001109294600002

JCR分区：Q1

影响因子：21.8

年份：2023

卷号：20

期号：12

开始页：1487

结束页：1498

文献类型：Article; Early Access

关键词：ICF syndrome; ZBTB24; CD19; IL-5Ra; hypogammaglobulinemia

摘要："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."

基金机构："U.S. Department of Health & Human Services | National Institutes of Health (NIH) [1R01AI12140301A1, CA16672]; National Institutes of Health (NIH), Core Facility Support Award [RP170002]; Cancer Prevention and Research Institute of Texas (CPRIT); Center for Cancer Epigenetics (CCE) at MD Anderson Cancer Center; Sam and Freda Davis Fund"

基金资助正文："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."