title: The early activation of memory B cells from Wiskott-Aldrich syndrome patients is suppressed by CD19 downregulation.
abstract: Wiskott-Aldrich syndrome (WAS) pediatric patients exhibit a deficiency in humoral immune memory. However, the mechanism by which Wiskott-Aldrich syndrome protein (WASP) regulates the differentiation and activation of memory B cells remains elusive. Here we examine the early activation events of memory B cells from the peripheral blood mononuclear cells of WAS patients and age-matched healthy controls (HCs) using total internal reflection fluorescence microscopy. In response to stimulation through the B-cell receptor (BCR), memory B cells from HCs showed significantly higher magnitudes of BCR clustering and cell spreading than naive B cells from the same individuals. This was associated with increases in CD19 recruitment to the BCR and the activation of its downstream signaling molecule Btk and decreases in FcγRIIB recruitment and the activation of its downstream molecule Src homology 2-containing inositol 5' phosphatase (SHIP). However, these enhanced signaling activities mediated by CD19 and Btk are blocked in memory B cells from WAS patients, whereas the activation of FcγRIIB and SHIP was increased. Although the expression levels of CD19, Btk, and FcγRIIB did not change between CD27(-) and CD27(+) B cells of HCs, the protein and mRNA levels of CD19 but not Btk and FcγRIIB were significantly reduced in both CD27(-) and CD27(+) B cells of WAS patients, compared with those of HCs. Overall, our study suggests that WASP is required for memory B-cell activation, promoting the activation by positive regulating CD19 transcription and CD19 recruitment to the BCR.
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Bai
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Linlin
authors.initials: L
authors.lastname: Niu
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Hongyan
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Rongxin
authors.initials: R
authors.lastname: Dai
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Lina
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Intracellular Pathogens, National Institute of Allergy and Infectious Diseases, Hamilton, MT;
authors.forename: Heather
authors.initials: H
authors.lastname: Miller
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD; and.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Song
authors.affiliation: Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China;
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Liu
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002675:Child, Preschool; D015536:Down-Regulation; D006801:Humans; D007156:Immunologic Memory; D007223:Infant; D008213:Lymphocyte Activation; D009154:Mutation; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics
chemical_list: D018941:Antigens, CD19; C000604811:CD19 molecule, human; C499173:FCGR2B protein, human; D012333:RNA, Messenger; D017452:Receptors, IgG; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases