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OVERACTIVE WASP IN X-LINKED NEUTROPENIA LEADS TO ABERRANT B-CELL DIVISION AND ACCELERATED PLASMA CELL GENERATION
Minghui, He et al. | Date Issued: 2022
Author
Minghui, He
Saeed, Mezida B.
Record, Julien
Keszei, Marton
Pinho, Lia Gonc¸alves
Fontes, Larissa Vasconcelos
D`Aurelio, Roberta
Vieira, Raissa
Oliveira, Mariana M. S.
Geyer, Chiara
Bohaumilitzky, Lena
Thiemann, Meike
Deordieva, Ekaterina
Buedts, Lieselot
Lopes, Joao Pedro Matias
Pershin, Dmitry
Hammarström, Lennart
Xia, Yu
Zhao, Xiaodong
Cunningham-Rundles, Charlotte
Thrasher, Adrian J.
Burns, Siobhan O.
Almeida, Vinicius Cotta de
Liu, Chaohong
Shcherbina, Anna
Vandenberghe, Peter
Westerberg, Lisa S.
Affilliation
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm / Fundação Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm / Fundação Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm.
The Department of Immunology, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow
Center for Human Genetics, University Hospital Leuven, Leuven
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York / Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, UH Rainbow Babies and Children’s Hospital, Cleveland.
Department of Immunology, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow.
Department of Laboratory Medicine, Karolinska Institutet, Stockholm.
Department of Rheumatology and Immunology, Shenzhen Children’s Hospital, Shenzhen.
Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA.
UCL Great Ormond Street Institute of Child Health, London / Great Ormond Street Hospital for Children NHS Foundation Trust, London.
Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing / Institute of Immunity and Transplantation, University College London, London.
Fundação Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.
Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan.
Department of Immunology, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow.
Center for Human Genetics, University Hospital Leuven, Leuven.
Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing.
Abstract
Background: B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA. Objective: We investigated the role of B cells in XLN pathogenesis. Methods: We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response. Results: XLN patients had normal naive B cells and plasmablasts, but reduced IgA1 B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells. Conclusions: Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching. (
Keywords in Portuguese
Células B
Neutropenia ligada ao X
Actina
Vespa
IgA
Centro germinativo
Células plasmáticas
Imunodeficiência primária
 
Keywords
B cells
X-linked neutropenia
Actin
WASp
IgA
Germinal center
Plasma cells
Primary immunodeficiency
 
Publisher
Elsevier
Citation
Minghui, He et al. Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation. J. Allergy Clin. Immunol., v. 149, n. 3, p. 1 - 16, Mar. 2022.
DOI
10.1016/j.jaci.2021.07.033
ISSN
0091-6749