Overactive WASp in X-linked neutropenia leads to aberrant B-cell division and accelerated plasma cell generation.

Autor: He M; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address: Minghui.He@ki.se., Saeed MB; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Record J; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Keszei M; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Gonçalves Pinho L; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil., Vasconcelos-Fontes L; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil., D'Aulerio R; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Vieira R; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Oliveira MMS; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Geyer C; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Bohaumilitzky L; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Thiemann M; Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Deordieva E; Department of Immunology, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Buedts L; Center for Human Genetics, University Hospital Leuven, Leuven, Belgium., Matias Lopes JP; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY; Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, UH Rainbow Babies and Children's Hospital, Cleveland, Ohio., Pershin D; Department of Immunology, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Hammarström L; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden., Xia Y; Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, China., Zhao X; Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China., Cunningham-Rundles C; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY., Thrasher AJ; UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom., Burns SO; Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom; Institute of Immunity and Transplantation, University College London, London, United Kingdom., Cotta-de-Almeida V; Laboratory on Thymus Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil., Liu C; Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China., Shcherbina A; Department of Immunology, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia., Vandenberghe P; Center for Human Genetics, University Hospital Leuven, Leuven, Belgium., Westerberg LS; Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom. Electronic address: Lisa.Westerberg@ki.se.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Mar; Vol. 149 (3), pp. 1069-1084. Date of Electronic Publication: 2021 Aug 09.
DOI: 10.1016/j.jaci.2021.07.033
Abstrakt: 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 IgA + 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.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: