In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B Cells

Wiskott–Aldrich syndrome (WAS) is a primary immunodeficiency caused by mutations in the gene encoding the hematopoietic-specific WAS protein (WASp). WAS is frequently associated with autoimmunity, indicating a critical role of WASp in maintenance of tolerance. The role of B cells in the induction of...

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Main Authors: Anna Villa, Marita Bosticardo, Maria Carmina Castiello, Francesca Pala, Lucia Sereni, Elena Draghici, Donato Inverso, Aisha V. Sauer, Francesca Schena, Elena Fontana, Enrico Radaelli, Paolo Uva, Karla E. Cervantes-Luevano, Federica Benvenuti, Pietro L. Poliani, Matteo Iannacone, Elisabetta Traggiai
Format: Article
Language:English
Published: Frontiers Media S.A. 2017-05-01
Series:Frontiers in Immunology
Subjects:
Online Access:http://journal.frontiersin.org/article/10.3389/fimmu.2017.00490/full
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author Anna Villa
Anna Villa
Marita Bosticardo
Maria Carmina Castiello
Francesca Pala
Lucia Sereni
Lucia Sereni
Elena Draghici
Donato Inverso
Aisha V. Sauer
Francesca Schena
Elena Fontana
Enrico Radaelli
Paolo Uva
Karla E. Cervantes-Luevano
Federica Benvenuti
Pietro L. Poliani
Matteo Iannacone
Matteo Iannacone
Matteo Iannacone
Elisabetta Traggiai
spellingShingle Anna Villa
Anna Villa
Marita Bosticardo
Maria Carmina Castiello
Francesca Pala
Lucia Sereni
Lucia Sereni
Elena Draghici
Donato Inverso
Aisha V. Sauer
Francesca Schena
Elena Fontana
Enrico Radaelli
Paolo Uva
Karla E. Cervantes-Luevano
Federica Benvenuti
Pietro L. Poliani
Matteo Iannacone
Matteo Iannacone
Matteo Iannacone
Elisabetta Traggiai
In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B Cells
Frontiers in Immunology
Wiskott–Aldrich syndrome
autoimmunity
B cells
toll-like receptors
apoptotic cells
lymphocytic choriomeningitis virus
author_facet Anna Villa
Anna Villa
Marita Bosticardo
Maria Carmina Castiello
Francesca Pala
Lucia Sereni
Lucia Sereni
Elena Draghici
Donato Inverso
Aisha V. Sauer
Francesca Schena
Elena Fontana
Enrico Radaelli
Paolo Uva
Karla E. Cervantes-Luevano
Federica Benvenuti
Pietro L. Poliani
Matteo Iannacone
Matteo Iannacone
Matteo Iannacone
Elisabetta Traggiai
author_sort Anna Villa
title In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B Cells
title_short In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B Cells
title_full In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B Cells
title_fullStr In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B Cells
title_full_unstemmed In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B Cells
title_sort in vivo chronic stimulation unveils autoreactive potential of wiskott–aldrich syndrome protein-deficient b cells
publisher Frontiers Media S.A.
series Frontiers in Immunology
issn 1664-3224
publishDate 2017-05-01
description Wiskott–Aldrich syndrome (WAS) is a primary immunodeficiency caused by mutations in the gene encoding the hematopoietic-specific WAS protein (WASp). WAS is frequently associated with autoimmunity, indicating a critical role of WASp in maintenance of tolerance. The role of B cells in the induction of autoreactive immune responses in WAS has been investigated in several settings, but the mechanisms leading to the development of autoimmune manifestations have been difficult to evaluate in the mouse models of the disease that do not spontaneously develop autoimmunity. We performed an extensive characterization of Was−/− mice that provided evidence of the potential alteration in B cell selection, because of the presence of autoantibodies against double-stranded DNA, platelets, and tissue antigens. To uncover the mechanisms leading to the activation of the potentially autoreactive B cells in Was−/− mice, we performed in vivo chronic stimulations with toll-like receptors agonists (LPS and CpG) and apoptotic cells or infection with lymphocytic choriomeningitis virus. All treatments led to increased production of autoantibodies, increased proteinuria, and kidney tissue damage in Was−/− mice. These findings demonstrate that a lower clearance of pathogens and/or self-antigens and the resulting chronic inflammatory state could cause B cell tolerance breakdown leading to autoimmunity in WAS.
topic Wiskott–Aldrich syndrome
autoimmunity
B cells
toll-like receptors
apoptotic cells
lymphocytic choriomeningitis virus
url http://journal.frontiersin.org/article/10.3389/fimmu.2017.00490/full
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spelling doaj-c14f7a2eaf3f45258aa3ece941eee02d2020-11-25T00:25:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-05-01810.3389/fimmu.2017.00490259615In Vivo Chronic Stimulation Unveils Autoreactive Potential of Wiskott–Aldrich Syndrome Protein-Deficient B CellsAnna Villa0Anna Villa1Marita Bosticardo2Maria Carmina Castiello3Francesca Pala4Lucia Sereni5Lucia Sereni6Elena Draghici7Donato Inverso8Aisha V. Sauer9Francesca Schena10Elena Fontana11Enrico Radaelli12Paolo Uva13Karla E. Cervantes-Luevano14Federica Benvenuti15Pietro L. Poliani16Matteo Iannacone17Matteo Iannacone18Matteo Iannacone19Elisabetta Traggiai20San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy0Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, ItalyDynamics of Immune Responses, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, ItalyLaboratory of Immunology and Rheumatic Disease, IGG, Genova, ItalyDepartment of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, ItalyVIB11 Center for the Biology of Disease, Center for Human Genetics, KU Leuven, Leuven, BelgiumCRS4, Science and Technology Park Polaris, Pula, ItalyCellular Immunology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, ItalyCellular Immunology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, ItalyDepartment of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, ItalyVita-Salute San Raffaele University, Milan, ItalyDynamics of Immune Responses, Division of Immunology, IRCCS San Raffaele Scientific Institute, Milan, ItalyExperimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, ItalyLaboratory of Immunology and Rheumatic Disease, IGG, Genova, ItalyWiskott–Aldrich syndrome (WAS) is a primary immunodeficiency caused by mutations in the gene encoding the hematopoietic-specific WAS protein (WASp). WAS is frequently associated with autoimmunity, indicating a critical role of WASp in maintenance of tolerance. The role of B cells in the induction of autoreactive immune responses in WAS has been investigated in several settings, but the mechanisms leading to the development of autoimmune manifestations have been difficult to evaluate in the mouse models of the disease that do not spontaneously develop autoimmunity. We performed an extensive characterization of Was−/− mice that provided evidence of the potential alteration in B cell selection, because of the presence of autoantibodies against double-stranded DNA, platelets, and tissue antigens. To uncover the mechanisms leading to the activation of the potentially autoreactive B cells in Was−/− mice, we performed in vivo chronic stimulations with toll-like receptors agonists (LPS and CpG) and apoptotic cells or infection with lymphocytic choriomeningitis virus. All treatments led to increased production of autoantibodies, increased proteinuria, and kidney tissue damage in Was−/− mice. These findings demonstrate that a lower clearance of pathogens and/or self-antigens and the resulting chronic inflammatory state could cause B cell tolerance breakdown leading to autoimmunity in WAS.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00490/fullWiskott–Aldrich syndromeautoimmunityB cellstoll-like receptorsapoptotic cellslymphocytic choriomeningitis virus