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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-05-01
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| Series: | Frontiers in Immunology |
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| 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 |
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-16T17:57:33Z |
| format | Article |
| id | doaj.art-c14f7a2eaf3f45258aa3ece941eee02d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T17:57:33Z |
| publishDate | 2017-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c14f7a2eaf3f45258aa3ece941eee02d2022-12-21T22:22:08ZengFrontiers 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 |
| 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 |
| title | 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_short | 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 |
| 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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