Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein.
Wiskott-Aldrich Syndrome protein (WASP) is a key regulator of the actin cytoskeleton in hematopoietic cells. Defective expression of WASP leads to multiple abnormalities in different hematopoietic cells. Despite severe impairment of T cell function, WAS patients exhibit a high prevalence of autoimmu...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0086942 |
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| author | Marita Bosticardo Silvia Musio Elena Fontana Stefano Angiari Elena Draghici Gabriela Constantin Pietro L Poliani Rosetta Pedotti Anna Villa |
| author_facet | Marita Bosticardo Silvia Musio Elena Fontana Stefano Angiari Elena Draghici Gabriela Constantin Pietro L Poliani Rosetta Pedotti Anna Villa |
| author_sort | Marita Bosticardo |
| collection | DOAJ |
| description | Wiskott-Aldrich Syndrome protein (WASP) is a key regulator of the actin cytoskeleton in hematopoietic cells. Defective expression of WASP leads to multiple abnormalities in different hematopoietic cells. Despite severe impairment of T cell function, WAS patients exhibit a high prevalence of autoimmune disorders. We attempted to induce EAE, an animal model of organ-specific autoimmunity affecting the CNS that mimics human MS, in Was(-/-) mice. We describe here that Was(-/-) mice are markedly resistant against EAE, showing lower incidence and milder score, reduced CNS inflammation and demyelination as compared to WT mice. Microglia was only poorly activated in Was(-/-) mice. Antigen-induced T-cell proliferation, Th-1 and -17 cytokine production and integrin-dependent adhesion were increased in Was(-/-) mice. However, adoptive transfer of MOG-activated T cells from Was(-/-) mice in WT mice failed to induce EAE. Was(-/-) mice were resistant against EAE also when induced by adoptive transfer of MOG-activated T cells from WT mice. Was(+/-) heterozygous mice developed an intermediate clinical phenotype between WT and Was(-/-) mice, and they displayed a mixed population of WASP-positive and -negative T cells in the periphery but not in their CNS parenchyma, where the large majority of inflammatory cells expressed WASP. In conclusion, in absence of WASP, T-cell responses against a CNS autoantigen are increased, but the ability of autoreactive T cells to induce CNS autoimmunity is impaired, most probably because of an inefficient T-cell transmigration into the CNS and defective CNS resident microglial function. |
| format | Article |
| id | doaj-art-0258c4233d0d43f88b93b3773fcfbedb |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-0258c4233d0d43f88b93b3773fcfbedb2025-08-20T03:46:24ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0191e8694210.1371/journal.pone.0086942Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein.Marita BosticardoSilvia MusioElena FontanaStefano AngiariElena DraghiciGabriela ConstantinPietro L PolianiRosetta PedottiAnna VillaWiskott-Aldrich Syndrome protein (WASP) is a key regulator of the actin cytoskeleton in hematopoietic cells. Defective expression of WASP leads to multiple abnormalities in different hematopoietic cells. Despite severe impairment of T cell function, WAS patients exhibit a high prevalence of autoimmune disorders. We attempted to induce EAE, an animal model of organ-specific autoimmunity affecting the CNS that mimics human MS, in Was(-/-) mice. We describe here that Was(-/-) mice are markedly resistant against EAE, showing lower incidence and milder score, reduced CNS inflammation and demyelination as compared to WT mice. Microglia was only poorly activated in Was(-/-) mice. Antigen-induced T-cell proliferation, Th-1 and -17 cytokine production and integrin-dependent adhesion were increased in Was(-/-) mice. However, adoptive transfer of MOG-activated T cells from Was(-/-) mice in WT mice failed to induce EAE. Was(-/-) mice were resistant against EAE also when induced by adoptive transfer of MOG-activated T cells from WT mice. Was(+/-) heterozygous mice developed an intermediate clinical phenotype between WT and Was(-/-) mice, and they displayed a mixed population of WASP-positive and -negative T cells in the periphery but not in their CNS parenchyma, where the large majority of inflammatory cells expressed WASP. In conclusion, in absence of WASP, T-cell responses against a CNS autoantigen are increased, but the ability of autoreactive T cells to induce CNS autoimmunity is impaired, most probably because of an inefficient T-cell transmigration into the CNS and defective CNS resident microglial function.https://doi.org/10.1371/journal.pone.0086942 |
| spellingShingle | Marita Bosticardo Silvia Musio Elena Fontana Stefano Angiari Elena Draghici Gabriela Constantin Pietro L Poliani Rosetta Pedotti Anna Villa Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein. PLoS ONE |
| title | Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein. |
| title_full | Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein. |
| title_fullStr | Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein. |
| title_full_unstemmed | Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein. |
| title_short | Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein. |
| title_sort | development of central nervous system autoimmunity is impaired in the absence of wiskott aldrich syndrome protein |
| url | https://doi.org/10.1371/journal.pone.0086942 |
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