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Bosticardo, M; Musio, S; Fontana, E; Angiari, S; Draghici, E; Constantin, G; Poliani, PL; Pedotti, R; Villa, A.
Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein.
PLoS One. 2014; 9(1): e86942-e86942. Doi: 10.1371/journal.pone.0086942 [OPEN ACCESS]
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Co-authors Med Uni Graz: Angiari Stefano
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Abstract:: 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.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Autoimmunity - immunology; Blotting, Western -; Cell Adhesion -; Cell Movement -; Cell Proliferation -; Cells, Cultured -; Central Nervous System - immunology; Central Nervous System - metabolism; Cytokines - metabolism; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Female -; Humans -; Immunoenzyme Techniques -; Integrins - metabolism; Lymphocyte Activation - immunology; Male -; Mice -; Mice, Inbred C57BL -; Mice, Knockout -; Microglia -; Myelin Sheath -; Wiskott-Aldrich Syndrome Protein - physiology