Development of central nervous system autoimmunity is impaired in the absence of wiskott-aldrich syndrome protein

Marita Bosticardo, Silvia Musio, Elena Fontana, Stefano Angiari, Elena Draghici, Gabriela Constantin, Pietro L. Poliani, Rosetta Pedotti, Anna Villa

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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.

Original languageEnglish
Article numbere86942
JournalPLoS One
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 23 2014

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Bosticardo, M., Musio, S., Fontana, E., Angiari, S., Draghici, E., Constantin, G., Poliani, P. L., Pedotti, R., & Villa, A. (2014). Development of central nervous system autoimmunity is impaired in the absence of wiskott-aldrich syndrome protein. PLoS One, 9(1), [e86942]. https://doi.org/10.1371/journal.pone.0086942