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 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.
TIGET, San Raffaele Scientific Institute, Milan, Italy.
Marita
M
Bosticardo
Foundation IRCCS Neurological Institute "C.Besta", Neuroimmunology and Neuromuscular Disorders Unit, Milan, Italy.
Silvia
S
Musio
Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy.
Elena
E
Fontana
Department of Pathology and Diagnosis, Section of General Pathology, University of Verona, Verona, Italy.
Stefano
S
Angiari
TIGET, San Raffaele Scientific Institute, Milan, Italy.
Elena
E
Draghici
Department of Pathology and Diagnosis, Section of General Pathology, University of Verona, Verona, Italy.
Gabriela
G
Constantin
Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy.
Pietro L
PL
Poliani
Foundation IRCCS Neurological Institute "C.Besta", Neuroimmunology and Neuromuscular Disorders Unit, Milan, Italy.
Rosetta
R
Pedotti
TIGET, San Raffaele Scientific Institute, Milan, Italy ; Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy.
Anna
A
Villa
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D016023:Integrins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia; D009186:Myelin Sheath; D051316:Wiskott-Aldrich Syndrome Protein / Q000502:physiology*
D016207:Cytokines; D016023:Integrins; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein