Development of Central Nervous System Autoimmunity Is Impaired in the Absence of Wiskott-Aldrich Syndrome Protein

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

doi:10.1371/journal.pone.0086942

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.

Highlights

Wiskott-Aldrich syndrome (WAS) is a severe X-linked disorder characterized by microthrombocytopenia, eczema, immunodeficiency and increased risk of developing autoimmunity and lymphomas [1]
Was2/2 mice are resistant against EAE To study the development of autoimmune CNS demyelination in Wiskott-Aldrich Syndrome protein (WASP) deficiency, we induced chronic EAE with MOG35–55 peptide in Was2/2 and WT control mice
Immunostains for CD3 and Iba-1 revealed a dramatic decrease of T cells infiltrating the CNS parenchyma (Figure 1C, upper panels) in Was2/2 mice as compared to WT mice, and microglial cells, which in WT mice with EAE were intensely activated and expressed WASP (Figure S1), were only weakly or not activated in the CNS of Was2/2 mice (Figure 1C, lower panels)

Summary

Introduction

Wiskott-Aldrich syndrome (WAS) is a severe X-linked disorder characterized by microthrombocytopenia, eczema, immunodeficiency and increased risk of developing autoimmunity and lymphomas [1]. As a consequence of impaired signaling through the TCR and co-stimulatory molecules, WASP-deficient T cells show defective proliferation and decreased secretion of IL-2 and Th-1 cytokines [7,8]. These findings might help explaining the unbalanced Th1/ Th2 cytokine production observed in patients and in the murine counterpart [7]. The precise relationship between T-cell abnormalities and autoimmunity in WAS patients remains to be fully elucidated In these patients, as in several other primary immunodeficient (PID) patients, immunodeficiency is often accompanied by the development of autoimmune disorders [9], reported to affect 25% to 72% of patients [10,11,12], irrespectively of WASP expression levels and disease severity [12]

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Discussion

Conclusion