Lang, PA; Brenner, D; Mak, TW; Ohashi, PS; Shaabani, N; Honke, N; Meryk, A; ... Bouma, G; + view all Lang, PA; Brenner, D; Mak, TW; Ohashi, PS; Shaabani, N; Honke, N; Meryk, A; Häussinger, D; Lang, KS; Borkens, S; Scheu, S; Barthuber, C; Booth, S; Griffiths, GM; Recher, M; Thrasher, AJ; Bouma, G; - view fewer (2013) Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency. Journal of Allergy and Clinical Immunology , 131 (3) 815-824.e2. 10.1016/j.jaci.2012.08.050.

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Abstract

Background: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by absence of Wiskott-Aldrich syndrome protein (WASP) expression, resulting in defective function of many immune cell lineages and susceptibility to severe bacterial, viral, and fungal infections. Despite a significant proportion of patients with WAS having recurrent viral infections, surprisingly little is known about the effects of WASP deficiency on antiviral immunity. Objective: We sought to evaluate the antiviral immune response in patients with WASP deficiency in vivo. Methods: Viral clearance and associated immunopathology were measured after infection of WASP-deficient (WAS KO) mice with lymphocytic choriomeningitis virus (LCMV). Induction of antiviral CD8 T-cell immunity and cytotoxicity was documented in WAS KO mice by means of temporal enumeration of total and antigen-specific T-cell numbers. Type I interferon (IFN-I) production was measured in serum in response to LCMV challenge and characterized in vivo by using IFN-I reporter mice crossed with WAS KO mice. Results: WAS KO mice showed reduced viral clearance and enhanced immunopathology during LCMV infection. This was attributed to both an intrinsic CD8 T-cell defect and defective priming of CD8 T cells by dendritic cells (DCs). IFN-I production by WAS KO DCs was reduced both in vivo and in vitro. Conclusions: These studies use a well-characterized model of persistence-prone viral infection to reveal a critical deficiency of CD8 T-cell responses in murine WASP deficiency, in which abrogated production of IFN-I by DCs might play an important contributory role. These findings might help us to understand the immunodeficiency of WAS. © 2012 American Academy of Allergy, Asthma & Immunology.

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