Mice Lacking Wasp-Interacting Protein Evolve Anti-Platelet IgAs That Impair Platelet Responses Mediated by the Collagen Receptor GPVI.

Wiskott-Aldrich Syndrome (WAS) is a hematopoietic disorder characterized by immune deficiency, eczema and severe thrombocytopenia with small platelets. However, the role of the WAS protein (WASp), mutated or absent in WAS, is unclear in platelets because platelets that lack WASp function normally. WASp constitutively associates with WIP in resting and activated platelets. We investigated the role of the platelet WIP-WASp complex by using mice that lack either WIP or WASp. WIP knockout (KO) platelets lack WASp and WIP expression is reduced in WASp KO platelets, indicating a requirement for both proteins for each other’s integrity. WIP KO, but not WASp KO mice evolve platelet-associated antibodies of the IgA class, as evidenced by immunoblot analysis and flow cytometry. We present evidence that platelet-associated IgAs specifically target the collagen receptor GPVI in WIP KO mice:

1. protein tyrosine phosphorylation, including that of phospholipase C-γ2, and calcium mobilization are impaired in IgA-presenting WIP KO platelets stimulated through GPVI, resulting in α-granule secretion, integrin αIIbβ3 activation and actin assembly defects;

2. binding of the anti-GPVI antibody JAQ1 to normally expressed GPVI is reduced in IgA-presenting WIP KO platelets;

3. JAQ1 induces the irreversible loss of GPVI from circulating platelets in WT mice, but not in WIP KO mice that bear anti-platelet IgAs.

Together, the data indicate that platelet-associated IgAs negatively modulate GPVI signaling in WIP KO mice.