Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation

L Sereni, MC Castiello, Francesco Marangoni, A Anselmo, D di Silvestre, S Motta, E Draghici, S Mantero, AJ Thrasher, S Giliani, A Aiuti, P Mauri, Luigi Daniele Notarangelo, M Bosticardo, A Villa

Research output: Contribution to journalArticlepeer-review


© 2018 American Academy of Allergy, Asthma & Immunology Background: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections, and susceptibility to autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. Objective: To dissect the basis of the WAS platelet defect, we used a novel conditional mouse model (CoWas) lacking Wiskott-Aldrich syndrome protein (WASp) only in the megakaryocytic lineage in the presence of a normal immunologic environment, and in parallel we analyzed samples obtained from patients with WAS. Methods: Phenotypic and functional characterization of megakaryocytes and platelets in mutant CoWas mice and patients with WAS with and without autoantibodies was performed. Platelet antigen expression was examined through a protein expression profile and cluster proteomic interaction network. Platelet immunogenicity was tested by using ELISAs and B-cell and platelet cocultures. Results: CoWas mice showed increased megakaryocyte numbers and normal thrombopoiesis in vitro, but WASp-deficient platelets had short lifespan and high expression of activation markers. Proteomic analysis identified signatures compatible with defects in cytoskeletal reorganization and metabolism yet surprisingly increased antigen-processing capabilities. In addition, WASp-deficient platelets expressed high levels of surface and soluble CD40 ligand and were capable of inducing B-cell activation in vitro. WASp-deficient platelets were highly immunostimulatory in mice and triggered the generation of antibodies specific for WASp-deficient platelets, even in the context of a normal immune system. Patients with WAS also showed platelet hyperactivation and increased plasma soluble CD40 ligand levels correlating with the presence of autoantibodies. Conclusion: Overall, these findings suggest that intrinsic defects in WASp-deficient platelets decrease their lifespan and dysregulate immune responses, corroborating the role of platelets as modulators of inflammation and immunity. © 2018 American Academy of Allergy, Asthma & Immunology
Original languageEnglish
Pages (from-to)1272-1284
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Issue number4
Publication statusPublished - 2018


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