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

doi:10.1016/j.jaci.2017.12.1000

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

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article

Abstract

© 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 language	English
Pages (from-to)	1272-1284
Number of pages	13
Journal	Journal of Allergy and Clinical Immunology
Volume	142
Issue number	4
DOIs	https://doi.org/10.1016/j.jaci.2017.12.1000
Publication status	Published - 2018

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Sereni, L., Castiello, MC., Marangoni, F., Anselmo, A., di Silvestre, D., Motta, S., Draghici, E., Mantero, S., Thrasher, AJ., Giliani, S., Aiuti, A., Mauri, P., Notarangelo, L. D., Bosticardo, M., & Villa, A. (2018). Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation. Journal of Allergy and Clinical Immunology, 142(4), 1272-1284. https://doi.org/10.1016/j.jaci.2017.12.1000

Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation. / Sereni, L; Castiello, MC; Marangoni, Francesco; Anselmo, A; di Silvestre, D; Motta, S; Draghici, E; Mantero, S; Thrasher, AJ; Giliani, S; Aiuti, A; Mauri, P; Notarangelo, Luigi Daniele; Bosticardo, M; Villa, A.

In: Journal of Allergy and Clinical Immunology, Vol. 142, No. 4, 2018, p. 1272-1284.

Research output: Contribution to journal › Article

Sereni, L, Castiello, MC, Marangoni, F, Anselmo, A, di Silvestre, D, Motta, S, Draghici, E, Mantero, S, Thrasher, AJ, Giliani, S, Aiuti, A, Mauri, P, Notarangelo, LD, Bosticardo, M & Villa, A 2018, 'Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation', Journal of Allergy and Clinical Immunology, vol. 142, no. 4, pp. 1272-1284. https://doi.org/10.1016/j.jaci.2017.12.1000

Sereni, L ; Castiello, MC ; Marangoni, Francesco ; Anselmo, A ; di Silvestre, D ; Motta, S ; Draghici, E ; Mantero, S ; Thrasher, AJ ; Giliani, S ; Aiuti, A ; Mauri, P ; Notarangelo, Luigi Daniele ; Bosticardo, M ; Villa, A. / Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation. In: Journal of Allergy and Clinical Immunology. 2018 ; Vol. 142, No. 4. pp. 1272-1284.

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title = "Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation",

abstract = "{\textcopyright} 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. {\textcopyright} 2018 American Academy of Allergy, Asthma & Immunology",

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

year = "2018",

doi = "10.1016/j.jaci.2017.12.1000",

language = "English",

volume = "142",

pages = "1272--1284",

journal = "Journal of Allergy and Clinical Immunology",

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T1 - Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation

AU - Sereni, L

AU - Castiello, MC

AU - Marangoni, Francesco

AU - Anselmo, A

AU - di Silvestre, D

AU - Motta, S

AU - Draghici, E

AU - Mantero, S

AU - Thrasher, AJ

AU - Giliani, S

AU - Aiuti, A

AU - Mauri, P

AU - Notarangelo, Luigi Daniele

AU - Bosticardo, M

AU - Villa, A

PY - 2018

Y1 - 2018

N2 - © 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

AB - © 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

U2 - 10.1016/j.jaci.2017.12.1000

DO - 10.1016/j.jaci.2017.12.1000

M3 - Article

VL - 142

SP - 1272

EP - 1284

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

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ER -