Sereni, L;
Castiello, MC;
Marangoni, F;
Anselmo, A;
di Silvestre, D;
Motta, S;
Draghici, E;
... Villa, A; + view all
(2018)
Autonomous role of Wiskott-Aldrich Syndrome platelet deficiency in inducing autoimmunity and inflammation.
Journal of Allergy and Clinical Immunology
, 142
(4)
pp. 1272-1284.
10.1016/j.jaci.2017.12.1000.
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Abstract
BACKGROUND: Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections and susceptibility to develop autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. OBJECTIVE: To dissect the basis of WAS platelet (PLT) defect we used a novel conditional mouse model (CoWas) lacking WASp only in the megakaryocytic lineage in presence of a normal immunological environment and in parallel we analysed samples obtained from WAS patients. METHODS: Phenotypical and functional characterization of megakaryocytes and platelets in mutant CoWas mice and WAS patients with and without autoantibodies were performed. Platelet antigen expression was examined through protein expression profile and cluster proteomic interaction network. Platelet immunogenicity was tested by ELISA assays and B and PLTs co-culture. RESULTS: CoWas displayed increased MK numbers and normal thrombopoiesis in vitro but WASp-deficient PLTs 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 PLTs expressed high levels of surface and soluble CD40L and were capable of inducing B-cell activation in vitro. WASp-deficient PLTs were highly immunostimulatory in mice and triggered the generation of antibodies specific for WASp-deficient PLTs even in the context of a normal immune system. WAS patients also showed PLT hyperactivation and elevated plasma soluble CD40L levels correlating with the presence of auto-antibodies. CONCLUSION: Overall, these findings suggest that intrinsic defects in WASp-deficient PLTs decrease their lifespan and dysregulate immune responses, corroborating the role of PLTs as modulators of inflammation and immunity.
| Type: | Article |
|---|---|
| Title: | Autonomous role of Wiskott-Aldrich Syndrome platelet deficiency in inducing autoimmunity and inflammation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jaci.2017.12.1000 |
| Publisher version: | https://doi.org/10.1016/j.jaci.2017.12.1000 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | CD40 ligand, Wiskott-Aldrich syndrome, autoantibodies, autoimmunity, platelet deficiency |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10043421 |
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