Aiolfi, R

Aiuti, A

Anselmo, A

Bosticardo, M

Castiello, MC

Di Silvestre, D

Draghici, E

Giliani, S

Iannacone, M

Inverso, D

Marangoni, F

Mauri, P

Motta, S

Notarangelo, LD

Sereni, L

Thrasher, AJ

Villa, A

UCL Discovery

Lack of WASp Unveils Intrinsic Platelet Defects Sustaining Inflammation and Autoimmunity  Authors Lucia Sereni1, Maria Carmina Castiello1, Achille Anselmo2, Francesco Marangoni3, Dario Di Silvestre4, Sara Motta4, Donato Inverso1, Roberto Aiolfi1, Elena Draghici1, Adrian J. Thrasher5, Silvia Giliani6, Alessandro Aiuti1, Matteo Iannacone1, Pierluigi Mauri4, Luigi D. Notarangelo7, Marita Bosticardo1, Anna Villa1  1San Raffaele Hospital, Milano, Italy,2Humanitas Hospital, Milano, Italy,3Massachusetts General Hospital, Harvard Medical School, Boston, MA,4National Research Council (ITB-CNR), Milano, Italy,5Institute of Child Health, University College London, London, United Kingdom,6Institute of Molecular Medicine "A. Nocivelli", University Hospital "Spedali Civili", Brescia, Italy,7Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD  Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency characterized by thrombocytopenia, eczema, high susceptibility to develop autoimmune manifestations and malignancies. Although thrombocytopenia is one of the main causes of death, the pathogenesis of platelet (PLT) defect is poorly understood. Here, we evaluated the role of WAS protein (WASp) in PLTs in a new conditional mouse model (CoWas) lacking WASp only in the megakaryocytic (MK) lineage.We observed an increased number of MKs and their progenitors both in CoWas mice and complete Was-/- mice (WKO), as well as normal in vitro PLT production by Was-/- MKs. Upon in vivo depletion of PLTs, WKO and CoWas mice are able to restore PLT count with kinetics comparable to wild-type (WT) mice, suggesting no defect in thrombopoiesis. Of note, WASp-deficient PLTs both in WKO and CoWas mice have a shorter half-life and hyper-activated status before and after ADP stimulation and are more prone to apoptosis. We also found that WKO and CoWas mice develop anti-PLT autoantibodies against Was-/- PLTs in line with different proteomic profile. Was-/- PLTs show decreased metabolic activity, increased ubiquitination pathways and Immunoglobulin content. Moreover, Was-/- PLTs release higher amount of soluble CD40L and are able to induce B-cells activation in vitro culture. Finally, WAS patients show increased CD62P and PAC1 expression at steady state and higher sCD40L plasma levels. The activation profile of human PLTs improves after LV-gene therapy treatment, in all the patients, especially in those with a follow up longer than two years.  

Lack of WASp Unveils Intrinsic Platelet Defects Sustaining Inflammation and Autoimmunity

http://discovery.ucl.ac.uk/1559135/1/Thrasher_SERENI.pdf

Lack of WASp Unveils Intrinsic Platelet Defects Sustaining Inflammation and Autoimmunity

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UCL Discovery