title: Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by the involvement of multiple organs and an immune response against nuclear components. Although its pathogenesis remains poorly understood, type I interferon (IFN) and CD40 ligand (CD154) are known to contribute. Because platelets are involved in inflammatory processes and represent a major reservoir of CD154, we hypothesized that they participate in SLE pathogenesis. Here, we have shown that in SLE patients, platelets were activated by circulating immune complexes composed of autoantibodies bound to self-antigens through an Fc-gamma receptor IIa (CD32)-dependent mechanism. Further, platelet activation correlated with severity of the disease and activated platelets formed aggregates with antigen-presenting cells, including monocytes and plasmacytoid dendritic cells. In vitro, activated platelets enhanced IFN-alpha secretion by immune complex-stimulated plasmacytoid dendritic cells through a CD154-CD40 interaction. Finally, in lupus-prone mice, depletion of platelets or administration of the P2Y(12) receptor antagonist (clopidogrel) improved all measures of disease and overall survival; transfusion of activated platelets worsened the disease course. Together, these data identify platelet activation as an important contributor to SLE pathogenesis and suggest that this process and its sequelae may provide a new therapeutic target.
authors.affiliation: CNRS UMR 5164, 33076 Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Duffau
authors.forename: Julien
authors.initials: J
authors.lastname: Seneschal
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Christophe
authors.initials: C
authors.lastname: Richez
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Lazaro
authors.forename: Isabelle
authors.initials: I
authors.lastname: Douchet
authors.forename: Cécile
authors.initials: C
authors.lastname: Bordes
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Viallard
authors.forename: Claire
authors.initials: C
authors.lastname: Goulvestre
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Pellegrin
authors.forename: Bernard
authors.initials: B
authors.lastname: Weil
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.forename: Patrick
authors.initials: P
authors.lastname: Blanco
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D000077144:Clopidogrel; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000276:immunology*; D051379:Mice; D019007:P-Selectin / Q000276:immunology; D015539:Platelet Activation / Q000276:immunology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017452:Receptors, IgG / Q000276:immunology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; C080568:Fc gamma receptor IIA; D016898:Interferon-alpha; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D017452:Receptors, IgG; D023201:CD40 Ligand; D000077144:Clopidogrel; D013988:Ticlopidine