Research ArticleLupus

Platelet CD154 Potentiates Interferon-α Secretion by Plasmacytoid Dendritic Cells in Systemic Lupus Erythematosus

Science Translational Medicine  01 Sep 2010:
Vol. 2, Issue 47, pp. 47ra63
DOI: 10.1126/scitranslmed.3001001

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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-γ 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-α 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.

Footnotes

  • * These authors contributed equally to this work.

  • Citation: P. Duffau, J. Seneschal, C. Nicco, C. Richez, E. Lazaro, I. Douchet, C. Bordes, J.-F. Viallard, C. Goulvestre, J.-L. Pellegrin, B. Weil, J.-F. Moreau, F. Batteux, P. Blanco, Platelet CD154 potentiates interferon-α secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci. Transl. Med. 2, 47ra63 (2010).

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