Platelet CD154 Potentiates Interferon-α Secretion by Plasmacytoid Dendritic Cells in Systemic Lupus Erythematosus
Platelet CD154 Potentiates Interferon-α Secretion by Plasmacytoid Dendritic Cells in Systemic Lupus Erythematosus
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DOI：
10.1126/scitranslmed.3001001
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发表时间：
2010-09-01
影响因子：
17.1
通讯作者：
Blanco, Patrick
中科院分区：
文献类型：
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作者：
Duffau, Pierre;Seneschal, Julien;Blanco, Patrick
系统性红斑狼疮(SLE)是一种全身性炎症性自身免疫性疾病，以多器官受累和对核成分的免疫反应为特征。虽然其发病机制仍不清楚，但已知与I型干扰素(IFN)和CD40配体(CD154)有关。由于血小板参与炎症过程，并代表CD154的主要储存库，我们假设它们参与了SLE的发病。在这里，我们已经证明，在SLE患者中，通过Fc-Gamma受体IIa(CD32)依赖的机制，由自身抗体与自身抗原结合组成的循环免疫复合体激活了血小板。此外，血小板的激活与疾病的严重程度相关，激活的血小板与抗原呈递细胞形成聚集体，包括单核细胞和浆细胞样树突状细胞。在体外，活化的血小板通过CD154-CD40相互作用促进免疫复合体刺激的浆细胞样树突状细胞分泌干扰素-α。最后，在易患狼疮的小鼠中，去除血小板或给予P2Y(12)受体拮抗剂(氯吡格雷)可改善所有疾病指标和总体存活率；输注活化的血小板会恶化病程。总之，这些数据表明，血小板激活是SLE发病机制的重要因素，并提示这一过程及其后遗症可能提供新的治疗靶点。
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.