Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.
Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.
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DOI：
10.1038/ncomms8737
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发表时间：
2015-07-17
影响因子：
16.6
通讯作者：
Ni H
中科院分区：
文献类型：
--
作者：
Li J;van der Wal DE;Zhu G;Xu M;Yougbare I;Ma L;Vadasz B;Carrim N;Grozovsky R;Ruan M;Zhu L;Zeng Q;Tao L;Zhai ZM;Peng J;Hou M;Leytin V;Freedman J;Hoffmeister KM;Ni H
免疫性血小板减少症（ITP）是一种常见的出血性疾病，主要由抗血小板GPIIbIIIa和/或GPIb复合物的自身抗体引起。目前的理论表明，抗体介导的血小板破坏发生在脾脏，通过巨噬细胞通过Fc-FcγR相互作用。然而，我们和其他人已经证明，抗gpib α（而不是GPIIbIIIa）介导的ITP通常对靶向FcγR通路的治疗具有难治性。在这里，我们生成了小鼠抗小鼠单克隆抗体（mab），可以识别不同物种的GPIbα和GPIIbIIIa。利用这些独特的单克隆抗体和人ITP血浆，我们发现抗gpib α抗体，而非抗gpiibiiia抗体，诱导fc非依赖性血小板活化、唾液酸酶神经氨酸酶-1易位和去脂酰化。这导致通过肝细胞Ashwell-Morell受体清除肝脏中的血小板，这与经典的fc - fc γ r依赖性巨噬细胞吞噬有根本不同。重要的是，唾液酸酶抑制剂可改善小鼠抗gpib α介导的血小板减少症。这些发现揭示了fc非依赖性细胞减少症，指明去氮化是治疗难治性ITP的潜在诊断生物标志物和治疗靶点。免疫性血小板减少症（ITP）是由自身抗体介导的血小板清除引起的，但对当前免疫调节疗法的难治性是常见的。在这里，作者表明去盐化的血小板可以通过肝脏Ashwell-Morell受体清除，这一过程可以通过唾液酸酶抑制剂减弱，这提示了一种治疗ITP的新方法。
Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc–FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell–Morell receptors, which is fundamentally different from the classical Fc–FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP. Immune thrombocytopenia (ITP) is caused by autoantibody-mediated platelet clearance, but refractoriness to current immunomodulatory therapies is common. Here the authors show that desialylated platelets can be cleared via hepatic Ashwell–Morell receptor, a process that can be attenuated by sialidase inhibitors, suggesting a new therapy for ITP.