Jiangsu Institute of Hematology, The First Affiliated Hospital and Collaborative Innovation Center of Hematology, State Key Laboraotry of Radiation Medicine and Protection, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou, Jiangsu 215006, China.
Jiangsu Institute of Hematology, The First Affiliated Hospital and Collaborative Innovation Center of Hematology, State Key Laboraotry of Radiation Medicine and Protection, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou, Jiangsu 215006, China;
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10682-E10691. doi: 10.1073/pnas.1808217115. Epub 2018 Oct 18.
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count which can cause fatal hemorrhage. ITP patients with antiplatelet glycoprotein (GP) Ib-IX autoantibodies appear refractory to conventional treatments, and the mechanism remains elusive. Here we show that the platelets undergo apoptosis in ITP patients with anti-GPIbα autoantibodies. Consistent with these findings, the anti-GPIbα monoclonal antibodies AN51 and SZ2 induce platelet apoptosis in vitro. We demonstrate that anti-GPIbα antibody binding activates Akt, which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition. Genetic ablation or chemical inhibition of Akt or blocking of Akt signaling abolishes anti-GPIbα antibody-induced platelet apoptosis. We further demonstrate that the antibody-bound platelets are removed in vivo through an apoptosis-dependent manner. Phosphatidylserine (PS) exposure on apoptotic platelets results in phagocytosis of platelets by macrophages in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling or blockage of PS exposure protects the platelets from clearance. Therefore, our findings reveal pathogenic mechanisms of ITP with anti-GPIbα autoantibodies and, more importantly, suggest therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors.
免疫性血小板减少症（ITP）是一种自身免疫性疾病，其特征是血小板计数低，可能导致致命性出血。患有抗血小板糖蛋白（GP）Ib-IX 自身抗体的 ITP 患者对常规治疗表现出耐药性，其机制仍不清楚。在这里，我们显示患有抗 GPIbα 自身抗体的 ITP 患者的血小板发生凋亡。与这些发现一致，抗 GPIbα 单克隆抗体 AN51 和 SZ2 在体外诱导血小板凋亡。我们证明抗 GPIbα 抗体结合激活 Akt，通过激活磷酸二酯酶（PDE3A）和 PDE3A 介导的 PKA 抑制来引发血小板凋亡。 Akt 的基因缺失或化学抑制或 Akt 信号阻断消除了抗 GPIbα 抗体诱导的血小板凋亡。我们进一步证明，体内通过依赖凋亡的方式清除结合抗体的血小板。凋亡血小板上的磷脂酰丝氨酸（PS）暴露导致肝脏中的巨噬细胞吞噬血小板。值得注意的是，Akt 或 Akt 调节的凋亡信号的抑制或缺失或 PS 暴露的阻断可保护血小板免受清除。因此，我们的研究结果揭示了伴有抗 GPIbα 自身抗体的 ITP 的发病机制，更重要的是，为自身抗体或其他致病因素引起的血小板减少症提供了治疗策略。
