抗GPIbα抗体在免疫性血小板减少症中的作用及机制研究

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia, in which autoantibodies are directed against the patients’ own platelets, leading to platelet destruction. Conventional treatments such as intravenous immunoglobulin G (IVIG) in ITP are through blockade of Fc receptors of phagocytes to prevent platelet destruction. However, ITP patients with anti-glycoprotein (GP)Ibα autoantibodies do not respond to IVIG, and the mechanism has not been clarified. Our previous study shows that an anti-human GPIbα antibody induced GPIbα clustering, leading to platelet clearance in liver. Based on that, this study will further investigate: the changes induced in platelets by anti-GPIbα antibodies (apoptosis/activation); the mechanism by which the changes induce platelet clearance in vivo; whether platelets can be protected against clearance by inhibiting the changes. Finally, the changes and the underlying mechanism will be verified with platelets and plasma from ITP patients in in vitro phagocytosis experiments. This study will reveal the pathogenesis of anti-GPIbα antibody-induced thrombocytopenia and suggest new therapeutic strategies for refractory ITP.

免疫性血小板减少症（Immune thrombocytopenia, ITP）是以血小板数量减少为主要特征的自身免疫性疾病。抗血小板自身抗体的产生是ITP的主要致病因素。静脉注射免疫球蛋白，通过封闭吞噬细胞Fc受体阻止血小板被破坏达到治疗目的。然而，抗GPIbα抗体阳性的ITP患者通常对免疫球蛋白等常规治疗无效，机制未明。申请人前期研究发现，抗GPIbα抗体可引起GPIbα集簇，并导致血小板在肝脏被清除。本研究将进一步探明：抗GPIbα抗体引起血小板发生了哪些改变（凋亡/活化）；这些改变通过何种机制导致血小板被清除；通过阻断血小板的这种改变或被清除的途径，能否保护血小板不被清除；最后使用ITP病人的血小板、血浆进行验证。本研究将揭示抗GPIbα抗体导致血小板被清除的机制，为预防和治疗含抗GPIbα抗体的难治性ITP提供新思路和途径，具有重要理论价值和临床应用前景。

免疫性血小板减少症(ITP)是以血小板数量减少为主要特征的自身免疫性疾病。抗血小板自身抗体的产生是ITP的主要致病因素。静脉注射免疫球蛋白，通过封闭吞噬细胞Fc受体阻止血小板被破坏达到治疗目的。然而，抗GPIbα抗体阳性的ITP患者通常对免疫球蛋白等常规治疗无效，机制未明。本研究首先明确了抗GPIbα抗体可引起血小板凋亡和活化，弄清了抗体引起血小板凋亡的分子机制，并利用抗人及小鼠GPIbα抗体以及ITP病人体内抗GPIbα自身抗体在野生型、基因敲除及GPIbα人源化小鼠体内验证了该机制的存在。. 本项目有以下重要的研究结果：（1）抗GPIbα抗体通过引起血小板表面GPIbα发生集簇引起血小板凋亡和活化；（2）抗GPIbα抗体导致血小板凋亡，暴露在血小板表面的PS被肝巨噬细胞识别并吞噬；（3）在小鼠体内通过抑制GPIbα集簇、caspase活性以及螯合胞内钙离子抑制血小板凋亡活化均可抑制抗GPIbα抗体对小鼠血小板的清除；（4）ITP病人体内抗GPIbα自身抗体导致血小板凋亡并被清除。因此抗GPIbα抗体通过引起血小板表面GPIbα集簇导致血小板凋亡，暴露在血小板表面的PS被肝巨噬细胞识别并吞噬。. 综上，本研究完成了预期研究计划并达到了预期研究目标。本研究揭示了抗GPIbα抗体导致血小板减少的机制，不仅为血小板基础研究提供了新的资料，并为治疗含抗GPIbα抗体的难治性ITP提供新思路和途径,具有重要的理论价值和临床应用前景。