Atomic description of the immune complex involved in heparin-induced thrombocytopenia.
Atomic description of the immune complex involved in heparin-induced thrombocytopenia.
复制标题
参与肝素诱导的血小板减少症的免疫复合物的原子描述。
DOI：
10.1038/ncomms9277
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发表时间：
2015-09-22
影响因子：
16.6
通讯作者：
Greene MI
中科院分区：
文献类型：
--
作者：
Cai Z;Yarovoi SV;Zhu Z;Rauova L;Hayes V;Lebedeva T;Liu Q;Poncz M;Arepally G;Cines DB;Greene MI
肝素诱导的血小板减少症（HIT）是由含有血小板因子4（PF 4）、PF 4抗体和肝素或细胞糖胺聚糖（GAG）的免疫复合物引起的自身免疫血栓性疾病。在这里，我们解决了以下的晶体结构：（1）PF 4四聚体/磺达肝素复合物，（2）PF 4四聚体/KKO-Fab复合物（鼠单克隆HIT样抗体）和（3）PF 4单体/RTO-Fab复合物（非HIT抗PF 4单克隆抗体）。磺达肝癸钠与PF 4四聚体的“封闭”末端结合并稳定其构象。这种相互作用进而稳定了四聚体的“开放”末端上的KKO的表位。因此，磺达肝癸钠和KKO协作以“稳定”三元致病性免疫复合物。RTO与PF 4单体的结合防止PF 4四聚化并抑制体外KKO和人HIT IgG诱导的血小板活化和血小板聚集以及体内血栓进展。原子结构为开发HIT的新诊断和非抗凝治疗提供了基础。 肝素诱导的血小板减少症（HIT）是一种自身免疫性血栓性疾病，治疗选择有限。在这里，作者提出了致病免疫复合物的晶体学数据，为HIT的新诊断和治疗方法的发展提供了结构基础。
Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the ‘closed' end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open' end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize' the ternary pathogenic immune complex. Binding of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. The atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disease with limited treatment options. Here the authors present crystallographic data on the disease-causing immune complex, providing the structural basis for the development of new diagnostic and therapeutic approaches to HIT.