Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT).
Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT).
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DOI：
10.1016/j.autrev.2016.03.011
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发表时间：
2016-07
影响因子：
13.6
通讯作者：
Cines DB
中科院分区：
文献类型：
--
作者：
Cai Z;Zhu Z;Greene MI;Cines DB
在原子水平上对自身抗原的发展知之甚少。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，由血小板因子4（PF 4）和肝素或细胞糖胺聚糖（GAG）组成的抗原抗体引起。在溶液中，PF 4以单体、二聚体和四聚体之间的平衡形式存在。这些相互作用的成分的结构研究有助于描绘一个多步骤的过程中涉及的HIT的发病机制。首先，肝素结合到PF 4四聚体的“封闭”端，并稳定其构象并暴露“开放”端。第二，PF 4沿着肝素/GAG链沿着排列，这近似于四聚体，形成增强抗体亲合力的大抗原复合物。第三，致病性HIT抗体与稳定的PF 4四聚体的“开放”末端结合以形成IgG/PF 4/肝素三元免疫复合物，并且还传播含有多种IgG抗体的“超大免疫复合物”（ULC）的形成。第四，ULC通过FcγRIIA受体发出信号，直接激活血小板和单核细胞并产生凝血酶，凝血酶反式激活造血细胞和内皮细胞。非致病性抗PF 4抗体可防止四聚体形成、致病性抗体结合、血小板活化和血栓形成，为HIT的治疗提供了新的途径。对HIT发病机制的进一步了解可能会导致这种自身免疫性疾病的新诊断和治疗方法。
Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the ‘closed’ end of the PF4 tetramer, and stabilizes its conformation and exposing the ‘open’ end. Second, PF4 arrays along heparin/GAG chains, which approximates tetramers, forming large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the ‘open’ end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate formation of “ultralarge immune complexes” (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcγRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti-PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease.