Cellular signaling by antiphospholipid antibodies
Cellular signaling by antiphospholipid antibodies
复制标题
抗磷脂抗体的细胞信号传导
DOI：
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发表时间：
2014
影响因子：
10.4
通讯作者：
R. Urbanus
中科院分区：
文献类型：
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作者：
P. G. D. Groot;R. Urbanus
抗磷脂抗体的存在是血栓栓塞并发症和妊娠发病率最常见的后天风险因素之一[1]。“抗磷脂抗体”是一组具有密切相关但不同特异性的自身抗体的集合术语。将分离的患者抗体注射到小鼠体内的实验表明，针对血浆蛋白β 2糖蛋白I的自身抗体的特定子集可以解释血栓形成风险的增加[2，3]。多年来，这些抗体如何增加血栓形成的风险一直是个谜，因为它们延长了体外凝血试验，这通常是出血性疾病的标志。抗磷脂综合征小鼠模型的实验表明，抗β 2糖蛋白I的自身抗体结合并激活细胞，如内皮细胞、单核细胞和血小板。这些细胞均参与止血调节，其激活导致向血栓前状态转变[4]。b2-糖蛋白I可以以不同的构象存在[5]。b2-糖蛋白I由五个连续的结构域组成，并且患者自身抗体所针对的表位已经在其第一个结构域中鉴定[6]。在血浆中，第一个结构域与第五个结构域相互作用，导致蛋白质的环状构象。这种构象不能与细胞结构结合。患者抗体的存在可以干扰第一个和最后一个结构域之间的相互作用，导致蛋白质的开放。因此，存在于其第五结构域上的表位变得暴露，通过该表位，与抗体复合的b2-糖蛋白I可以与细胞相互作用。虽然大多数科学家同意抗磷脂综合征中的血栓形成风险是由能够激活细胞的抗β 2-糖蛋白I抗体引起的，但他们完全不同意参与β 2糖蛋白I-抗体复合物与细胞结合的受体。据报道，几种受体与β 2糖蛋白I-抗体复合物相互作用：其中包括Toll样受体（TLR）2、TLR 4、TLR 8、膜联蛋白A2、糖蛋白Iba和低密度脂蛋白（LDL）受体家族成员LDL受体相关蛋白（LRP）8，也称为ApoER 2（综述见[4]）。对鼠血栓形成模型的研究证实了TLR 4、膜联蛋白A2或LRP 8的作用，因为抑制或不存在个别受体导致在用抗磷脂抗体攻击时血栓形成表型改善。其他受体参与抗体与细胞的结合仅在体外实验中显示。很难想象所有这些受体如何参与抗磷脂抗体介导的信号传导。不太可能每种细胞类型都有自己的自身抗体受体，因为大多数提出的受体在所有细胞类型上都可用。Brandt等人[7]进行的实验并发表在本期杂志上，支持TLR 2在自身抗体激活单核细胞中的重要作用。这篇文章的重要性并不在于作者增加了另一篇文章，其中有额外的实验显示了他们最喜欢的受体TLR 2的重要性。在这方面的贡献具有里程碑意义的观察是，作者已经优雅地表明，这是必不可少的抗磷脂抗体诱导的细胞信号，抗体被单核细胞。他们表明，抗体结合到珠不能激活单核细胞。换句话说，没有抗体的内吞作用，没有细胞信号传导。内吞作用一直被认为是下调细胞信号传导的有效机制。激动剂和受体被内化并转运至溶酶体进行降解。然而，内体并不总是直接转运到溶酶体隔室。相反，它们作为几种受体的信号平台，包括G蛋白偶联受体家族的成员，受体对应：菲利普G。de Groot，临床化学和血液学系（G03.550），乌得勒支大学医学中心，Heidelberglaan 100，3584 CX Utrecht，the Netherlands。联系电话：+31 88 755 7769;传真：+31 88 755 5418。电子邮件：ph.g. umcutrecht.nl
The presence of antiphospholipid antibodies is one of the most common acquired risk factors for thromboembolic complications and pregnancy morbidity [1]. ‘Antiphospholipid antibodies’ is a collective term for a set of autoantibodies with closely related but different specificities. Experiments in which isolated patient antibodies were injected into mice have shown that a specific subset of autoantibodies, those directed against the plasma protein beta2 glycoprotein I, can explain the increased risk of thrombosis [2,3]. For years, it was a mystery how these antibodies could increase the risk of thrombosis because they prolonged clotting assays in vitro, which is normally indicative of a bleeding disorder. Experiments with mouse models for the antiphospholipid syndrome have now shown that autoantibodies against beta2 glycoprotein I bind to and activate cells such as endothelial cells, monocytes, and platelets. Activation of these cells, all involved in the regulation of hemostasis, results in a shift toward a prothrombotic state [4]. b2-Glycoprotein I can exist in different conformations [5]. b2-Glycoprotein I consists of five successive domains, and the epitope to which the patient autoantibodies are directed has been identified within its first domain [6]. In plasma, this first domain interacts with the fifth domain, resulting in a circular conformation of the protein. This conformation is unable to bind to cellular structures. The presence of patient antibodies can disturb the interaction between the first and last domains, resulting in an opening of the protein. As a result, an epitope present on its fifth domain becomes exposed via which b2-glycoprotein I, in complex with the antibodies, can interact with cells. While most scientists agree that the thrombotic risk in the antiphospholipid syndrome is caused by anti–b2-glycoprotein I antibodies that are able to activate cells, they totally disagree on the receptor(s) involved in the binding of beta2 glycoprotein I–antibody complex to the cells. Several receptors have been reported to interact with the beta2 glycoprotein I–antibody complex: among others, Toll-like receptor (TLR)2, TLR4, TLR8, annexin A2, glycoprotein Iba, and the low-density lipoprotein (LDL) receptor family member LDL receptor–related protein (LRP)8, also known as ApoER2 (for review, see [4]). Studies with murine thrombosis models confirm the roles of TLR4, annexin A2, or LRP8, because the inhibition or absence of individual receptors results in an ameliorated thrombotic phenotype on challenge with antiphospholipid antibodies. The participation of the other receptors in the binding of the antibodies to cells has been shown with in vitro experiments only. It is difficult to envision how all these receptors can be involved in antiphospholipid antibody–mediated signaling. It is unlikely that every cell type has its own receptor for the autoantibodies because most of the proposed receptors are available on all cell types. Experiments performed by Brandt et al. [7] and published in this issue of the Journal support an important role of TLR2 in the activation of monocytes by the autoantibodies. The significance of this publication is not that the authors have added another article with additional experiments showing the importance of their favorite receptor: TLR2. The landmark observation in this contribution is that the authors have elegantly shown that it is essential for antiphospholipid antibody–induced cellular signaling that the antibodies are taken up by the monocyte. They show that antibodies bound to beads are unable to activate the monocyte. In other words―no endocytosis of the antibodies, no cellular signaling. Endocytosis has long been considered as an effective mechanism to downregulate cellular signaling. Agonist and receptor are internalized and transported to lysosomes for degradation. However, endosomes are not always directly transported to the lysosomal compartments. Instead, they function as signaling platforms for several receptors, including members of the G protein–coupled receptor family, receptor Correspondence: Philip G. de Groot, Department of Clinical Chemistry and Haematology (G03.550), University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. Tel.: +31 88 755 7769; fax: +31 88 755 5418. E-mail: ph.g.degroot@umcutrecht.nl
影响因子：
20.3
作者：
Arad, Ariela;Proulle, Valerie;Furie, Bruce
通讯作者：
Furie, Bruce