Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.
Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.
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DOI：
10.1056/nejmoa1611930
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发表时间：
2017-04-27
期刊：
影响因子：
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通讯作者：
Young SG
中科院分区：
文献类型：
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作者：
Beigneux AP;Miyashita K;Ploug M;Blom DJ;Ai M;Linton MF;Khovidhunkit W;Dufour R;Garg A;McMahon MA;Pullinger CR;Sandoval NP;Hu X;Allan CM;Larsson M;Machida T;Murakami M;Reue K;Tontonoz P;Goldberg IJ;Moulin P;Charrière S;Fong LG;Nakajima K;Young SG
一种在毛细血管内皮细胞上表达的蛋白质，称为 GPIHBP1（糖基磷脂酰肌醇锚定的高密度脂蛋白结合蛋白 1），与脂蛋白脂肪酶结合并将其运送到毛细血管腔中的作用位点。 GPIHBP1 的缺陷会阻止脂蛋白脂肪酶到达毛细血管腔。 GPIHBP1 缺乏的患者血浆脂蛋白脂肪酶水平较低，甘油三酯的血管内水解受损，以及严重的高甘油三酯血症（乳糜微粒血症）。在对基于单克隆抗体的 GPIHBP1 免疫测定进行表征时，我们遇到了两份血浆样本（均来自乳糜微粒血症患者），其中含有干扰物质，导致无法测量 GPIHBP1。这一发现提出了这些样本可能含有 GPIHBP1 自身抗体的可能性。我们结合免疫测定、蛋白质印迹分析和免疫细胞化学研究，检测了两份血浆样本（以及其他乳糜微粒血症患者的样本）中是否存在 GPIHBP1 自身抗体。我们还测试了 GPIHBP1 自身抗体阻断脂蛋白脂肪酶与 GPIHBP1 结合的能力。我们在 6 名乳糜微粒血症患者中鉴定出 GPIHBP1 自身抗体，并发现这些自身抗体可阻断脂蛋白脂肪酶与 GPIHBP1 的结合。与 GPIHBP1 缺乏症患者一样，具有 GPIHBP1 自身抗体的患者血浆脂蛋白脂肪酶水平较低。六名患者中的三名患有系统性红斑狼疮。其中一名携带 GPIHBP1 自身抗体的患者生下的婴儿的血浆中含有母体 GPIHBP1 自身抗体；该婴儿患有严重但短暂的乳糜微粒血症。其中两名患有乳糜微粒血症和 GPIHBP1 自身抗体的患者对免疫抑制剂治疗有反应。在六名乳糜微粒血症患者中，GPIHBP1自身抗体阻断了GPIHBP1结合和转运脂蛋白脂肪酶的能力，从而干扰脂蛋白脂肪酶介导的富含甘油三酯的脂蛋白的加工并导致严重的高甘油三酯血症。
A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody–based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase–mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia.