抗GPIHBP1自身抗体作为高甘油三酯血症的一个病因
Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.
作者信息
Beigneux Anne P, Miyashita Kazuya, Ploug Michael, Blom Dirk J, Ai Masumi, Linton MacRae F, Khovidhunkit Weerapan, Dufour Robert, Garg Abhimanyu, McMahon Maureen A, Pullinger Clive R, Sandoval Norma P, Hu Xuchen, Allan Christopher M, Larsson Mikael, Machida Tetsuo, Murakami Masami, Reue Karen, Tontonoz Peter, Goldberg Ira J, Moulin Philippe, Charrière Sybil, Fong Loren G, Nakajima Katsuyuki, Young Stephen G
机构信息
From the Departments of Medicine (A.P.B., M.A.M., N.P.S., X.H., C.M.A., M.L., L.G.F., S.G.Y.), Rheumatology (M.A.M.), Human Genetics (K.R., S.G.Y.), and Pathology and Laboratory Medicine (P.T.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, and the Cardiovascular Research Institute and Department of Physiological Nursing, University of California, San Francisco, San Francisco (C.R.P.); the Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi (K.M., T.M., M.M., K.N.), and the Department of Insured Medical Care Management, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (M.A.) - both in Japan; the Finsen Laboratory, Rigshospitalet, Copenhagen (M.P.); the Department of Medicine, University of Cape Town, Cape Town, South Africa (D.J.B.); the Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville (M.F.L.); the Department of Medicine, Faculty of Medicine, Chulalongkorn University and Thai Red Cross Society, Bangkok, Thailand (W.K.); Clinique de Prévention Cardiovasculaire, Institut de Recherches Cliniques de Montréal, University of Montreal, Montreal (R.D.); the Department of Medicine, University of Texas Southwestern Medical Center, Dallas (A.G.); the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, New York University School of Medicine, New York (I.J.G.); and Fédération d'Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, INSERM UMR-1060 Carmen, Université de Lyon, Lyon, France (P.M., S.C.).
出版信息
N Engl J Med. 2017 Apr 27;376(17):1647-1658. doi: 10.1056/NEJMoa1611930. Epub 2017 Apr 5.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).
背景
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），可结合脂蛋白脂肪酶并将其转运至毛细血管腔内的作用位点。GPIHBP1缺乏会阻止脂蛋白脂肪酶到达毛细血管腔。GPIHBP1缺乏的患者血浆中脂蛋白脂肪酶水平较低，血管内甘油三酯水解受损，并患有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免疫测定进行特性鉴定期间，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。这一发现增加了这些样本可能含有GPIHBP1自身抗体的可能性。
方法
我们使用免疫测定、蛋白质印迹分析和免疫细胞化学研究相结合的方法，检测了这两份血浆样本（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。我们还检测了GPIHBP1自身抗体阻断脂蛋白脂肪酶与GPIHBP1结合的能力。
结果
我们在6例乳糜微粒血症患者中鉴定出了GPIHBP1自身抗体，并发现这些自身抗体阻断了脂蛋白脂肪酶与GPIHBP1的结合。与GPIHBP1缺乏的患者一样，有GPIHBP1自身抗体的患者血浆中脂蛋白脂肪酶水平较低。6例患者中有3例患有系统性红斑狼疮。其中1例有GPIHBP1自身抗体的患者分娩的婴儿血浆中含有母体GPIHBP自身抗体；该婴儿患有严重但短暂的乳糜微粒血症。2例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。
结论
在6例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，从而干扰了脂蛋白脂肪酶介导的富含甘油三酯脂蛋白的加工过程，导致严重的高甘油三酯血症。（由美国国立心肺血液研究所和勒杜克基金会资助。）
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