Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia

Anne P Beigneux; Kazuya Miyashita; Michael Ploug; Jan Dirk Blom; Masumi Ai; MacRae F Linton; Weerapan Khovidhunkit; Robert Dufour; Abhimanyu Garg; Maureen A McMahon; Clive R Pullinger; Norma P Sandoval; Xuchen Hu; Christopher M Allan; Mikael Larsson; Tetsuo Machida; Masami Murakami; Karen Reue; Peter Tontonoz; Ira J Goldberg; Philippe Moulin; Sybil Charrière; Loren G Fong; Katsuyuki Nakajima; Stephen G Young

doi:10.1056/nejmoa1611930

Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia

Anne P Beigneux, Kazuya Miyashita, Michael Ploug, Jan Dirk Blom, Masumi Ai, MacRae F Linton, Weerapan Khovidhunkit, Robert Dufour, Abhimanyu Garg, Maureen A McMahon, Clive R Pullinger, Norma P Sandoval, Xuchen Hu, Christopher M Allan, Mikael Larsson, Tetsuo Machida, Masami Murakami, Karen Reue, Peter Tontonoz, Ira J GoldbergPhilippe Moulin, Sybil Charrière, Loren G Fong, Katsuyuki Nakajima, Stephen G Young

70 Citations (Scopus)

Abstract

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.

Original language	English
Journal	New England Journal of Medicine
Volume	376
Issue number	17
Pages (from-to)	1647-1658
Number of pages	12
ISSN	0028-4793
DOIs	https://doi.org/10.1056/nejmoa1611930
Publication status	Published - 27 Apr 2017

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Beigneux, A. P., Miyashita, K., Ploug, M., Blom, J. D., Ai, M., Linton, M. F., Khovidhunkit, W., Dufour, R., Garg, A., McMahon, M. A., Pullinger, C. R., Sandoval, N. P., Hu, X., Allan, C. M., Larsson, M., Machida, T., Murakami, M., Reue, K., Tontonoz, P., ... Young, S. G. (2017). Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia. New England Journal of Medicine, 376(17), 1647-1658. https://doi.org/10.1056/nejmoa1611930

Beigneux, AP, Miyashita, K, Ploug, M, Blom, JD, 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 2017, 'Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia', New England Journal of Medicine, vol. 376, no. 17, pp. 1647-1658. https://doi.org/10.1056/nejmoa1611930

@article{b64d79001a62497d82f12ce8239459a9,

title = "Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia",

abstract = "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.",

author = "Beigneux, {Anne P} and Kazuya Miyashita and Michael Ploug and Blom, {Jan Dirk} and Masumi Ai and Linton, {MacRae F} and Weerapan Khovidhunkit and Robert Dufour and Abhimanyu Garg and McMahon, {Maureen A} and Pullinger, {Clive R} and Sandoval, {Norma P} and Xuchen Hu and Allan, {Christopher M} and Mikael Larsson and Tetsuo Machida and Masami Murakami and Karen Reue and Peter Tontonoz and Goldberg, {Ira J} and Philippe Moulin and Sybil Charri{\`e}re and Fong, {Loren G} and Katsuyuki Nakajima and Young, {Stephen G}",

year = "2017",

month = apr,

day = "27",

doi = "10.1056/nejmoa1611930",

language = "English",

volume = "376",

pages = "1647--1658",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "17",

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TY - JOUR

T1 - Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia

AU - Beigneux, Anne P

AU - Miyashita, Kazuya

AU - Ploug, Michael

AU - Blom, Jan Dirk

AU - Ai, Masumi

AU - Linton, MacRae F

AU - Khovidhunkit, Weerapan

AU - Dufour, Robert

AU - Garg, Abhimanyu

AU - McMahon, Maureen A

AU - Pullinger, Clive R

AU - Sandoval, Norma P

AU - Hu, Xuchen

AU - Allan, Christopher M

AU - Larsson, Mikael

AU - Machida, Tetsuo

AU - Murakami, Masami

AU - Reue, Karen

AU - Tontonoz, Peter

AU - Goldberg, Ira J

AU - Moulin, Philippe

AU - Charrière, Sybil

AU - Fong, Loren G

AU - Nakajima, Katsuyuki

AU - Young, Stephen G

PY - 2017/4/27

Y1 - 2017/4/27

N2 - 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.

AB - 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.

U2 - 10.1056/nejmoa1611930

DO - 10.1056/nejmoa1611930

M3 - Journal article

C2 - 28402248

SN - 0028-4793

VL - 376

SP - 1647

EP - 1658

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 17

ER -

Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia

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