GPIHBP1 autoantibody syndrome during interferon β1a treatment

Abstract

BACKGROUND Autoantibodies against GPIHBP1 cause chylomicronemia by blocking the ability of GPIHBP1 to bind lipoprotein lipase (LPL) and transport the enzyme to its site of action in the capillary lumen. OBJECTIVE A patient with multiple sclerosis developed chylomicronemia during interferon (IFN) β1a therapy. The chylomicronemia resolved when the IFN β1a therapy was discontinued. Here, we sought to determine whether the drug-induced chylomicronemia was caused by GPIHBP1 autoantibodies. METHODS We tested plasma samples collected during and after IFN β1a therapy for GPIHBP1 autoantibodies (by western blotting and with enzyme-linked immunosorbent assays). We also tested whether the patient’s plasma blocked the binding of LPL to GPIHBP1 on GPIHBP1-expressing cells. RESULTS During IFN β1a therapy, the plasma contained GPIHBP1 autoantibodies, and those autoantibodies blocked GPIHBP1’s ability to bind LPL. Thus, the chylomicronemia was due to the GPIHBP1 autoantibody syndrome. Consistent with that diagnosis, the plasma levels of GPIHBP1 and LPL were very low. After IFN β1a therapy was stopped, the plasma triglyceride levels returned to normal, and GPIHBP1 autoantibodies were undetectable. CONCLUSION The appearance of GPIHBP1 autoantibodies during IFN β1a therapy caused chylomicronemia. The GPIHBP1 autoantibodies disappeared when the IFN β1a therapy was stopped, and the plasma triglyceride levels fell within the normal range.

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

“…We report our clinical and research experience with LipidSeq, a targeted hybrid panel designed for clinical resequencing of genomic loci known to be associated with dyslipidemia and related metabolic traits and disorders. Since 2014, the results from this panel have contributed to 39 publications reporting original scientific findings, including seven on FH [32,43,44,[46][47][48][49], seven on hypertriglyceridemia [42,45,[50][51][52][53][54], four on extremes of HDL cholesterol [39,[55][56][57], and 21 case reports [40,41,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76]. We have published an additional 15 reviews and methods articles related to this work [4, 5, 7, 11-13, 20, 34, 77-83].…”

“…As well, we diagnosed several patients whose severe hypertriglyceridemia was due to subclinical undiagnosed partial lipodystrophy [59], which altered monitoring and management. Other examples of positive clinical outcomes from use of LipidSeq include: 1) ending the protracted diagnostic odyssey endured by some patients [72,74,75]; 2) increasing the diagnostic yield in MODY diabetes by~6% through simultaneous screening for CNVs [40,76]; 3) switching some patients with GCK CNVs (diagnosed with MODY2) from insulin to oral hypoglycemic agents [40]; 4) diagnosing sitosterolemia in patients who were initially diagnosed with homozygous FH, resulting in a dramatic change in management [48]; and 5) ruling out genetic contributions in several patients with severe dyslipidemias due to secondary causes [52,60,65].…”

GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism

“…Chylomicronemia occasionally appears spontaneously, and some of these ''acquired'' cases are caused by GPIHBP1 autoantibodies (''GPIHBP1 autoantibody syndrome'') (Beigneux et al, 2017;Eguchi et al, 2019;Hu et al, 2017a;Kersten, 2017). This disorder was discovered fortuitously while characterizing a monoclonal antibody-based ELISA designed to measure plasma levels of GPIHBP1 (Beigneux et al, 2017;Miyashita et al, 2018a).…”

A Comprehensive Update on the Chylomicronemia Syndrome

“…These findings point to the "GPIHBP1 autoantibody syndrome" (17) as a novel form of autoimmune hyperlipidemia. Moreover, GPIHBP1 autoantibodies were identified as the cause of the CS in a patient treated with interferon for multiple sclerosis (20). Interferon is known to increase the risk of autoimmune disease and discontinuation of the interferon caused the antibody to disappear.…”