Chylomicronemia from GPIHBP1 autoantibodies

Abstract

Some cases of chylomicronemia are caused by autoantibodies against GPIHBP1, an endothelial cell protein that shuttles lipoprotein lipase (LPL) to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the “GPIHBP1 autoantibody syndrome” and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody–based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in 5 patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

“…The ability of GPIHBP1 to undergo bidirectional transcytosis with a monoclonal antibody as cargo (Davies et al, 2012) may exacerbate the syndrome by preventing renewed loading of GPIHBP1 with LPL in the subendothelial spaces (Figure 1D). Normal plasma triglyceride levels were restored in some of these patients by immunosuppressive treatments with mycophenolate mofetil or prednisolone, but rituximab appeared to induce a more frequent and persistent remission (Ashraf et al, 2020;Lutz et al, 2020;Miyashita et al, 2020).…”

“…A oligomeric complex of ANGPTL3 and ANGPTL8 helps regulate LPL activity in oxidative tissues (Chi et al, 2017;Gusarova et al, 2017;Haller et al, 2017;Kovrov et al, 2019;Chen et al, 2020;Oldoni et al, 2020). (D) The discovery of inhibitory GPIHBP1 autoantibodies revealed a new etiology of acquired hypertriglyceridemia in some patients without any documented mutations in LPL, GPIHBP1, APOC2, APOA5, or LMF1 (Beigneux et al, 2017;Lutz et al, 2020;Miyashita et al, 2020). The immunofluorescence micrographs were modified and reproduced with permission (Davies et al, 2010).…”

“…Recently, GPIHBP1 auto-antibodies were shown to cause lateonset chylomicronemia by blocking the interaction between LPL and GPIHBP1 in 22 patients with a hitherto unexplained form of acquired hypertriglyceridemia (Beigneux et al, 2017;Miyashita et al, 2020). The ability of GPIHBP1 to undergo bidirectional transcytosis with a monoclonal antibody as cargo (Davies et al, 2012) may exacerbate the syndrome by preventing renewed loading of GPIHBP1 with LPL in the subendothelial spaces (Figure 1D).…”

Current Diagnosis and Management of Primary Chylomicronemia

“…ApoA-V has dual binding management of secondary factors. PCM is caused by defects in LPL pathway genes (LPL, APOC2, APOA5, GPIHBP1, LMF1) due to genetic mutations or presence of autoantibodies against LPL pathway proteins (GPIHBP1, LPL, and apoC-II) [6][7][8][9] .…”

“…• Autoantibodies against LPL pathway proteins: Autoimmune chylomicronemia due to autoantibodies against LPL pathway proteins (GPIHBP1, LPL, apoC-II) has been reported [6][7][8][9] . Autoimmune chylomicronemia may be complicated by other autoimmune diseases and be ameliorated by steroid or immune-suppressive therapy.…”