Abstract
Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles 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 five 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.
Highlights
Supplementary key words glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 lipoprotein lipase triglycerides autoimmune disease immunoglobulin A immunoglobulin G4
The lymphocyte antigen 6/urokinase-type plasminogen activator receptor (LU) domain is primarily responsible for the stability of the Glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1)–LPL complex, whereas the acidic domain is responsible for enhancing the encounter rate between GPIHBP1 and LPL [6, 8]
We have summarized findings in 22 chylomicronemia patients with GPIHBP1 autoantibodies
Summary
Levels of GPIHBP1 autoantibodies in different immunoglobulin classes were scored as grades 1–5, based on the optical density in the ELISA (see Fig. 7). In one patient (patient 1 in Table 1), plasma triglyceride levels normalized after infusions of rituximab, a CD20-specific monoclonal antibody that is commonly used to treat other autoimmune diseases (e.g., pemphigus vulgaris, thrombotic thrombocytopenic purpura, SLE) [84,85,86]. A 27-year-old woman with a history of antiphospholipid syndrome and Graves’ disease (patient 11 in Table 1) developed severe chylomicronemia (plasma triglycerides 5,960 mg/dl). Her serum contained GPIHBP1 autoantibodies; the plasma LPL levels were extremely low, and the plasma levels of GPIHBP1 were undetectable. GPIHBP1 autoantibodies were not tested after rituximab treatment, but given the normalization of triglyceride levels it is likely that the autoantibodies disappeared
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