Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Circulating auto-antibodies recognizing Apolipoprotein B (ApoB) correlate with clinical obesity and hypertension

T. Marchini1, S. Malchow1, S. Hansen1, C. Bode1, D. Wolf1

1Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH, Freiburg im Breisgau;

Rationale: Atherosclerosis is a chronic inflammatory disease of middle- to large-sized arteries that involves an autoimmune response with autoreactive T cells and auto-antibodies recognizing Apolipoprotein B (ApoB), the core protein of low-density lipoprotein (LDL). Here, we aimed to establish an association between circulating levels of human ApoB auto-antibodies with atherosclerosis and its clinical risk factors using a novel assay to detect auto-antibodies against a pool of highly immunogenic ApoB-peptides. Methods and Results: To detect polyclonal IgM and IgG auto-antibodies recognizing ApoB, we developed a sandwich ELISA with 30 ApoB peptides selected by an in-silico assay for a high binding affinity to MHC-II, which cover more than 80% of known MHC-II variants in a Caucasian population. This pre-selection of immunogenic self-peptides accounted for the high variability of MHC-II in human populations, which is fundamental to allow T cell dependent generation of IgG antibodies. The ELISA was optimized for the detection of both plasma IgM- and IgG-antibodies binding to ApoB-peptides by chemiluminescent detection. We quantified levels of ApoB-autoantibodies in a clinical cohort of 307 patients that underwent coronary angiography. Plasma anti-ApoB IgG and IgM concentration showed no differences across healthy individuals (n=67), patients with coronary artery disease (n=179), and patients with acute coronary syndrome (n=61). However, plasma levels of anti-ApoB IgG, which are considered pro-inflammatory, were significantly increased in patients with obesity (p=0.0436) and arterial hypertension (p<0.0001). In addition, patients diagnosed with the metabolic syndrome showed significantly elevated anti-ApoB IgG levels (p=0.0016). Even when normalized for total IgG plasma concentrations, anti-ApoB IgGs remained highly upregulated in hypertensive patients (p<0.0001). We observed no association with triglycerides, total cholesterol, VLDL, or LDL plasma levels. However, total and normalized anti-ApoB IgG levels negatively correlated with HDL. In contrast, total and normalized anti-ApoB IgM levels that have been suggested as anti-inflammatory were significantly lower in diabetic patients (p=0.0117) and in patients with the metabolic syndrome (p=0.0050). Conclusion: Using a novel ELISA method to detect IgM and IgG auto-antibodies against ApoB in humans, we show that anti-ApoB IgG antibodies positively correlate with cardiovascular risk factors but not with the clinical appearance of atherosclerosis, suggesting that humoral immune responses against ApoB are shaped by cardiovascular risk factors but not disease status itself. This tool will be informative to develop novel immune-based risk stratification tools for atherosclerosis in the future.

https://dgk.org/kongress_programme/jt2022/aV593.html