Abstract
Impaired high-density lipoprotein (HDL) levels and antioxidant functionality of HDL, mainly attributed to a decreased paraoxonase-1 (PON1) functionality, have been described in autoimmune conditions. In this setting, a role for humoral response in cardiovascular disease is emerging. This study evaluates the role of immunoglobulin G (IgG) antibodies against HDL and disease-related autoantibodies on HDL dysfunction in immune-driven diseases. Serum IgG anti-HDL antibodies, PON1 activity, and total antioxidant capacity (TAC) were quantified in 381 patients with different immune-driven diseases [18 mixed connective tissue disease (MCTD), 35 primary Sjögren syndrome (pSS), 38 systemic sclerosis (SSc), 33 ANCA-associated vasculitis (AAV), 60 diabetes mellitus 1, 29 autoimmune B12 deficiency/pernicious anemia, 29 primary biliary cirrhosis, 46 IBD/Crohn, 54 IBD/UC, and 39 celiac disease (CD)] and 138 healthy controls. IgG anti-HDL antibodies were increased in MCTD, pSS, AAV, and inflammatory bowel disease (IBD) [Crohn and ulcerative colitis (UC)], even after correcting for total IgG levels, but not in organ-specific autoimmune diseases. Anti-HDL antibodies were negatively associated with PON1 activity in MCTD (r = -0.767, p < 0.001) and AAV (r = -0.478, p = 0.005), whereas both anti-HDL and anti-neutrophil cytoplasm antibod levels were related to an impaired PON1 activity and TAC in IBD/UC. In SSc, anti-centromere antibodies correlated PON1 activity. anti-Saccharomyces cerevisiae antibodies levels were negatively associated with PON1 activity (r = -0.257, p = 0.012) and PON1/TAC ratio (r = -0.261, p = 0.009) in IBD/Crohn. HDL dysfunction in CD was only related to anti-transglutaminase levels. IgG anti-HDL antibodies and HDL dysfunction are common hallmarks of systemic autoimmunity. Anti-HDL and disease-related autoantibodies account for the HDL antioxidant dysfunction in immune-driven conditions, mainly in systemic autoimmune disorders.
Highlights
Systemic autoimmune disorders are commonly associated with an increased risk of cardiovascular disease (CVD) occurrence compared to the general population [1, 2]
Levels of immunoglobulin G (IgG) anti-High-density lipoproteins (HDL) antibodies were found to be increased in mixed connective tissue disease (MCTD) [40.98 (164.65) arbitrary units (AU), p < 0.001], primary Sjögren Syndrome (pSS) [19.72 (51.38) AU, p = 0.012], anti-neutrophil cyto plasm antibodies (ANCA)-associated vasculitis (AAV) [23.90 (42.26) AU, p = 0.030], celiac disease (CD) [11.23 (31.63) AU, p = 0.050], IDB/Crohn [12.16 (53.03) AU, p = 0.020], and Inflammatory Bowel Diseases (IBD)/ulcerative colitis (UC) [17.34 (79.79) AU, p < 0.001] patients compared to those in healthy control (HC) [2.44 (12.92) AU]
Since a notable heterogeneity was found among immune-driven diseases concerning the IgG anti-HDL levels observed and regarding the association between the latter and serum paraoxonase 1 (PON1) activity, we aimed to evaluate whether disease-related autoantibodies (Table 3) can explain these discrepancies
Summary
Systemic autoimmune disorders are commonly associated with an increased risk of cardiovascular disease (CVD) occurrence compared to the general population [1, 2]. Altered levels of HDL and blood lipids have been described in systemic autoimmune diseases, and a paradoxical effect on CV risk (the so-called “lipid paradox,” whereby low lipid levels are associated with increased CV risk) is widely accepted [8, 9], poorly understood. Impaired HDL functionality, mainly due to a decreased enzymatic activity of the calciumdependent esterase paraoxonase 1 (PON1), has been reported in these conditions [10–12]. Due to their association with CVD development, understanding changes in lipid levels and/or functionality as well as the underlying mechanisms, represents a major research topic
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