Effects of simvastatin on circulating autoantibodies to oxidized LDL antigens: relation with immune stimulation markers

Abstract

Statins exert a number of anti-inflammatory and immunomodulatory effects in vitro. However, the immunomodulatory effects in vivo are less clarified. In the present study, we investigated whether simvastatin treatment changed the levels of autoantibodies against specific oxidized LDL (oxLDL) antigens as well as their association with leukocyte activation markers. Eighty volunteers with mild-to-moderate hypercholesterolemia were randomized to either simvastatin 40 mg or placebo for 6 weeks. Autoantibodies against apo B peptide antigens, C-reactive protein (CRP) and interleukin (IL)-6 in plasma were determined by ELISA. Subsets of circulating B and T cells were studied by flow cytometry. Simvastatin significantly reduced CRP by 26%, whereas IL-6 remained unchanged. Levels of IgG against the apo B peptide P-240 (amino acids 3586-3605) increased by 16% (p = 0.03) in the simvastatin group whereas autoantibody levels to other apo B peptides did not change. At baseline and after 6 weeks, the P-240 IgG levels were significantly correlated with the number of CD57+CD28 - CD8+T cells but not to other lymphocyte subsets or inflammatory markers. The P-240 IgG levels after 6 weeks simvastatin therapy was strongly correlated to the relative increase in CD57+CD28 - CD8+T cells (p = 0.003). Simvastatin treatment induced an increase in autoantibodies against an oxLDL antigen. The effect was related to an expansion of a CD8+T cell subset and may involve an immunostimulation by simvastatin.

Serum interleukin-1 and interleukin-6 are correlated neither with oxidized low density lipoprotein, nor with low-grade inflammation in patients with type 2 diabetes

“…These markers induce smooth muscle cell proliferation and increased cell adhesion, which play important roles in the pathogenesis of atherosclerosis [32]. Interestingly, Goncalves et al showed that simvastatin treatment induces an increase in production of auto-antibodies against ox-LDL [33]. Statin treatment was an exclusion criterion in our study.…”

The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery

“…Gruenbacher et al (2010) reported that IL-2 co-stimulation enabled statin-mediated activation of human NK cells. In a clinical study, it was reported that simvastatin treatment induced an increase in autoantibodies against oxLDL, and this induction was accompanied by an expansion of CD8 + T cells (Gonç alves et al, 2009). Collectively, these findings question the simple conclusion that inhibition of the MVA pathway is immune-suppressive and raise interesting questions about possible context-dependent effects.…”

Simvastatin Efficiently Lowers Small LDL-IgG Immune Complex Levels: A Therapeutic Quality beyond the Lipid-Lowering Effect

“…So far it has not been shown that statin treatment decreases LDL-IgG-IC to a higher extent than LDL [ 20 , 22 , 23 ]. A number of studies have suggested that statins have pleiotropic effects on immune response [ 54 , 55 ]. LDL-IgG-IC may trigger a variety of effects as Fcγ-receptors are expressed by all kinds of blood cells except erythrocytes.…”