High Avidity Anti-β2-Glycoprotein i Antibodies Activate Human Coronary Artery Endothelial Cells and Trigger Peripheral Blood Mononuclear Cell Migration

Abstract

Anti-p2-glycoprotein I antibodies (ap2GPI) represent a potential pathogenic candidate for coronary artery diseases. High avidity ap2GPI (HAv ap2GPI) are known to be associated with thrombotic and obstetric manifestations in patients with antiphospholipid syndrome, who are also susceptible to the development of premature atherosclerosis. However, there is little information about how human coronary artery endothelial cells (HCAEC) are affected by HAv ap2GPI. The purpose of our study was to evaluate the pathophysiological effects of HAv ap2GPI on HCAEC and determine their influence on cytokine expression and migration of peripheral blood mononuclear cells. Following the two hit hypothesis, we co-stimulated HAv ap2GPI-treated HCAEC in the presence and absence of the acute phase protein serum amyloid A (SAA). HAv ap2GPI induced in vitro HCAEC dysfunction, through the ERIO/2 signaling pathway, promoted the expression of chemokines (MCP-l, GROa and IL-8) and IL-6, which led to the attraction and migration of peripheral blood mononuclear cells. These effects were potentiated and intensified in conditions with SAA, indicating that HAv ap2GPI, in the presence of physiological concentrations of acute-phase proteins represent pathogenic autoantibodies, which could lead to the development of premature atherosclerosis and/or thrombosis development.

Immunoreactivity and avidity of IgG anti-β2-glycoprotein I antibodies from patients with autoimmune diseases to different peptide clusters of β2-glycoprotein I

“…Interestingly, positivity to peptide B more likely occurred in patients with only APS as compared to patients with APS associated with SLE, while the opposite association was detected for positivity of same sera for peptides C and F. On the other hand, the positivity for peptide A was a stronger predictor for the presence of LAv anti-b2GPI as compared to HAv IgG anti-b2GPI. The clinical study by Shoenfeld et al on 295 patients with APS showed that the positivity for peptide A ( 58 LKTPRV 63 ; domains I-II) was negatively associated with overall thrombosis [34]. The study also revealed that anti-peptide C antibodies were a significant predictor of recurrent spontaneous abortions [34], which was not confirmed in our study.…”

“…The clinical study by Shoenfeld et al on 295 patients with APS showed that the positivity for peptide A ( 58 LKTPRV 63 ; domains I-II) was negatively associated with overall thrombosis [34]. The study also revealed that anti-peptide C antibodies were a significant predictor of recurrent spontaneous abortions [34], which was not confirmed in our study. However, peptide C was significantly involved in the prediction of overall thrombosis (negatively) and disease type (APS associated with SLE).…”

“…This is in contrast to low avidity (LAv) IgG anti-b2GPI, which were more prevalent in autoimmune patients without APS [29,33]. The involvement of HAv IgG anti-b2GPI in the pathogenesis of APS was also confirmed in an in vitro study on human coronary artery endothelial cells [34]. In this study, HAv IgG anti-b2GPI were shown to increase the expression of inflammatory and chemotactic cytokines leading to higher migration of monocytes.…”

“…In this study, HAv IgG anti-b2GPI were shown to increase the expression of inflammatory and chemotactic cytokines leading to higher migration of monocytes. These effects were further intensified in the presence of the major acute-phase protein serum amyloid A [34], denoting that along with lipopolysaccharide [7], serum amyloid A as a marker of inflammation also represents a trigger or a second hit uncovering the full pathological potential of anti-b2GPI [34]. Using heptamer phage display libraries, two binding epitopes of HAv IgG anti-b2GPI have been characterized: FNPYWYV and QGOAHSK [27].…”

Binding of plasma proteins to titanium dioxide nanotubes with different diameters

“…Oxidatively altered IgG (oxIgG) with increased immunoreactivity to β2GPI and its peptide clusters influence human coronary artery endothelial cells. 62 42 The amino acid sequence QGPAHSK represents a mimotope of the conformational epitope that resides on the third domain of β2GPI and is recognized by more than 30% share of high-avidity anti-β2GPI antibodies. The amino acid sequence KMDGNHP represents a mimotope of the conformational epitope between the third and fourth domain of β2GPI that is recognized by more than 30% share of polyclonal low avidity anti-β2GPI antibodies when β2GPI is in open conformation.…”