Anticardiolipin from Periodontitis Patients Impact Fetal Loss and Annexin V

Abstract

Anticardiolipin antibodies, found at elevated serum concentrations in 15% to 20% of individuals with periodontitis, are associated with adverse pregnancy outcomes, thrombotic conditions, and accelerated atherosclerosis in autoimmune disease such as the antiphospholipid syndrome. Our previous studies demonstrated that antibodies raised in mice against Porphyromonas gingivalis caused fetal loss in a mouse pregnancy model due to anticardiolipin antibodies. Such antibodies are induced via molecular mimicry with the serum protein β2-glycoprotein 1 (β2GP1), the target antigen of anticardiolipin. Furthermore, human anticardiolipin IgG is associated with increased serum markers of vascular inflammation, and IgG purified from periodontitis subjects with elevated anticardiolipin stimulates inflammatory cytokine production by endothelial cells and a trophoblastic cell line. Activation of the trophoblastic cells by anticardiolipin occurs through Toll-like receptor 4. In the present study, we observed that IgG anticardiolipin from periodontitis subjects also causes fetal loss in mice. Displacement of the protective 2-dimensional lattice formed by annexin V on trophoblast surfaces by anticardiolipin, via its interaction with its target antigen β2GP1, leading to fibrin clot formation due to exposure of anionic phospholipids to plasma, is a plausible pathogenic mechanism explaining adverse obstetrical outcomes in antiphospholipid syndrome. Therefore, we assessed such interactions in periodontitis. We observed that anticardiolipin from periodontitis subjects competes for annexin V on an artificial phosphatidylserine monolayer, replicating a key activity of autoantibodies found in patients with antiphospholipid syndrome. In addition, we found that anticardiolipin from periodontitis subjects increases annexin V levels on the BeWo choriocarcinoma cell line, consistent with mobilization of annexin V to the cell surface to facilitate repair following membrane damage. The data indicate that sera and IgG from periodontitis subjects with elevated anticardiolipin levels may influence pregnancy outcomes due to interactions with annexin V.