Periodontitis, Anti-phospholipids, Dendritic Cells, and Atherosclerosis

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DESCRIPTION (provided by applicant): A subset of periodontitis patients has elevated levels of anti-phospholipid Abs including anti-cardiolipin (anti- CL) and anti-phosphorylcholine (anti-PC). These Abs react with periodontal pathogens including P. gingivalis and A. actinomycetemcomitans and immune responses to periodontal bacteria appear to explain why these Abs are elevated. Markers of vascular inflammation including soluble VCAM-1 and E-selectin correlated with elevated levels of anti-CL in our periodontitis patients further supporting our hypothesis that the subset of patients with elevated anti-phospholipid antibodies may be at increased risk for cardiovascular sequelae. These anti-phospholipids also interact with minimally modified LDL (mmLDL) and form immune complexes (ICs) and ICs are rapidly trapped by immature dendritic cells (DCs) that are present in blood, along the subendothelial layer of non-diseased arterial wall, and in atheromas. Fc and complement receptors expressed on DCs facilitate 1C trapping and in the atherogenic plaque DCs express membrane C1q and this is also thought to assist in trapping ICs including mmLDL-ICs. DCs also efficiently trap bacteria in ICs and this may help explain why Ags and DNA from periodontal pathogens, including P. gingivalis, are in atherosclerotic plaque. A current concept is that atherosclerosis develops as a consequence of inflammatory mechanisms coupled with dyslipidaemia. Preliminary data indicate that P. gingivalis and LDL stimulate production of proinflammatory cytokines including IL-12 from DCs and IFN-y from DC stimulated NK cells. Furthermore, converting mmLDL or P. gingivalis into ICs with anti-phospholipid Abs enhanced proinflammatory cytokine production. These data prompt the hypothesis that IC-stimulated DCs induce NK cells, and T cells to produce elevated levels of proinflammatory cytokines and participate in the pathogenesis of atherosclerosis. Recurrent exposure to ICs could promote chronic inflammation and help explain epidemioloqical data suggesting that periodontitis patients are more likely to develop atherosclerosis. We propose to confirm and extend our data supporting this Ab mediated mechanism. A biological mechanism linking periodontitis and atherosclerosis would lend credibility to the epidemiological associations and help provide rationale for long-term longitudinal studies required to demonstrate causality.