Association of Autoantibodies to Heat-Shock Protein 60 With Arterial Vascular Events in Patients With Antiphospholipid Antibodies

A growing body of evidence suggests that auto-antibodies to heat-shock protein 60 (anti-Hsp60) constitute an important nontraditional risk factor for cardiovascular disease (1). Immunity to the Hsp60 family has been implicated in endothelial cell stress/activation and the development of atherosclerosis (2). Heat-shock proteins show considerable sequence homology among species, and immune reactions to Hsp60 in infections by microorganisms that express Hsp65 have been widely described (3). Anti-Hsp65 antibodies, induced in response to these pathogens, can cross-react with self Hsp60 expressed on endothelial cells (4–7). Elevated levels of anti-Hsp60 have been associated with progression and severity of atherosclerosis (8–15), with vasculitis in systemic autoimmune diseases (16), and with thrombotic events in the context of systemic lupus erythematosus (SLE) and lupus anticoagulant (LAC) positivity (17). Moreover, anti-Hsp60 from SLE patients were shown to bind to the surface of endothelial cells and induce apoptosis in these cells (17). We have recently demonstrated that anti-Hsp60 enhance thrombus formation and promote endothelial changes in an in vivo murine model of carotid artery injury (18), supporting the notion that these autoantibodies have a prothrombotic role. Based on these findings and others reported in the current literature, we hypothesized that individuals with circulating anti-Hsp60 might be at risk for vascular events. We further hypothesized that anti-Hsp60 might increase the risk of vascular events in individuals with known thrombovascular risk factors, such as antiphospholipid antibodies (aPL). Antiphospholipid antibodies (LAC, anticardiolipin antibody [aCL], and anti–β2-glycoprotein I [anti-β2GPI]) are associated with thrombovascular events (19–21), but it remains unclear why clinical events occur in only some individuals with aPL. Our findings demonstrate that the presence of anti-Hsp60 itself is associated with an increased risk of arterial, but not venous, vascular events. We further show that anti-Hsp60 confer a risk of arterial vascular events in aPL-positive individuals but not in aPL-negative individuals.