Autoimmune and Inflammatory Mechanisms in Atherosclerosis

Abstract

The present review focuses on the concept that cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis. Subjecting arterial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60. Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms.

Association of autoantibodies to heat‐shock protein 60 with arterial vascular events in patients with antiphospholipid antibodies

“…Differential endothelial cell expression of Hsp60 may at least partially explain the greater susceptibility of the arterial bed to antiHsp60. We and others have provided both in vitro and in vivo evidence that the presence of anti-Hsp60 is itself sufficient to cause endothelial cell dysfunction (apoptosis, activation, and/or injury) (2,(16)(17)(18). Such antiHsp60-induced endothelial damage would constitute the "first hit" and would favor the recruitment of aPL by exposing phosphatidylserine, a negatively charged phospholipid that interacts with phospholipid-binding proteins.…”

“…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).…”

Identification of atherosclerosis-associated conformational heat shock protein 60 epitopes by phage display and structural alignment

“…Autoimmunity to human HSP60, triggered by crossreactivity of the protective immune response directed against microbial HSP60's or by a bona fide autoimmune reaction against biochemically altered autologous HSP60, is believed to be involved in many autoimmune diseases, including atherosclerosis [31]. Purified human anti-bacterial HSP60 antibodies showed cytotoxicity on stressed, but not unstressed, human endothelial cells [19,32].…”

Integrating the cell stress response: a new view of molecular chaperones as immunological and physiological homeostatic regulators

“…Given the work of Georg Wick, who had proposed a role for immunity to Hsp60 in the pathogenesis of atherosclerosis and the development of coronary artery disease [126], it seemed sensible to see if there was any correlation between Hsp60 levels and heart disease. Wick and co-workers looked at levels of circulating Hsp60 in participants in the Bruneck Study, an Italian study of a general population to identify disease risk factors.…”