Is atherosclerosis an autoimmune disease?

BMC Medicine Is atherosclerosis an autoimmune disease? Eiji Matsuura 0 1 Fabiola Atzeni 2 Piercarlo Sarzi-Puttini 2 Maurizio Turiel 5 Luis R Lopez 4 Michael T Nurmohamed 3 0 Department of Cell Chemistry, Okayama University Graduate School of Medicine , Dentistry, and Pharmaceutical Sciences, Okayama , Japan 1 Collaborative Research Center (OMIC), Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 , Japan 2 Rheumatology Unit, L. Sacco University Hospital of Milan , Milan , Italy 3 VU University Medical Center and Jan van Breemen Research Institute , Amsterdam , Netherlands 4 Medical Department, Corgenix Inc , Broomfield, CO , USA 5 Cardiology Unit, Department of Biomedical Sciences for Health, Galeazzi Orthopedic Institute IRCCS, University of Milan , Milan , Italy Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds 2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that 2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/ interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease. Atherosclerosis; Auto-inflammatory disease; Autoimmunity; 2-glycoprotein I; Innate immunity; Inflammasome; Oxidized LDL - Background In the last decades, it has become apparent that patients with systemic autoimmune diseases develop premature and, quite often, severe atherosclerotic cardiovascular disease (CVD). Systemic autoimmune diseases are characterized by chronic inflammation and immune dysregulation. These abnormalities may produce dyslipidemia, platelet and vascular pathology, arterial lesions, and enhanced autoantibody production [1-3]. Current narrative for nonautoimmune atherosclerosis emphasizes the active inflammatory, complex or multi-factorial and long-term nature of the disease. These inflammatory mechanisms also cause dyslipidemia with vascular and immunologic dysfunction. Giving the similarities with autoimmune-mediated atherosclerosis, it is not surprising that investigators have postulated an autoimmune nature for atherosclerosis. Innate immune mechanisms have been demonstrated in atherosclerosis, particularly in early stages of the disease. Unraveling the roles of inflammatory molecular factors and signaling systems activated by a variety of pathogens and/or endogenous signals highlighted the prominent role of pro-inflammatory inflammasome/IL-1 cytokines and turned attention to auto-inflammatory mechanisms in atherosclerosis [4,5]. Whether these proinflammatory mechanisms progress into atherogenic adaptive immune responses in late stages of the disease or represent two independent pathologic processes remains unresolved. Understanding their nature and inter-relationship in atherosclerosis may provide new concepts with possible impact not only on early and accurate diagnosis but also on preventive programs and perhaps more effective therapeutic interventions. Chronic inflammatory mechanisms and immune dysregulation in atherosclerosis There is much evidence to suggest that endothelial dysfunction (the primum movens) is an early pro-atherogenic process associated with cardiovascular events that contributes to the formation, progression and complications of atherosclerosis [6]. It is also becoming increasingly clear that chronic inflammation and immune dysregulation play important roles in the development of atherosclerotic CVD, which can now be considered an inflammatory autoimmune condition [6,7]. Oxidized low-density lipoprotein (oxLDL) is pivotal in the development of atherosclerosis and represents a crucial pro-inflammatory stimulus [8]. Upon entering into the intima of arteries, oxLDL activates endothelial cells and up-regulates adhesion molecule expression and chemotactic chemokine secretion, all of which contribute to the recruitment of circulating leukocytes. Monocytes and/or macrophages infiltrating atherosclerotic sites take up oxLDL, forming foam cells that in turn promote further secretion of inflammatory mediators. The association between oxLDL autoantibodies and CVD in patients with rheumatoid arthritis (RA) has been reported [8]. OxLDL may interact with C-reactive protein (CRP) to form pro-atherogenic oxLDL/CRP complexes that may not only perpetuate vascular inflammation but also trigger autoimmune responses, accelerating the development of atherosclerosis [9]. OxLDL/2-glycoprotein I (2GPI) complexes also induce adaptive autoimmune responses, which may up-regulate the macrophage expression of FcRI and scavenger CD36 receptors and thus accelerate oxLDL uptake. OxLDL/2GPI complexes correlate with the size of atherosclerotic lesions in mouse models. In patients with CVD, these complexes correlate with disease severity and adverse outcomes [5]. Chronic inflammation is a major component of atherogenesis, and both in vitro and in vivo studies have shown that IL-1 is a potent pro-inflammatory and atherogenic cytokine [10,11]. The production of IL-1 depends on two separate signals: the induction of IL-1 mRNA as a result of the stimulation of pattern recognition receptors; and the activation of caspase-1, a protease that cleaves pro-IL-1 into its biologically active form [12]. The activation of caspase-1 is mediated by cytoplasmic large multi-protein complexes, called inflammasomes, that cleave pro-caspase-1 into its mature activated proteinase form. Caspase-1 is a key bridge linking metabolic stresses and innate immune sensors to produce proinflammatory cytokines and vascular inflammation [13]. IL-1 is a potent pro-inflammatory cytokine with a wide range of biological effects. IL-1 can be induced during infection, metabolic or endogenous injury [14], or immunological challenge and can control systemic and local inflammation by up-regulating the expression of many effector proteins through the (...truncated)