Abstract
Sjögren's syndrome (SS) is a systemic autoimmune disease mainly characterized by inflammatory involvement of exocrine gland. Atherosclerosis is a complex process leading to plaque formation in arterial wall with subsequent cardiovascular (CV) events. Recently, numerous studies demonstrated that SS patients bear an increased CV risk. Since activation of immune system is a key element in atherosclerosis, it is interesting to analyze whether and how the autoimmune and inflammatory events characterizing SS pathogenesis directly or indirectly contribute to atherosclerosis risk in these patients. An increase in circulating endothelial microparticles and integrins, which may be a consequence of endothelial damage and impaired repair mechanisms, has been demonstrated in SS. Increased endothelial expression of adhesion molecules with subsequent infiltration of inflammatory cells into arterial wall is also a critical event in atherosclerosis. The early inflammatory events taking place in the atherosclerotic plaque cause an increase in alarmins, such as S100A8/A9, which seems to be associated with SS disease activity and, in turn, induce up-regulation of interleukin (IL)-1β and other pro-atherogenic cytokines. Interestingly, increased IL-1β levels were also detected in tertiary lymphoid structures developing in vessel adventitia adjacent to the atherosclerotic plaque, suggesting a direct role of IL-1β in this process. Similar to these structures, germinal center-like structures arising in SS exocrine glands are also tertiary lymphoid systems where T-helper (Th) cell subsets govern the adaptive immune response. Th1 cells are the most prevalent subtype and have been shown to be strongly involved in both SS pathogenesis and atherosclerosis. Th17 cells are attracting great interest and few studies showed its importance in SS development. Albeit in low amounts, a Th17 signature was also detected in atherosclerotic plaques and some animal models demonstrated a significant pro-atherogenic role and positive effects of IL-17A blockade. Despite the fact that T cells have a pivotal role in the inflammatory process that ultimately leads to atherosclerosis, B cells have also been detected in atherosclerotic plaques, although their exact role is still mostly unknown with studies showing contrasting results. In this scenario, the role of inflammation in atherosclerosis pathogenesis in patients with SS needs to be further explored.
Highlights
Inflammation plays a pivotal role in the pathogenesis of atherosclerotic vascular damage and the causal relationship between chronic inflammation an atherosclerotic cardiovascular (CV) disease has been widely explored in the last years
There is evidence that some traditional CV risk factors are more prevalent in these patients in comparison to general population and, more importantly, some of these factors may exert a direct role in determining higher prevalence of subclinical atherosclerosis and higher risk of CV events, as recently observed [15,16,17]
Calprotectin levels correlate with CRP and recent findings suggest that this molecule may be an important prognostic factor for CV diseases independently of conventional risk factors, suggesting that calprotectin may be involved in the pathogenesis of CHD via inflammatory processes [36, 51]
Summary
Inflammation plays a pivotal role in the pathogenesis of atherosclerotic vascular damage and the causal relationship between chronic inflammation an atherosclerotic cardiovascular (CV) disease has been widely explored in the last years. Increased rate of CV events as well as enhanced prevalence of subclinical atherosclerosis, documented by imaging and vascular function instrumental methods are well-recognized in patients with ARDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), and Sjögren’s syndrome (SS) [4] In these patients, accelerated subclinical atherosclerosis has been associated to increased prevalence of classical CV risk factors, which induce atherosclerotic arterial wall damage enhancing the risk of CV disease [5, 6], and to chronic inflammatory burden [7]. SS, represents an interesting model to analyze the direct effect of autoimmunity and chronic inflammation on atherosclerosis without therapy interference In this setting, there is evidence that functional and organic subclinical atherosclerosis, characterized by higher prevalence of endothelial dysfunction, aortic stiffness, increased arterial wall intima-media thickness, left ventricular dysfunction and reduced coronary flow reserve, can been detected in young SS patients in comparison to healthy age-matched controls [11].
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