Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic inflammatory condition with immune competent cells in lesions producing mainly pro-inflammatory cytokines. Dead cells ...and oxidized forms of low density lipoproteins (oxLDL) are abundant. The major direct cause of CVD appears to be rupture of atherosclerotic plaques. oxLDL has proinflammatory and immune-stimulatory properties, causes cell death at higher concentrations and contains inflammatory phospholipids with phosphorylcholine (PC) as an interesting epitope. Antibodies against PC (anti-PC) may be atheroprotective, one mechanism being anti-inflammatory. Bacteria and virus have been discussed, but it has been difficult to find direct evidence, and antibiotic trials have not been successful. Heat shock proteins could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include pro-inflammatory cytokines, chemokines, and lipid mediators. To prove that inflammation is a cause of atherosclerosis and CVD, clinical studies with anti-inflammatory and/or immune-modulatory treatment are needed. The potential causes of immune reactions and inflammation in atherosclerosis and how inflammation can be targeted therapeutically to provide novel treatments for CVD are reviewed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The prognosis in systemic lupus erythematosus (SLE) has improved due to better treatment and care, but cardiovascular disease (CVD) still remains an important clinical problem, since the risk of CVD ...in SLE is much higher than among controls. Atherosclerosis is the main cause of CVD in the general population, and in SLE, increased atherosclerosis, especially the prevalence of atherosclerotic plaques, has been demonstrated. Atherosclerosis is an inflammatory condition, where immunity plays an important role. Interestingly, oxidized low‐density lipoprotein, defective clearance of dead cells, and inflammation, with a pro‐inflammatory T‐cell profile are characteristics of both atherosclerosis and SLE. In addition to atherosclerosis as an underlying cause of CVD in SLE, there are also other non–mutually exclusive mechanisms, and the most important of these are antiphospholipid antibodies (aPL) leading to the antiphospholipid antibody syndrome with both arterial and venous thrombosis. aPL can cause direct pro‐inflammatory and prothrombotic effects on endothelial and other cells and also interfere with the coagulation, for example, by inhibiting annexin A5 from its antithrombotic and protective effects. Antibodies against phosphorylcholine (anti‐PC) and other small lipid‐related epitopes, sometimes called natural antibodies, are negatively associated with CVD and atherosclerosis in SLE. Taken together, a combination of traditional risk factors such as hypertension and dyslipidemia, and nontraditional ones, especially aPL, inflammation, and low anti‐PC are implicated in the increased risk of CVD in SLE. Close monitoring of both traditional risk factors and nontraditional ones, including treatment of disease manifestations, not lest renal disease in SLE, is warranted.
Statins have pleiotropic effects, being both anti-inflammatory and immunomodulatory. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the low-density lipoprotein receptor (LDLR), which ...increases LDL levels due to the lower expression of LDLR.
Inhibition of PCSK9 by the use of antibodies represents a novel principle to lower LDL levels. LDL may have other properties than being a cholesterol carrier but is well established as a risk factor for cardiovascular disease and atherosclerosis. In atherosclerosis, the plaques are characterized by activated T cells and dendritic cells (DCs), dead cells, and OxLDL. The latter may be an important cause of the inflammation typical of atherosclerosis, by promoting a proinflammatory immune activation. This is inhibited by PCSK9 inhibition, and an anti-inflammatory type of immune activation is induced. OxLDL is raised in systemic lupus erythematosus (SLE), where both CVD and atherosclerosis are much increased compared to the general population. PCSK9 is reported to be associated with disease activity and complications in SLE. Also in other rheumatoid arthritis, PCSK9 may play a role.
PCSK9 has pleiotropic effects, being implicated in inflammation and immunity. Inhibition of PCSK9 is therefore interesting to study further as a potential therapy against inflammation and autoimmunity.
Recent findings indicate that presence of activated immune competent cells and inflammation are typical of atherosclerosis, the main cause of cardiovascular disease (CVD). The risk of CVD is very ...high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE), and is also raised in other autoimmune diseases such as rheumatoid arthritis. Autoimmunity-related CVD and atherosclerosis are important clinical problems. They may also shed light on interactions between immune reactions and atherosclerosis development and manifestations, not least in women, who have a much higher risk of autoimmune disease than men. In general, a combination of traditional and nontraditional risk factors, including dyslipidemia (and to a varying degree, hypertension, diabetes, and smoking), inflammation, antiphospholipid antibodies (aPLs), and lipid oxidation, contribute to CVD in autoimmune diseases. Premature atherosclerosis is likely to be a major underlying mechanism, although distinctive features, if any, of autoimmunity-related atherosclerosis compared with “normal” atherosclerosis are not clear. One interesting possibility is that factors such as inflammation, neoepitopes on endothelial cells, or aPLs make atherosclerotic lesions in autoimmune disease more prone to rupture than in “normal” atherosclerosis. Some cases of autoimmunity-related CVD may be more related to thrombosis than atherosclerosis. Whether premature atherosclerosis is a general feature of autoimmune diseases such as SLE or only affects a subgroup of patients whereas others do not have an increased risk remains to be demonstrated. Treatment of patients with autoimmune disease should also include CVD aspects and be focused on traditional risk factors as well as on disease-related factors. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation present in atherosclerotic lesions.
Chronic inflammatory diseases include cardiovascular disease (CVD), atherosclerosis, rheumatic and autoimmune diseases, and others, constituting a large part of the disease burden. It is therefore of ...major importance to improve understanding of underlying mechanisms, prediction, and treatment.
Broad fields including atherosclerosis, immunology, and inflammation are covered, through searches on PubMed and background knowledge. Phosphorylcholine (PC) is both a danger-associated molecular pattern (DAMP), present on oxidized LDL (OxLDL) in atherosclerotic lesions and dead cells, and a pathogen associated molecular pattern (PAMP), present on microorganisms. IgM and IgG1 antibodies against PC (anti-PC) are associated with protection in several chronic inflammatory conditions, especially in CVD and atherosclerosis where most research has been done. PC-immunization ameliorates atherosclerosis in animal models and several potential underlying mechanisms have been proposed, including anti-inflammatory, decreased uptake of OxLDL in the artery wall, promotion of T regulatory cells. Anti-PC develops during the first years of life. Low levels of IgM and IgG1 anti-PC may be caused by lack of exposure to microorganisms, including nematodes and helminths among others.
anti-PC could improve prediction of clinical outcome and raising anti-PC could be developed into a novel therapy.
Atherosclerosis and its main consequence, cardiovascular disease (CVD) are nowadays regarded as chronic inflammatory disease conditions, and CVD is the main cause of death in the world. Other ...examples of chronic inflammation are rheumatic and other autoimmune conditions, but also diabetes, obesity, and even osteoarthritis among others. In addition, infectious diseases can have traits in common with these conditions. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, where atherosclerosis is increased and the risk of CVD is very high. This is a clinical problem but could also shed light on the role of the immune system in atherosclerosis and CVD. Underlying mechanisms are of major interest and these are only partially known. Phosphorylcholine (PC) is a small lipid-related antigen, which is both a danger associated molecular pattern (DAMP), and a pathogen associated molecular pattern (PAMP). Antibodies against PC are ubiquitous and 5-10% of circulating IgM is IgM anti-PC. Anti-PC, especially IgM and IgG1 anti-PC, has been associated with protection in the chronic inflammatory conditions mentioned above, and develops during the first years of life, while being present at very low levels at birth. Animal experiments with immunization to raise anti-PC ameliorate atherosclerosis and other chronic inflammatory conditions. Potential mechanisms include anti-inflammatory, immune modulatory, clearance of dead cells and protection against infectious agents. An intriguing possibility is to raise anti-PC levels through immunization, to prevent and/or ameliorate chronic inflammation.
Abstract
Brown bears (
Ursus arctos
) hibernate for 5–6 months during winter, but despite kidney insufficiency, dyslipidemia and inactivity they do not seem to develop atherosclerosis or ...cardiovascular disease (CVD). IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) are associated with less atherosclerosis, CVD and mortality in uremia in humans and have anti-inflammatory and other potentially protective properties. PC but not MDA is exposed on different types of microorganisms. We determine anti-PC and anti-MDA in brown bears in summer and winter. Paired serum samples from 12 free ranging Swedish brown bears were collected during hibernation in winter and during active state in summer and analyzed for IgM, IgG, IgG1/2 and IgA anti-PC and anti-MDA by enzyme linked immunosorbent assay (ELISA). When determined as arbitrary units (median set at 100 for summer samples), significantly raised levels were observed in winter for anti-PC subclasses and isotypes, and for IgA anti-PC the difference was striking; 100 IQR (85.9–107.9) vs 782.3, IQR (422.8–1586.0; p < 0.001). In contrast, subclasses and isotypes of anti-MDA were significantly lower in winter except IgA anti-MDA, which was not detectable. Anti-PCs are significantly raised during hibernation in brown bears; especially IgA anti-PC was strikingly high. In contrast, anti-MDA titers was decreased during hibernation. Our observation may represent natural immunization with microorganisms during a vulnerable period and could have therapeutic implications for prevention of atherosclerosis.
Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) which raises LDL-levels. In addition, PCSK9 has proinflammatory immunological effects. Here, we investigate the role ...of PCSK9 in relation to the inflammatory activity in patients with rheumatoid arthritis (RA).
PCSK9-levels were determined at baseline by ELISA in 160 patients with RA not previously treated with biologics. The patients started anti-TNF-α (adalimumab, infliximab, or etanercept) treatment and were followed-up for 1 year. Disease activity was determined by DAS28. Effects of PCSK9 on cytokine production from macrophages of healthy individuals and synoviocytes from RA patients and inhibition by anti-PCSK9 antibodies were studied in supernatants by ELISA.
A significantly lower level of PCSK9 at baseline, p = 0.035, was observed in patients who reached remission within 1 year, defined as DAS28 < 2.6, compared to those not in remission. At 12 months of TNF-α antagonist treatment, the mean DAS28 was reduced but was significantly greater in patients with highest quartile PCSK9 (Q4) compared to those at lowest PCSK9 (Q1) in both crude (p = 0.01) and adjusted analysis (p = 0.004). In vitro, PCSK9 induced TNF-alpha and IL-1beta in macrophages and monocyte chemoattractant protein-1 (MCP1) in synoviocytes. These effects were inhibited by anti-PCSK9 antibodies.
Low levels of PCSK9 at baseline are associated with being DAS28-responder to anti-TNF-α treatment in RA. An underlying cause could be that PCSK9 stimulates the production of proinflammatory cytokines from macrophages and synoviocytes, effects inhibited by anti-PCSK9 antibodies. PCSK9 could thus play an immunological role in RA.
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