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Age Related Inflammatory Characteristics of Coronary Artery Disease
Abstract
Coronary heart disease, often associated with fatal outcomes, is increasingly common. Immune dysregulation is a key process in atherogenesis, yet age and other immune related factors are poorly characterised, especially in premature disease. The current study is to investigate the differential immunological mediators in the plaque specific to older and younger decedents.
Coronary artery plaques were collected from male decedents as follows: Younger (< 50 years; n=30), older (> 60 years; n=30) and control (n=10). Demographic and forensic pathological data were collected. Plaques were investigated, using detailed immunohistochemistry.
Older subjects had 20% elevated heart to body weight ratio compared to younger subjects (p<0.05), as well as 40% higher levels of plaque necrosis (p<0.05) and 90% more calcification (p<0.05). There was a three-fold higher amount of infiltrating CD3(+) T cells (p<0.05) and myeloperoxidase production (p<0.05) within plaque from older subjects than younger. Interestingly, older subjects had 50% and 70% lower numbers of infiltrating macrophage (p<0.05) and Foxp3(+) Treg cells (p<0.05), respectively, in the plaque compared to younger subjects. There were no significant age-dependent differences in IL-17 or IL-10 secretion.
Our data suggests that there are indeed age-dependent characteristics of culprit coronary plaque inflammation. In particular, older subjects demonstrate a plaque phenotype with higher amounts of inflammation and lower levels of Treg cells. Despite lower levels of inflammation, younger subjects also had fatal outcomes, indicating that alternative factors may be more important in plaque stability. These observations may have therapeutic consequences and hence warrant further investigation.
... Although inflammation is a key process in atherogenesis, little is known about specific regulators of inflammation in premature onset CAD. Inflammation contributes to the development of CAD, and cytokines are specifically implicated in the pathogenesis of premature CAD [2]. Knowledge regarding novel interleukins, e.g. ...
... Coronary artery specimens were obtained from 50 premature (≤60 y) and 50 mature (N60 y) male decedents where CAD was the cause of death at post-mortems performed at the NSW Department of Forensic Medicine, Australia, between 2009 and 2012, as described previously [2]. These cases had no recorded history of illicit drug use. ...
... Each of the polyclonal rabbit anti-human primary antibodies (Abcam, Sydney, Australia) were followed by polymer HRP goat anti-rabbit immunoglobulin (Dako, Sydney, Australia). The positive staining was photographed and quantified using Image-Pro® Plus 7, as described [2]. Statistical analysis was performed by parametric one-way ANOVAs and Tukey post-hoc tests. ...
... Although inflammation is a key process in atherogenesis, little is known about specific regulators of inflammation in premature onset CAD. Inflammation contributes to the development of CAD, and cytokines are specifically implicated in the pathogenesis of premature CAD [2]. Knowledge regarding novel interleukins, e.g. ...
... Coronary artery specimens were obtained from 50 premature (≤60 y) and 50 mature (N60 y) male decedents where CAD was the cause of death at post-mortems performed at the NSW Department of Forensic Medicine, Australia, between 2009 and 2012, as described previously [2]. These cases had no recorded history of illicit drug use. ...
... Each of the polyclonal rabbit anti-human primary antibodies (Abcam, Sydney, Australia) were followed by polymer HRP goat anti-rabbit immunoglobulin (Dako, Sydney, Australia). The positive staining was photographed and quantified using Image-Pro® Plus 7, as described [2]. Statistical analysis was performed by parametric one-way ANOVAs and Tukey post-hoc tests. ...
... It has been revealed that an abnormal quantity or dysfunction of Tregs might be associated with many different conditions, including carcinoma [6], diabetes [7], organ transplant reactions [8], systemic autoimmune disorders [9], and CAD [10][11][12]. A few studies have shown that a downregulation in Tregs might contribute to the development of ACS [11,12], although others have reported conflicting results, some describing an upregulation of Tregs in patients with ACS [13][14][15], and others suggesting no significant finding in patients with ACS [16,17]. Meanwhile, the definition of Treg marker patterns has long been controversial. ...
... Although several studies have investigated the role of Tregs in ACS, the changes in Treg levels and the expression patterns of Tregs in ACS patients remain controversial. Some studies have reported that Tregs are downregulated in patients with ACS [11,12], whereas others reported different results [13][14][15]. Furthermore, some authors have reported that the suppression function of CD4 +CD25hi Tregs was not altered in patients [32], whereas others claim that Foxp3+ Tregs are not able to suppress the inflammatory cytokines [21,22]. Whether CD25 and Foxp3, the once canonical typical markers of Tregs, truly are real specific markers for Tregs with a suppression function is now questioned. ...
Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS.
... Recently, some investigators have suggested that a decrease in Tregs might contribute to the development and progression of ACS [11][12][13]. However, other studies have reported elevated Treg numbers in ACS patients [8,[14][15][16]. Beyond assessing their numbers, few studies have evaluated the function of Tregs in ACS, and some have reported conflicting results regarding the immunosuppressive effect of Tregs on Teffs [17][18][19]. ...
... Recently, several groups have reported lower Treg frequencies in ACS patients when compared with Treg frequencies in healthy agematched control subjects [29]. In contrast, another study found no decrease in Tregs counts in ACS patients [15]; thus the role of Tregs cultured for 5 days. The levels of FOXP3 mRNA expression in non-cultured Tregs obtained from ACS patients were significantly lower than the levels in Tregs obtained from control subjects (P < 0.05). ...
Atherosclerosis is an immune-mediated inflammatory process, which acts as the main cause of acute coronary syndrome (ACS). Regulatory CD4+CD25+FOXP3+T cells (Tregs) are thought to play a major role in inhibiting the formation and progression of atherosclerosis. However, the exact role played by Tregs in the pathogenesis of ACS is yet remained unclear. FOXP3 is a key regulator of Treg formation and function. Demethylation at the CpG-rich island of FOXP3 upstream enhancers can alter FOXP3 expression, and may affect Treg function during the development of ACS. This study investigated the immunosuppressive function and methylation status of a FOXP3 upstream enhancer in Tregs in ACS patients. Notably, Tregs from ACS patients exhibited a significantly lower immunosuppressive effect on Teffs. Furthermore, the methylation status of the FOXP3 upstream enhancer was significantly increased in ACS patients. Consistent with these observations, Tregs originated from ACS patients manifested significantly lower levels of FOXP3 mRNA. The immunosuppressive effect of Tregs on Teffs was compromised in ACS patients. Together, our data suggest that examination of the methylation status of the FOXP3 upstream enhancer might be a novel approach to diagnose ACS and to differentiate ACS subtypes.
... The ability to combine pharmaceutical compounds with biomaterials opens up many new avenues to synergistically deliver drugs in a controlled manner, enhance drug adsorption (e.g., conjugation of the drug and nanoparticles with enhanced cell membrane permeability) [13][14][15][16][17] and support tissue regeneration through the delivery of chemical [18] and biochemical agents such as proteins and peptides [19][20][21][22][23]. Furthermore, current advances in tissue engineering provide a new solution both to engineer reliable three-dimensional (3D) cell models for testing drug delivery (including drug metabolism) and to build tissue substitutes that address the problem with shortage in available tissues for transplantation [24][25][26][27][28]. ...
... These materials not only can act as drug carriers, which release the drug cargo at the rate that is controlled by the breakdown of the structure, but also their breakdown products (amino acids) have potentially beneficial effects on the cells/tissues to aid the tissue regeneration/remodeling. The synergies can also include the regulation of drug uptake through the changes to the cell membrane permeability [16]. ...
Introduction:
Search for new, functional biomaterials that can be used to synergistically deliver a drug, enhance its adsorption and stimulate the post-injury recovery of tissue function, is one of the priorities in biomedicine. Currently used materials for drug delivery fail to satisfy one or more of these functionalities, thus they have limited potential and new classes of materials are urgently needed.
Areas covered:
Natural materials, due to their origin, physical and chemical structure can potentially fulfill these requirements and there is already strong evidence of their usefulness in drug delivery. They are increasingly utilized in various therapeutic applications due to the obvious advantages over synthetic materials. Particularly in pulmonary drug delivery, there have been limitations in the use of synthetic materials such as polymers and lipids, leading to an increase in the use of natural and protein-based materials such as silk, keratin, elastin and collagen. Literature search in each specialized field, namely, silk, keratin and collagen was conducted, and the benefits of each material for future application in pulmonary drug delivery are highlighted.
Expert opinion:
The natural materials discussed in this review have been well established in their use for other applications, yet further studies are required in the application of pulmonary drug delivery. The properties exhibited by these natural materials seem positive for their application in lung tissue engineering, which may allow for more extensive testing for validation of pulmonary drug delivery systems.
... Age is a primary risk factor for the occurrence of atherosclerosis [48], and previous research has confirmed the age-dependent inflammatory characteristics of coronary artery plaques. In elderly patients, coronary plaques exhibit increased CD3 + T-cell infiltration and increased myeloperoxidase (MPO) production, indicating a plaque phenotype that promotes atherogenesis and inflammation [49]. Age is also a predictive factor for CKD and is often associated with elevated blood creatinine levels in older patients [50]. ...
Background
The neutrophil percentage-to-albumin ratio (NPAR), which is defined as the percentage of neutrophils divided by the concentration of albumin, is a cost-effective and readily available biomarker of inflammation. This study aimed to evaluate the association between the NPAR and the severity of coronary atherosclerosis in patients with chronic kidney disease (CKD).
Methods
A total of 280 CKD patients who underwent coronary angiography were retrospectively enrolled in this study. The severity of coronary atherosclerosis was evaluated using the Gensini score (GS). Patients were divided into low-, medium- and high-NPAR groups according to the tertiles of the NPAR values. Logistic regression analysis was conducted to analyze the relationship between the NPAR and the GS. The cutoff points for the sensitivity and specificity of the NPAR in predicting the GS were estimated via receiver operating characteristic (ROC) analysis.
Results
There was a higher prevalence of coronary artery disease (CAD) among CKD patients with higher NPARs (P =0.041). More patients in the high-NPAR group had complex CAD (triple-vessel disease and/or left main coronary artery stenosis) and chronic total occlusion lesions, and more of these patients required revascularization therapy (P<0.05). Multivariate logistic regression analysis revealed a significant positive correlation between the NPAR and the severity of coronary stenosis (adjusted OR 2.68, 95% CI 1.25-5.76, p=0.012), particularly among female and older (age ≥65) patients. The ROC analysis indicated that the optimal cutoff value for the NPAR in predicting severe coronary artery stenosis (GS>60) in CKD patients was 1.91 (sensitivity 0.495, specificity 0.749), with an area under the curve (AUC) of 0.650 (95% CI 0.581-0.719, P<0.001). A subgroup analysis according to sex revealed that the NPAR exhibited stronger predictive value in female patients (AUC 0.730, 95% CI 0.643-0.817) than in male patients (AUC 0.565, 95% CI 0.460-0.670) (P<0.001), and the optimal cutoff value for the NPAR in female patients was 1.80 (sensitivity 0.667, specificity 0.705).
Conclusions
Our study demonstrated that the NPAR is independently associated with the severity of coronary atherosclerosis in CKD patients, especially in female and elderly patients (≥65 years old). Moreover, the NPAR can effectively predict the severity of coronary atherosclerosis, exhibiting greater predictive value in females than in males.
... Adaptive immune cells are also abundant in CAD, but the importance of adaptive immunity for atherosclerosis progression remains less clear than for innate immunity and is a topic of ongoing investigation. T cells of both the helper and cytotoxic phenotype are detected in advanced plaque stages and in culprit lesions, whereas the anti-inflammatory regulatory T cells have been reported in higher numbers in younger compared with older patients with CAD [7,10,[13][14][15]. The role for B cells in CAD appears a two-edged sword as well: pro-inflammatory when they assist in T cell activation and possibly anti-inflammatory upon production of antibodies against oxidation and other epitopes presented in the atherosclerotic plaque [7,18,19]. ...
Background
Aim of this study was to investigate immune cells and subsets in different stages of human coronary artery disease with a novel multiplex immunohistochemistry (mIHC) technique.
Methods
Human left anterior descending coronary artery specimens were analyzed: eccentric intimal thickening (N = 11), pathological intimal thickening (N = 10), fibroatheroma (N = 9), and fibrous plaque (N = 9). Eccentric intimal thickening was considered normal, and pathological intimal thickening, fibroatheroma, and fibrous plaque were considered diseased coronary arteries. Two mIHC panels, consisting of six and five primary antibodies, autofluoresence, and DAPI, were used to detect adaptive and innate immune cells. Via semi-automated analysis, (sub)types of immune cells in whole plaques and specific plaque regions were quantified.
Results
Increased numbers of CD3⁺ T cells (P < 0.001), CD20⁺ B cells (P = 0.013), CD68⁺ macrophages (P = 0.003), CD15⁺ neutrophils (P = 0.017), and CD31⁺ endothelial cells (P = 0.024) were identified in intimas of diseased coronary arteries compared to normal. Subset analyses of T cells and macrophages showed that diseased coronary arteries contained an abundance of CD3⁺CD8⁻ non-cytotoxic T cells and CD68⁺CD206⁻ non-M2-like macrophages. Proportions of CD3⁺CD45RO⁺ memory T cells were similar to normal coronary arteries. Among pathological intimal thickening, fibroatheroma, and fibrous plaque, all immune cell numbers and subsets were similar.
Conclusions
The type of immune response does not differ substantially between different stages of plaque development and may provide context for mechanistic research into immune cell function in atherosclerosis. We provide the first comprehensive map of immune cell subtypes across plaque types in coronary arteries demonstrating the potential of mIHC for vascular research.
... Atherosclerotic plaque is classified into stable and unstable phenotypes (3). The stable atherosclerotic plaque is characterised by a thick fibrous cap covering a small necrotic core, which can withstand haemodynamic changes and stresses and is therefore less susceptible to rupture (3,12). In contrast, the unstable atherosclerotic plaque that is prone to rupture is associated with a thin fibrous cap covering a large necrotic core (10). ...
Atherosclerosis, which is a primary cause of cardiovascular disease (CVD) deaths around the world, is a chronic inflammatory disease that is characterised by the accumulation of lipid plaques in the arterial wall, triggering inflammation that is regulated by cytokines/chemokines that mediate innate and adaptive immunity. This review focuses on IL-32,-34 and-37 in the stable vs. unstable plaques from atherosclerotic patients. Dysregulation of the novel cytokines IL-32,-34 and-37 has been discovered in atherosclerotic plaques. IL-32 and-34 are pro-atherogenic and associated with an unstable plaque phenotype; whereas IL-37 is anti-atherogenic and maintains plaque stability. It is speculated that these cytokines may contribute to the explanation for the increased occurrence of atherosclerotic plaque rupture seen in patients with COVID-19 infection. Understanding the roles of these cytokines in atherogenesis may provide future therapeutic perspectives, both in the management of unstable plaque and acute coronary syndrome, and may contribute to our understanding of the COVID-19 cytokine storm.
... I have further collaborated with Cris and his PhD student with fruitful outcome (Chhabra et al. 2002). I have listed few selective publications over 31 years (Ramsay et al. 1994, Bao et al. 1996, Bao et al. 2000, Najib et al. 2012, Fang et al. 2013, Puranik et al. 2016, Liao et al. 2018, Fan et al. 2020a, initial achievement from Cris's group, and the following achievement by my own research group, but is benefit greatly from the great 3 years of PhD training under Prof dos Remedios. ...
As a non-English-speaking PhD student without previous scientific skills, I have been so lucky to be supervised and mentored by Professor Cristobal dos Remedios. In this commentary, I have commented my experience in dos Remedios laboratory. Finally, I would like to express my greatest appreciation to Professor dos Remedios for his kindness and mentorship over the last 31 years. His continuous support, which continues to the present, has been instrumental for the achievement of my current position.
... The role of immune dysregulation in the etiology of chronic diseases has been a topic of much recent research, including studies on the etiology of hematologic malignancies (reviewed in ref. 1), solid tumors (2)(3)(4)(5)(6), and nonmalignant conditions (7)(8)(9). Studies of immune marker-disease associations are often limited to a single mea-surement of each biomarker per study participant, using blood samples that may have been collected years before a target disease is diagnosed. It is important to understand the within-person temporal stability of the immunologic biomarkers of interest so that the potential misclassification of immune status of the participants is adequately considered in the interpretation of the etiologic data. ...
Background:
Prospective cohort studies often quantify serum immune biomarkers at a single time point to determine risk of cancer and other chronic diseases that develop years later. Estimates of the within-person temporal stability of serum markers partly assess the utility of single biomarker measurements and may have important implications for the design of prospective studies of chronic disease risk.
Methods:
Using archived sera collected from 200 HIV-seronegative men at three visits spaced over approximately 2 years, concentrations of 14 biomarkers (ApoA1, sCD14, sgp130, sIL-6R, sIL-2Rα, sTNFR2, BAFF/BLyS, CXCL13, IFN-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, and TNF-α) were measured in a single laboratory. Age- and ethnicity-adjusted intraclass correlation coefficients (ICC) were calculated for each biomarker, and mixed linear regression models were used to examine the influence of age, ethnicity, season, and study site on biomarker concentrations.
Results:
Across all three study visits, most biomarkers had ICC values indicating fair to excellent within-person stability. ApoA1 (ICC = 0.88) and TNF-α (ICC = 0.87) showed the greatest stability; the ICC for IL-8 (ICC = 0.33) was remarkably less stable. The ICCs were similar when calculated between pairs of consecutive visits. The covariables did not influence biomarker levels or their temporal stability. All biomarkers showed moderate to strong pairwise correlations across visits.
Conclusions:
Serum concentrations of most evaluated immune biomarkers displayed acceptable to excellent within-person temporal reliability over a 2-year period. Further investigation may be required to clarify the stability of IL-8.
Impact:
These findings lend support to using these serologic immune biomarkers in prospective studies investigating associations with chronic diseases.
... Several studies report that increased levels of circulating proinflammatory cytokines, such as IL-6 and TNFα and their receptors, serve as significant independent risk factors for mortality and morbidity in the elderly [130]. High levels of proinflammatory cytokines in the elderly were also correlated with 2-4 fold increase in production of several acute-phase chemokines such as vascular cell adhesion molecule 1 (VCAM-1), and C-reactive protein (CRP), both soluble molecules that are associated with several age-related pathologies including atherosclerosis and insulin resistance [88,[131][132][133][134]. ...
The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of pro-inflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has far-reaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad.
Background
Thrombocytosis and inflammation are vital elements in the pathogenesis of atherosclerosis. The platelet-to-lymphocyte ratio (PLR) is a novel biomarker that combines these parameters and has been shown to be associated with cardiovascular disease (CVD). This study aimed to determine whether PLR correlates with coronary artery disease (CAD) in high-risk patients, and if the relationship is affected by age.
Methods
Consecutive patients referred for coronary angiogram were evaluated (n = 822). with 608 patients demonstrating CAD, compared to 214 patients with normal coronary arteries. Patients were stratified into premature CAD (age < 55) and non-premature CAD (age ≥ 55). High and low PLR groups were defined as admission PLR in the highest (≥146.7) and lower two tertiles (<146.7) respectively. Multivariate logistic regression was undertaken to adjust for traditional cardiovascular risk factors.
Results
In univariate analysis, high PLR negatively correlated with premature CAD (OR 0.45, 95%CI 0.23–0.87, P = 0.017), while its association with CAD in older patients did not reach statistical significance (OR 1.32, 95%CI 0.89–1.97, P = 0.170). After adjustment for traditional risk factors, high PLR was significantly associated with increased CAD in older patients (OR 2.22, 95%CI 1.28–3.82, P = 0.004) but decreased premature CAD (OR 0.31, 95%CI 0.11–0.87, P = 0.026).
Conclusions
There is an age-related effect on the correlation between PLR and CAD. While high PLR was an independent marker of CAD in older high-risk patients, it was negatively correlated with premature CAD in younger patients. PLR is widely available and inexpensive, and could be used in highlighting patients at high risk for CAD.
Cardiovascular diseases remain a major global health issue, with the development of atherosclerosis as a major underlying cause. Our treatment of cardiovascular disease has improved greatly over the past three decades, but much remains to be done reduce disease burden. Current priorities include reducing atherosclerosis advancement to clinically significant stages and preventing plaque rupture or erosion. Inflammation and involvement of the adaptive immune system influences all these aspects and therefore is one focus for future therapeutic development. The atherosclerotic vascular wall is now recognized to be invaded from both sides (arterial lumen and adventitia), for better or worse, by the adaptive immune system. Atherosclerosis is also affected at several stages by adaptive immune responses, overall providing many opportunities to target these responses and to reduce disease progression. Protective influences that may be defective in diseased individuals include humoral responses to modified LDL and regulatory T cell responses. There are many strategies in development to boost these pathways in humans, including vaccine-based therapies. The effects of various existing adaptive immune targeting therapies, such as blocking critical co-stimulatory pathways or B cell depletion, on cardiovascular disease are beginning to emerge with important consequences for both autoimmune disease patients and the potential for wider use of such therapies. Entering the translation phase for adaptive immune targeting therapies is an exciting and promising prospect.
Linked articles:
This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
Objective:
The contribution of regulatory T cells (Tregs) to the pathogenesis of acute coronary syndrome (ACS) remains poorly understood. One core obstacle is the lack of Treg-specific markers. A highly conserved CpG enriched element in forkhead box P3 intron 1 (FOXP3 i l) is unmethylated only in Tregs, and measuring the unmethylation of FOXP3 i l can be used to identify the role of Tregs in clinical diseases. This study investigated whether analyzing the demethylation status of FOXP3 i 1 is a more reliable means than using Treg-specific surface markers in ACS.
Methods and results:
We evaluated circulating Tregs percentages on different levels including cell frequencies (CD4(+)CD25(hi)FOXP3(+)Tregs and CD4(+)CD25(hi)CD45(+)naïve Tregs) or FOXP3 mRNA, FOXP3 i 1 demethylation status and related cytokine secretion in 89 patients with ACS and 35 controls. FOXP3 i 1 demethylation assay showed that the amount of Tregs in ACS patients was significantly reduced than that in controls (p = 0.0005). However, flow cytometry analysis did not identify any reduction of CD4(+)CD25(hi)FOXP3(+)Tregs in ACS patients. Notably, younger patients had higher percentage of CD4(+)CD25(hi)FOXP3(+)Tregs but decreased percentage of CD4(+)CD25(hi)CD45(+)naïve Tregs than either controls or older patients. Furthermore, a DNA hypomethylation agent increased the amount of CD4(+)CD25(hi)FOXP3(+)Tregs and Tregs related cytokine IL-10 and suppressed the production of pro-inflammatory cytokine interferon-γ by inducing FOXP3 i 1 demethylation in vitro.
Conclusions:
A quantitative defect of Tregs, suggestive of decreased peripheral tolerance, could be a potential hallmark of ACS disease. Targeting FOXP3 i l demethylation might elevate the inhibitory activity of Tregs in ACS.
Inflammation is important in plaque vulnerability but the role of atheroprotective mediators in unstable plaques is not defined. The apolipoproteinA-I (apoA-I) component of HDL, and CD4+/CD25+ regulatory T cells (with their major transcription factor, Foxp3), have been implicated in the suppression of vascular inflammation. Our aim was to characterise the presence of these novel "protective" markers (apoA-I and Foxp3) in carotid plaques from symptomatic and asymptomatic subjects.
Plaques from 57 patients (25 symptomatic, 32 asymptomatic) were stained immunohistochemically for macrophages (CD68), T cells (CD3), monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2), myeloperoxidase (MPO), apoA-I and Foxp3. Twelve randomly selected plaques (6 asymptomatic, 6 symptomatic) were immunostained for interleukin-10 (IL-10) and interleukin-17 (IL-17). Staining was quantified using Image-Pro Plus software. Significantly greater areas of positive immunostaining for CD68, CD3, MCP-1, MMP-2, IL-17 and MPO were found in plaques from symptomatic patients compared with asymptomatic patients (p<0.05 for all). Furthermore, significantly greater areas of positive immunostaining for apoA-I, Foxp3 and IL-10 were found in symptomatic versus asymptomatic plaques (p<0.05 for all). The presence of apoA-I was correlated significantly and co-localised with CD3, CD68, MCP-1, MMP-2 and MPO immunostaining (R=0.70, 0.63, 0.52, 0.55 and 0.79, respectively; p<0.01 for all). Foxp3 immunostaining also correlated significantly with CD3 (R=0.42), CD68 (R=0.47), MCP-1 (R=0.55) and MMP-2 (R=0.44) immunostaining (p<0.05 for all).
ApoA-I and Foxp3 are over-abundant in plaques from symptomatic subjects and co-localise with key inflammatory mediators. These data suggest ineffective/insufficient protection against atherosclerosis-mediated inflammation by these "atheroprotective" moieties.
Biochemical, physiologic, and ultrastructural modifications which appear in the aortic intima and atrioventricular valves before monocyte diapedesis and foam cell formation were investigated in rabbits fed a cholesterol-rich diet. In the first 2 weeks of the diet, while plasma beta-VLDL cholesterol was increased up to 15-fold, the intima showed an enhanced uptake and deposition of dietary 3H-cholesterol, 125I-beta-VLDL, and the fluorescent beta-VLDL-1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine conjugate. beta-VLDL-gold complex perfused in situ was transcytosed across endothelium by plasmalemmal vesicles. Concomitantly, within the intima, a progressive accumulation of extracellular densely packed uni- or multilamellar vesicles took place. These commonly occurred in cell-free subendothelial spaces and were not associated with any sign of cytolysis. In freeze-fracture preparations, these vesicles appeared as smooth surfaces, suggesting the absence of translamellar proteins. Upon incubation with filipin, these extracellular liposomes (EL) displayed characteristic approximately 20 nm filipin-sterol complexes, revealing the presence of preparations unesterified cholesterol in the phospholipid lamellas. EL deposition was paralleled by proliferation of basal lamina-like material, microfibrils, and proteoglycans, and continued to increase during foam cell formation. For the entire period of our experiments, the endothelium was morphologically intact, and no platelet involvement was detected. The results show that an early prelesional ultrastructural change in lesion-prone aortic and valvular areas is the accumulation of extracellular phospholipid liposomes rich in unesterified cholesterol.
Atherosclerosis represents one of the main causes of death and disease in industrialized societies. Patho-genetically, it is characterized by a focal, slow, and progressive accumulation of cells, extracellular matrix, and lipid in the intima of medium-sized and large arteries. The resulting luminal occlusion and thrombosis lead to fatal or severely disabling clinical manifestations such as myocardial and cerebral infarction. Large epidemiological studies have provided important information on atherosclerosis, which has been used in attempts to prevent the disease. It has been estimated, however, that only approximately 50% of the incidence of cardiovascular disease can be explained by the major risk factors. Consequently, there is room for substantial, as yet unknown, contributing factors. Furthermore, epidemiology has not provided an understanding of the pathophysiological mechanisms of atherosclerosis. With the exception of a small number of genetic disorders of lipid metabolism, the cause and molecular and cellular pathogenesis of atherosclerosis remain unclear. The growing realization of the presence of T lymphocytes in the plaque [1] and the finding of antibody responses to plaque constituents has reawakened the interest in inflammatory and immune components in atherogenesis. Much of the current interest in atherosclerosis research is focused on cell recruitment and cellular communication in the evolving atherosclerotic plaque. The presence of activated T cells and signs of T cell cytokine secretion in atherosclerotic lesions suggest a role for local T cell responses in atherogenesis. Several studies demonstrating the presence of autoantibodies to modified lipoproteins or heat shock proteins indicate that atherosclerosis may also involve B cell responses. The present review aims to summarize and discuss recent progress in this area.
HDLs have antiinflammatory and antioxidant properties in vitro. This study investigates these properties in vivo.
Chow-fed, normocholesterolemic New Zealand White rabbits received a daily infusion of (1) saline, (2) reconstituted HDL (rHDL) containing 25 mg apolipoprotein (apo) A-I and 50 mg of either 1-palmitoyl-2-linoleoyl phosphatidylcholine (PLPC) or 1,2-dipalmitoyl phosphatidylcholine (DPPC), (3) 25 mg lipid-free apoA-I, or (4) 50 mg of either PLPC-small unilamellar vesicles (SUVs) or DPPC-SUVs on each of 3 consecutive days. Nonocclusive carotid periarterial collars were implanted after the second dose of treatment. Forty-eight hours after insertion of the collars, the arteries were removed and analyzed for the presence of reactive oxygen species, the infiltration of neutrophils, and the expression of adhesion proteins and chemokines. Insertion of the periarterial collar induced a 4.1-fold increase in presence of vascular wall reactive oxygen species. This effect was completely abolished in the animals infused with rHDL. The periarterial collar was associated with a dense infiltration of the arterial wall by polymorphonuclear leukocytes. This infiltration was inhibited by 73% to 94% in the animals infused with rHDL, by 75% in the animals infused with lipid-free apoA-I, and by 51% to 65% in animals infused with SUVs. There were no significant differences between the effects of PLPC and DPPC in either the rHDL or SUVs. Endothelial expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 was also increased by the collar insertion and inhibited by rHDL, lipid-free apoA-I, and, to a lesser extent, also by the SUVs.
Infusion of rHDL, apoA-I, and phospholipid-SUVs inhibits the early pro-oxidant and proinflammatory changes induced by a periarterial collar in normocholesterolemic rabbits.
ecent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. This review highlights the role of inflammation in the pathogen- esis of atherosclerotic CAD. It will recount the evidence that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree. A decade ago, the treatment of hypercholesterolemia and hypertension was expect- ed to eliminate CAD by the end of the 20th century. Lately, however, that optimistic pre- diction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world. 1 Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.
Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis in several mouse models. These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells.
T cell mediated inflammation contributes to atherogenesis and the onset of acute cardiovascular disease. Effector T cell functions are under a tight control of a specialized T cell subset, regulatory T cells (Treg). At present, nothing is known about the in situ presence of Treg in human atherosclerotic tissue. In the present study we investigated the frequency of naturally occurring Treg cells in all developmental stages of human atherosclerotic lesions including complicated thrombosed plaques.
Normal arteries, early lesions (American Heart Association classification types I, II, and III), fibrosclerotic plaques (types Vb and Vc) and 'high risk' plaques (types IV, Va and VI) were obtained at surgery and autopsy. Serial sections were immunostained for markers specific for regulatory T cells (FOXP3 and GITR) and the frequency of these cells was expressed as a percentage of the total numbers of CD3+ T cells. Results were compared with Treg counts in biopsies of normal and inflammatory skin lesions (psoriasis, spongiotic dermatitis and lichen planus).
In normal vessel fragments T cells were virtually absent. Treg were present in the intima during all stages of plaque development (0.5-5%). Also in the adventitia of atherosclerotic vessels Treg were encountered, in similar low amounts. High risk lesions contained significantly increased numbers of Treg compared to early lesions (mean: 3.9 and 1.2%, respectively). The frequency of FOXP3+ cells in high risk lesions was also higher compared to stable lesions (1.7%), but this difference was not significant. The mean numbers of intimal FOXP3 positive cells in atherosclerotic lesions (2.4%) was much lower than those in normal (24.3%) or inflammatory skin lesions (28%).
Low frequencies of Treg in all developmental stages of human plaque formation could explain the smoldering chronic inflammatory process that takes place throughout the longstanding course of atherosclerosis.
CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) are potent suppressors of the adaptive immune system, but their effects on innate immune cells are less well known. Here we demonstrate a previously uncharacterized function of Tregs, namely their ability to steer monocyte differentiation toward alternatively activated macrophages (AAM). AAM are cells with strong antiinflammatory potential involved in immune regulation, tissue remodeling, parasite killing, and tumor promotion. We show that, after coculture with Tregs, monocytes/macrophages display typical features of AAM, including up-regulated expression of CD206 (macrophage mannose receptor) and CD163 (hemoglobin scavenger receptor), an increased production of CCL18, and an enhanced phagocytic capacity. In addition, the monocytes/macrophages have reduced expression of HLA-DR and a strongly reduced capacity to respond to LPS in terms of proinflammatory mediator production (IL-1β, IL-6, IL-8, MIP-1α, TNF-α), NFκB activation, and tyrosine phosphorylation. Mechanistic studies reveal that CD4⁺CD25⁺CD127lowFoxp3⁺ Tregs produce IL-10, IL-4, and IL-13 and that these cytokines are the critical factors involved in the suppression of the proinflammatory cytokine response. In contrast, the Treg-mediated induction of CD206 is entirely cytokine-independent, whereas the up-regulation of CD163, CCL18, and phagocytosis are (partly) dependent on IL-10 but not on IL-4/IL-13. Together these data demonstrate a previously unrecognized function of CD4⁺CD25⁺Foxp3⁺ Tregs, namely their ability to induce alternative activation of monocytes/macrophages. Moreover, the data suggest that the Treg-mediated induction of AAM partly involves a novel, cytokine-independent pathway.
• alternatively activated macrophages
• mannose receptor
• phagocytosis
• proinflammatory response
• interleukin-10
Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.
The advanced lesions of atherosclerosis represent the culmination of a specialized form of chronic inflammation followed by a fibroproliferative process that takes place within the intima of the affected artery. Proliferation of smooth muscle cells and generation of connective tissue occur. Proliferation results from interactions between arterial smooth muscle, monocyte-derived macrophages, T lymphocytes, and endothelium. The initial lesion of atherosclerosis, the fatty streak, begins as an accumulation of monocytederived macrophages and T lymphocytes, which adhere and migrate into the intima of the affected artery. Smooth muscle cells, which are present in the intima or which migrate into the intima from the media, then replicate. Monocyte-derived macrophages and T cells also replicate during lesion formation and progression due to the production of cytokines and growth-regulatory molecules. These molecules determine whether there is proliferation and lesion progression or inhibition of proliferation and lesion regression. Several growthregulatory molecules may play critical roles in this process, including platelet-derived growth factor (PGDF), transforming growth factor beta, fibroblast growth factor, heparinbinding epidermal growth factor-like growth factor, and others. PDGF may be one of the principal components in this process because protein containing the PDGF B-chain has been demonstrated within activated lesion macrophages during every phase of atherogenesis. The presence of this growth factor and its receptors on lesion smooth muscle cells creates opportunities for smooth muscle chemotaxis and replication. Smooth muscle proliferation depends upon a series of complex signals based upon cellular interactions in the local microenvironment of the artery. The intracellular signalling pathways for mitogenesis versus chemotaxis are being investigated for smooth muscle. The roles of the cytokines and growth-regulatory peptides involved in these cellular interactions represent critical points of departure for intervention and the development of new diagnostic methods. In addition, magnetic resonance imaging has been developed to demonstrate the fine structure of lesions of atherosclerosis in peripheral arteries not subject to cardiac motion. This noninvasive methodology holds great promise for the future of these approaches.
JID: 8200291; 2008/11/17 [received]; 2008/11/17 [accepted]; 2008/11/28 [aheadofprint]; ppublish
The concept of an alternative pathway of macrophage activation has stimulated interest in its definition, mechanism, and functional significance in homeostasis and disease. We assess recent research in this field, argue for a restricted definition, and explore pathways by which the T helper 2 (Th2) cell cytokines interleukin-4 (IL-4) and IL-13 mediate their effects on macrophage cell biology, their biosynthesis, and responses to a normal and pathological microenvironment. The stage is now set to gain deeper insights into the role of alternatively activated macrophages in immunobiology.
Although inflammation is a key process in atherogenesis, little is known about the inflammatory characteristics of culprit plaque in premature coronary artery disease (CAD). We investigated inflammation in coronary atheroma from subjects who died of premature CAD. From 2001-2005, we collected coronary plaque samples from consecutive cases of CAD (n=23) reported to the Department of Forensic Medicine which led to unexpected death in men aged <45 years. Coronary plaque from younger CAD decedents (<35 years, n=12) had lower levels of T cells (CD3+) (p=0.03), higher macrophage (CD 68+) (p=0.01) and T regulator cells (FOXP3+) (p=0.03) infiltration when compared to older CAD decedents (>35 years, n=11). Interestingly, there was no significant age-related difference between groups in the smooth muscle cell, apoA-I, myeloperoxidase and MMP-2 content within plaque. Hence, we demonstrate that higher expression of FOXP3 is associated with younger age at the time of fatal outcomes from CAD. These findings may have implications for plaque pathophysiology and thus warrant further investigation.
Localized scleroderma is a connective tissue disorder that is limited to the skin and subcutaneous tissue. Macrophages have been reported to be particularly activated in patients with skin disease including systemic sclerosis and are potentially important sources for fibrosis-inducing cytokines, such as transforming growth factor beta. To clarify the features of immunohistochemical characterization of the immune cell infiltrates in localized scleroderma focusing on macrophages, skin biopsy specimens were analysed by immunohistochemistry. The number of cells stained with monoclonal antibodies, CD68, CD163 and CD204, was calculated. An evident macrophage infiltrate and increased number of alternatively activated macrophages (M2 macrophages) in their fibrotic areas were observed along with their severity of inflammation. This study revealed that alternatively activated macrophages (M2 macrophages) may be a potential source of fibrosis-inducing cytokines in localized scleroderma, and may play a crucial role in the pathogenesis of localized scleroderma.
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Thus the lesions of atherosclerosis represent a protective, inflammatory-fibroproliferative response against the different agents that can cause the disease. If the injury continues over a long period of time, it may become excessive, and in its excess it becomes the disease itself. It has been shown that this excessive, inflammatory, fibroproliferative response can be reversed given sufficient opportunity for the injurious factors to be modified. Approaches to modifying specific cellular interactions, growth- regulatory molecules, or intracellular signaling molecules may afford opportunities to modify these processes and lead to lesion prevention or regression.
Atherosclerosis is an inflammatory disease. Its lesions are filled with immune cells that can orchestrate and effect inflammatory responses. In fact, the first lesions of atherosclerosis consist of macrophages and T cells. Unstable plaques are particularly rich in activated immune cells, suggesting that they may initiate plaque activation. We have seen a rapid increase in the understanding of the mechanisms that govern the recruitment, differentiation, and activation of immune cells in atherosclerosis. Experimental research has identified several candidate antigens, and there are encouraging data suggesting that immune modulation as well as immunization can reduce the progression of the disease. This review provides an overview of our current understanding of the role of immune mechanisms in atherosclerosis.
This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis. Rapidly mobilized arms of innate immunity, including phagocytic leukocytes, complement, and proinflammatory cytokines, contribute to atherogenesis. In addition, adaptive immunity, with its T cells, antibodies, and immunoregulatory cytokines, powerfully modulates disease activity and progression. Atherogenesis involves cross talk between and shared pathways involved in adaptive and innate immunity. Immune processes can influence the balance between cell proliferation and death, between synthetic and degradative processes, and between pro- and antithrombotic processes. Various established and emerging risk factors for atherosclerosis modulate aspects of immune responses, including lipoproteins and their modified products, vasoactive peptides, and infectious agents. As we fill in the molecular details, new potential targets for therapies will doubtless emerge.
Suppressor T cells play important roles in the regulation of immune responses and the mediation of dominant immunologic tolerance. Studies of suppressor T-cell function have been hampered until their recent identification as a minor fraction (approximately 10%) of CD4 ( +) T cells that coexpress CD25. CD4(+)CD25(+ ) T cells have been shown to play a critical role in the prevention of organ- specific autoimmunity and allograft rejection. Because tumor antigens are self- antigens, it is not surprising that CD4(+)CD25(+) T cells also inhibit the induction of tumor immunity. The spectrum of activity of CD4(+ ) CD25(+) cells extends to non-self-antigens, including infectious agents. Indeed, T cell-mediated suppression might be responsible for the low level of chronic infection seen with many pathogens. Interestingly, however, this persistent level of infection might be beneficial to the host and needed for maintenance of immunologic memory. Although CD4(+ ) CD25(+) T cells are capable of inhibiting T(H)2 responses, their role in the suppression of allergic responses has not been firmly established. Depending on the desired immune response, enhancement or restraint of suppressor T-cell function might be required. Therefore immunologic or pharmacologic manipulation of regulatory T-cell populations represents an important future approach to immunotherapy of a wide range of immune responses.
The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
Macrophage heterogeneity used to be a research topic on which the careers of many postdoctoral fellows were misspent. The lack of definitive markers and dubious biochemical assays prevented the unequivocal identification of specific cell subsets. There has now been significant progress in establishing the heterogeneity of activated macrophages. There are at least three distinct populations of macrophages, and each cell type appears to have different biological roles. The interplay among these populations of cells may help to shape not only the magnitude but also the character of the immune response. The manipulation of these cells may lead to new approaches to treat or prevent disease.
Inflammation plays a pivotal role in both the development of atherosclerosis and the acute activation of the vascular wall with consequent local thrombosis and vasoconstriction (with or without plaque fissure). In many patients with unstable angina and acute myocardial infarction, systemic signs of inflammation are detectable. The use of systemic inflammatory markers, such as C-reactive protein as marker of disease activity and short- and long-term prognosis, seems to be of clinical value. Therefore, acute inflammatory reaction, detectable systematically, appears to be an independent determinant of prognosis in some patients with acute ischemic syndromes, but is not detectable in all. Understanding the causes of inflammation and the additional elusive components that result in the progression to aggressive acute coronary syndromes, is the future goal of cardiology.
CD4+CD25+ T(reg) cells inhibit colitis in the severe combined immune deficient (SCID) T cell adoptive transfer model. Cells with this function are present in the thymus suggesting that T(reg) cells capable of inhibiting bacteria-induced immune pathology are similar to those that inhibit organ-specific autoimmunity. CD4+CD25+ T(reg) cells inhibit both T cell-dependent and T cell-independent intestinal inflammation. The latter point illustrates that in addition to direct effects on other T cells, T(reg) cells can alsoprevent immune pathology in vivo by inhibiting the actions of innate immune cells. T(reg) cells suppress intestinal inflammation through mechanisms that involve interleukin 10 and transforming growth factor beta and blockade of the negative regulator of T cell activation CTLA4 abrogates T(reg) cell function in vivo. Importantly adoptive transfer of CD4+CD25+ T(reg) cells to mice with established colitis reverses inflammation and restores normal intestinal architecture suggesting that CD4+CD25+ T(reg) cells may be utilized for cellular therapy of inflammatory diseases.
Sudden death is rare in young people, but it has a disproportionate impact on the community.
The purpose of this study was to determine the causes of sudden, natural death in persons aged 5-35 years.
All autopsies conducted at a forensic medicine facility in the years 1995-2004 (inclusive) were reviewed. This facility serves more than 2.5 million people in the eastern part of Sydney, Australia. Data collected included subject age, height, weight, gender, circumstances of death, and pathologic findings at autopsy. Deaths caused by trauma, accidental causes, drowning, and drug toxicity were excluded from analysis.
There were 427 nontraumatic, sudden deaths in the 10-year period (70.7% male). Cardiac causes accounted for 56.4%, noncardiac causes 39.3%, and undetermined cause 4.3%. The most common cardiac cause of sudden death was presumed arrhythmia in those with no or minimal structural heart disease (29.0%). Other cardiac causes were acute myocardial infarction (24.5%), myocarditis (11.6%), hypertrophic cardiomyopathy (5.8%), aortic dissection (5.4%), and dilated cardiomyopathy (5.4%). More than two thirds of deaths caused by acute myocardial infarction occurred in the age group from 30-35 years. Sudden cardiac death occurred during physical activity in 10.8% of cases. Sudden cardiac death was reported in a first-degree relative in 4.5% of decedents. The most common noncardiac causes of sudden death were epilepsy (23.8%), intracerebral hemorrhage (23.8%), asthma (16.1%), and pulmonary embolism (12.5%).
Presumed cardiac arrhythmia is the most common cause of sudden, natural death in the young. There was no reported history of sudden death among the relatives of most decedents.
PURPOSE: The aim of this article is to discuss the role of inflammation in atherosclerosis. SUMMARY: An initial chemical, mechanical or immunological insult induces endothelial dysfunction. This triggers a cascade of inflammatory reactions, in which monocytes, macrophages, T lymphocytes and vascular smooth muscle cells participate. Leukocyte adhesion molecules, cytokines, growth factors and metalloproteinases participate in all stages of atherogenesis. Almost all of the traditional risk factors for atherosclerosis are associated with and participate in the inflammatory process. Many infectious agents, mainly Chlamydia pneumoniae, have been proposed as potential triggers of the cascade. The immune system has been implicated in plaque formation, through the activation of cellular and humoral immunity against innate or microbial heat shock protein 60. Methods of detection of systemic or local plaque inflammation have been developed and research is being conducted on the potential use of anti-inflammatory and antibiotic drugs in atherosclerosis.
The immune system has evolved numerous mechanisms of peripheral T cell immunoregulation, including a network of regulatory T (Treg) cells, to modulate and down-regulate immune responses at various times and locations and in various inflammatory circumstances. Amongst these, naturally occurring CD4(+)CD25(+) Treg cells (nTreg) represent a major lymphocyte population engaged in the dominant control of self-reactive T responses and maintaining tolerance in several models of autoimmunity. CD4(+)CD25(+) Treg cells differentiate in the normal thymus as a functionally distinct subpopulation of T cells bearing a broad T cell receptor repertoire, endowing these cells with the capacity to recognize a wide range of self and nonself antigen specificities. The generation of CD4(+)CD25(+) Treg cells in the immune system is genetically controlled, influenced by antigen recognition, and various signals, in particular, cytokines such as interleukin-2 and transforming growth factor-beta1, control their activation, expansion, and suppressive effector activity. Functional abrogation of these cells in vivo or genetic defects that affect their development or function unequivocally promote the development of autoimmune and other inflammatory diseases in animals and humans. Recent progress has shed light on our understanding of the cellular and molecular basis of CD4(+)CD25(+) Treg cell-mediated immune regulation. This article discusses the relative contribution of CD4(+)CD25(+) nTreg cells in the induction of immunologic self-tolerance and provides a comprehensive overview of recent finding regarding the functional properties and effector mechanism of these cells, as revealed from various in vitro and in vivo models.
CD4+CD25+ regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and preventing autoimmune disease. The transcription factor forkhead box protein 3 (Foxp3) has been identified as a molecular marker for Treg cells. Foxp3 is highly expressed in lymphoid tissue and several signalling pathways influence its expression. It plays an essential role in the development and function of Treg cells. Mutations in Foxp3 are responsible for the scurfy (sf) mutant mouse, and for autoimmune human diseases including the X-linked fatal "immune dysregulation, polyendocrinopathy, enteropathy, X-linked" (IPEX), autoimmune colitis and rheumatoid arthritis. Recent studies have also revealed an important and novel anti-atherogenic role for Treg cells and consequently for Foxp3. These data open up potential novel therapeutic avenues for the management of atherosclerosis.
Inflammation plays an important role in the initiation and progression of atherosclerosis but many of its underlying mechanisms remain to be explored. Atherosclerotic plaques which are more prone to destabilisation and rupture, leading to clinical events, are characterised by increased infiltration of leukocytes and other inflammatory mediators, compared with stable fibrotic plaques. T cell mediated responses, through expression of cytokines and chemokines, play an important role in the inflammatory process; and more recently potentially anti-inflammatory markers have also been identified. Current management involves both mechanical restoration of blood flow and pharmacotherapy aimed in part at suppressing the underlying inflammatory mechanisms. The aims of this review are to outline the pro- and anti-inflammatory processes in atherosclerosis, as well as their clinical implications.
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