CD4(+)CD28(null) T Cells are related to previous cytomegalovirus infection but not to accelerated atherosclerosis in ANCA-associated vasculitis (original) (raw)
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Atherosclerosis, 2001
The possible contribution of cytomegalovirus (CMV) to pathogenetic events associated with atherosclerotic lesion establishment and progression is still controversial. We evaluated the possibility that active ongoing CMV infection could be correlated to evolution of unstable atheromatous lesion, by analyzing patients suffering from unstable angina (n = 61), acute myocardial infarction (n=43), stable angina (n= 26) and peripheral arteriopathy (n = 22) as compared to healthy subjects (n =30). Particularly, we assessed: past exposure to CMV by evaluating anti-CMV IgG antibodies; ongoing CMV infection by evaluating anti-CMV IgM antibodies and circulating interleukin (IL)-8 in serum; and CMV DNAemia in peripheral blood mononuclear cells (PBMC). Mean IgG values were significantly increased in patients from all groups, as compared to healthy subjects. CMV-specific IgM, as well as CMV DNAemia, were undetectable in both controls and patients. Circulating IL-8, significantly elevated in a group of individuals experiencing active CMV infection, was not significantly higher in cardiovascular disease patients, as compared to control subjects. These findings confirm previous evidence from the increased exposure to CMV infection in patients with atheromatous lesions. However, they provide further evidence against a direct implication of active systemic CMV infection in the pathogenesis of cardiovascular diseases, particularly those involving plaque instability.
Clinical and Experimental Rheumatology, 2021
Objective Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aims of this study were to study the associations between subsets of T-cells, subclinical atherosclerosis assessed by intima-media thickness (IMT) and serological status for CMV in patients with RA. Methods Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were included in a prospective study of atherosclerosis. Controls matched for age and sex were also included (n=44). Ultrasound measurement of IMT in the common carotid artery was undertaken at inclusion (T0), after 1.5 years (T1.5) and after 11 years (T11). At T11, flow-cytometry analysis was undertaken to investigate subsets of T-cells. Serological analysis for CMV was undertaken from samples collected at T0. Results At T0, 66% of the patients and controls were CMV immunoglobulin G-positive. CMV-IgG positive patients had a significantly more rapid increase in IMT at T1.5, compared with controls and CMV-IgG negative patients. CMV-IgG positive patients had a significantly higher percentage of T-cells lacking CD28 (both CD4 + CD28null and CD8 + CD28null T-cells) than CMV-IgG negative patients. Increased levels of CD4 + CD28null and CD8 + CD28null T-cells were significantly associated with IMT at T11, adjusted for systolic blood pressure. CX3CR1 was expressed in CD4 + and CD8 + CD28null T-cells, but CX3CR1 per se was not associated with increased IMT. Conclusion Presence of CMV IgG-antibodies in patients with RA is associated with altered T-cell-populations and an increased burden of atherosclerosis. A possible protective effect of antiviral treatment in CMV-positive patients with new-onset RA should be considered.
Journal of Clinical Virology, 2006
Background: Over the last 30 years multiple micro-organisms have been associated with different types of vascular disease, like atherosclerosis, restenosis or transplant arteriosclerosis. Nonetheless, it is still ambiguous which molecular mechanisms are exactly involved in the exacerbating effect of microbes in these disorders. Objectives and study design: The present review summarizes sero-epidemiological, in vitro and animal data supporting the role of cytomegalovirus, a member of the herpes virus family, in vascular disease. Additionally, various ways by which the virus can potentially affect the disease will be discussed. Results: Rodent models as well as in vitro studies suggested that CMV might enhance lesion formation in various ways, like augmentation of the oxLDL uptake, altering monocyte adhesion or increasing the production of pro-inflammatory cytokines. Nevertheless, recent data from our lab and others suggest that alternative mechanisms also may contribute to CMV induced. Inspired by this, we will hypothesise alternative mechanisms by which CMV might affect atherosclerosis. Conclusions: Although researchers have tried for many years to unravel the tactics by which micro-organisms, like CMV, aggravate atherosclerosis, so far most suggested mechanisms failed to fully explain both experimental and clinical observations. Therefore, new means to elucidate the observed effects are required.
Human cytomegalovirus infection and atherothrombosis
Journal of Thrombosis and Thrombolysis, 2012
Vascular endothelium, as a key regulator of hemostasis, mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. Endothelial dysfunction caused by acute or chronic inflammation, such as in atherosclerosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites, and at the same time promotes coagulation, thrombin generation, and fibrin deposition in an attempt to close the wound. Life-long persistent infection with human cytomegalovirus (HCMV) has been associated with atherosclerosis. In vivo studies have revealed that HCMV infection of the vessel wall affects various cells including monocytes/macrophages, smooth muscle cells (SMCs) and endothelial cells (ECs). HCMV-infected SMCs within vascular lesions display enhanced proliferation and impaired apoptosis, which contribute to intimamedia thickening, plaque formation and restenosis. Monocytes play a central role in the process of viral dissemination, whereas ECs may represent a viral reservoir, maintaining persistent infection in HCMV-infected atherosclerotic patients following the primary infection. Persistent infection leads to dysfunction of ECs and activates proinflammatory signaling involving nuclear factor jB, specificity protein 1, and phosphatidylinositol 3-kinase, as well as expression of platelet-derived growth factor receptor. Activation of these pathways promotes enhanced proliferation and migration of monocytes and SMCs into the intima of the vascular wall as well as lipid accumulation and expansion of the atherosclerotic lesion. Moreover, HCMV infection induces enhanced expression of endothelial adhesion molecules and modifies the proteolytic balance in monocytes and macrophages. As a consequence, infected endothelium recruits naive monocytes from the blood stream, and the concomitant interaction between infected ECs and monocytes enables virus transfer to migrating monocytes. Endothelial damage promotes thrombin generation linking inflammation and coagulation. HCMV, in turn, enhances the thrombin generation. The virus carries on its surface the molecular machinery necessary to initiate thrombin generation, and in addition, may interact with the prothrombinase protein complex thereby facilitating thrombin generation. Thus, infection of endothelium may significantly increase the production of thrombin. This might not only contribute to thrombosis in patients with atherosclerosis, but might also induce thrombin-dependent proinflammatory cell activation. This review summarizes the existing evidence on the role of HCMV in vascular inflammation.
Heart, 2012
Background Several studies have reported a conflicting association between cytomegalovirus (CMV) infection and coronary artery disease (CAD) based on the levels of total anti-CMV antibodies. However, none have estimated the levels of specific neutralising antibodies (NA) to CMV, which may be clinically more relevant. Objective To determine whether CMVeNA titres show a better association with CAD compared with total anti-CMV antibody levels. Design CMVeNA titres were measured by microneutralisation assay and anti-CMV IgG antibodies using ELISA in 391 consecutive CAD patients compared with the same number of controls (N¼782), and 91 patients reporting recurrent cardiac events during a 4-year followup compared with those without a recurrent event (N¼182). Levels of inflammatory markers, interleukin 6, high-sensitivity C reactive protein, fibrinogen and secretory phospholipase A2 (sPLA2), were measured by ELISA. Analysis of variance and logistic regression were used for statistical analyses. Results High CMVeNA titres showed a positive association with CAD occurrence (OR 2.24, 95% CI 1.31 to 3.85, p¼0.003) and recurrent cardiac events in CAD patients (OR 4.65, 95% CI 1.21 to 17.86, p¼0.025) compared with total CMV antibodies (OR 1.67, 95% CI 1.04 to 2.69, p¼0.034, and 2.70, 1.04 to 7.02, p¼0.040, respectively). Patients with higher quartile of CMVeNA titres and sPLA2 levels had an adjusted OR of 7.82 (95% CI 1.87 to 32.65, 0.005) for recurrent cardiac events compared with those with the lowest quartiles for both markers. Conclusion These findings suggest that high CMVeNA titres in combination with inflammatory markers improve prediction of cardiac events in the Asian Indian population.
Herpesviridae, 2013
Background: Human cytomegalovirus (HCMV) infection is associated with cardiovascular disease (CVD) but the role of this virus in CVD progression remains unclear. We aimed to examine the HCMV serostatus in Russian patients (n = 90) who had undergone carotid endarterectomy (CEA) and controls (n = 82) as well as to determine the prevalence of HCMV immediate early (IE) and late (LA) antigens in carotid atherosclerotic plaques obtained from 89 patients. In addition, we sought to determine whether HCMV infection was associated with inflammatory activity in the plaque by quantifying infiltrating CD3 and CD68 positive cells and 5-LO immunoreactivity.
Human cytomegalovirus (CMV) infection is associated with a higher risk of cardiovascular disease in immunocompromised organ transplant patients. It has been linked with the pathogenesis of elevated arterial blood pressure. However, controversy exists as to whether CMV infection is associated with endothelial function, and little is known about its role as a potential risk factor for early atherosclerosis development at a young age. We aimed to discover if CMV antibody titres are associated with early vascular changes (carotid intima-media thickness, carotid artery distensibility and brachial artery flowmediated dilation), blood pressure elevation or other traditional cardiovascular risk factors. CMV antibody titres were measured in 1074 women and 857 men (aged 24-39 years) taking part in the Cardiovascular Risk in Young Finns study. CMV antibody titres were significantly higher in women compared to men. In men, high CMV antibody titres were associated directly with age (P < 0·001) and systolic (P = 0·053) and diastolic (P = 0·002) blood pressure elevation, and associated inversely with flow-mediated dilation (P = 0·014). In women, CMV antibody titres did not associate with any of the analysed parameters. In a multivariate regression model, which included traditional atherosclerotic risk factors, CMV antibody titres were independent determinants for systolic (P = 0·029) and diastolic (P = 0·004) blood pressure elevation and flow-mediated dilation (P = 0·014) in men. High CMV antibody titres are associated independently with blood pressure and brachial artery flow-mediated dilation in young men. This association supports the hypothesis that common CMV infection and/or an immune response to CMV may lead to impaired vascular function at a young age.