| 1. |
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| 2. |
- Alves Dias, Joana, et al.
(författare)
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Low-grade inflammation, oxidative stress and risk of invasive post-menopausal breast cancer - A nested case-control study from the Malmö diet and cancer cohort
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Although cancer promotes inflammation, the role of inflammation in tumor-genesis is less well established. The aim was to examine if low-grade inflammation is related to post-menopausal breast cancer risk, and if obesity modifies this association. Methods; In the Malmo Diet and Cancer cohort, a nested case-control study was defined among 8,513 women free of cancer and aged 55.73 years at baseline (1991.96); 459 were diagnosed with invasive breast cancer during follow-up (until December 31st, 2010). In laboratory analyses of blood from 446 cases, and 885 controls (matched on age and date of blood sampling) we examined systemic inflammation markers: oxidized (ox)-LDL, interleukin (IL)- 1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, white blood cells, lymphocytes and neutrophils. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer risk was calculated using multivariable conditional logistic regression. Results: Inverse associations with breast cancer were seen in fully-adjusted models, for 2nd and 3rd tertiles of ox-LDL, OR (95% CI): 0.65 (0.47.0.90), 0.63 (0.45.0.89) respectively, p-trend = 0.01; and for the 3rd tertile of TNF-α, 0.65 (0.43.0.99), p-trend = 0.04. In contrast, those in the highest IL-1β category had higher risk, 1.71 (1.05.2.79), p-trend = 0.01. Obesity did not modify associations between inflammation biomarkers and breast cancer. Conclusion; Our study does not suggest that low-grade inflammation increase the risk of post-menopausal breast cancer.
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| 3. |
- Alves Dias, Joana, et al.
(författare)
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Plasma variation and reproducibility of oxidized LDL-cholesterol and low-grade inflammation biomarkers among participants of the Malmö Diet and Cancer cohort
- 2016
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Ingår i: Biomarkers. - 1354-750X. ; 21:6, s. 562-571
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Tidskriftsartikel (refereegranskat)abstract
- Context: Large epidemiological studies often collect non-fasting samples, although the reliability of biomarkers may be uncertain. Objective: To explore the reliability and reproducibility of a single measurement of selected biomarkers in a sub-sample of the Malmö Diet and Cancer cohort. Methods: We estimated single- and average-measures intraclass correlation coefficients (ICC) for oxidized (ox)-LDL, interleukin (IL)-1β, IL-6, IL-8 and TNF-α. Results: Single-measures ICC in non-fasting samples of ox-LDL, IL-1β, IL-6, IL-8 and TNF-α were the following: 0.85, 0.71, 0.61, 0.78 and 0.66 for men, and 0.67, 0.81, 0.87, 0.69 and 0.81 for women. Biomarkers at non-fasting and fasting samples were highly correlated (all r > 0.80). Conclusions: The observed ICC suggest that most of the examined biomarkers (non-fasting blood) would allow meaningful analysis in epidemiological studies.
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| 4. |
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| 5. |
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| 6. |
- Berg, Katarina, et al.
(författare)
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Elevated CD14++CD16− Monocytes Predict Cardiovascular Events
- 2012
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 1942-325X .- 1942-3268. ; 5:1, s. 122-131
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Tidskriftsartikel (refereegranskat)abstract
- Background—Although monocytes in peripheral blood are no longer considered to be a homogeneous population, associations between distinct monocyte subsets and cardiovascular disease have not been highlighted in large epidemiological studies. Methods and Results—The study included 700 randomly selected subjects from the cardiovascular arm of the Malmö Diet and Cancer study. Among these, 123 subjects experienced ischemic cardiovascular events during the follow-up until December 2008. Mononuclear leukocytes frozen at the baseline investigation in 1991 to 1994 were thawed and analyzed with flow cytometry to enumerate monocyte subsets, based on CD14 and CD16 expression. The percentage and number of classical CD14++CD16− monocytes were increased in the cardiovascular-event group compared with the event-free subjects (median, 69% [interquartile range, 62% to 76%] versus 67% [59% to 72%], P=0.017; 344 [251 to 419] cells/μL versus 297 [212 to 384] cells/μL, P=0.003). The hazard ratio was 1.66 for suffering a cardiovascular event in the highest tertile of the number of CD14++CD16− monocytes compared with the lowest tertile, even after adjustment for common risk factors (HR, 1.66; 95% CI: 1.02 to 2.72). CD14++CD16− monocytes did not, however, associate with the extent of atherosclerosis at baseline. In contrast, the percentage of monocytes expressing CD16 was negatively associated to the extent of carotid atherosclerosis measured as intima-media thickness at baseline. The chemokine receptors CCR2, CX3CR1, and CCR5 were not differentially expressed between cases and controls on any of the monocyte subsets, but CCR5 expression on CD14+CD16++ monocytes was negatively associated to carotid intima-media thickness. Conclusions—This study shows that classical CD14++CD16− monocytes can predict future cardiovascular risk independently of other risk factors in a randomly selected population.
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| 7. |
- Berglund, Lisa, et al.
(författare)
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Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia
- 2010
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Ingår i: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. - Baltimore : Lippincott Williams & Wilkins. - 1079-5642. ; 30, s. 154-218
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca2+/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications. Methods and Results-An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice. Conclusions-These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Björkbacka, Harry, et al.
(författare)
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Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis - A review of the experimental evidence.
- 2013
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 227:1, s. 9-17
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Tidskriftsartikel (refereegranskat)abstract
- The role of inflammation in atherosclerosis and plaque vulnerability is well recognized. However, it is only during recent years it has become evident that this inflammation is modulated by immune responses against plaque antigens such as oxidized LDL. Interestingly, both protective and pathogenic immune responses exist and experimental data from animal studies suggest that modulation of these immune responses represents a promising new target for treatment of cardiovascular disease. It has been proposed that during early stages of the disease, autoimmune responses against plaque antigens are controlled by regulatory T cells that inhibit the activity of auto-reactive Th1 effector T cells by release of anti-inflammatory cytokines such as IL-10 and TGF-β. As the disease progresses this control is gradually lost and immune responses towards plaque antigens switch towards activation of Th1 effector T cells and release of pro-inflammatory cytokines such as interferon-γ, TNF-α and IL-1β. Several novel immune-modulatory therapies that promote or mimic tolerogenic immune responses against plaque antigens have demonstrated athero-protective effects in experimental models and a first generation of such immune-modulatory therapies are now in early or about to enter into clinical testing. A challenge in the clinical development of these therapies is that our knowledge of the role of the immune system in atherosclerosis largely rests on data from animal models of the disease. It is therefore critical that more attention is given to the characterization and evaluation of immune biomarkers for cardiovascular risk.
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| 12. |
- Björkbacka, Harry, et al.
(författare)
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Low Levels of Apolipoprotein B-100 Autoantibodies Are Associated With Increased Risk of Coronary Events.
- 2016
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 36, s. 765-771
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Previous smaller studies have indicated inverse associations between autoantibodies to oxidized low-density lipoprotein epitopes, and cardiovascular disease. The present study investigated associations between autoantibodies against the apolipoprotein B-100 peptides p45 and p210, respectively, and risk of incident cardiovascular disease in a large population-based cohort. APPROACH AND RESULTS: Apolipoprotein B-100 autoantibodies were analyzed by ELISA in a prospective study, including 5393 individuals (aged 46-68 years) belonging to the cardiovascular arm of the Malmö Diet and Cancer study with a follow-up time of >15 years. Subjects that suffered an acute coronary event during follow-up (n=382) had lower levels at baseline of IgM autoantibodies recognizing the native and malondialdehyde-modified apolipoprotein B-100 peptides p45 and p210 and also lower IgG levels recognizing native p210, whereas no association was found with risk for stroke (n=317). Subjects in the highest compared with lowest tertile of IgM-p45MDA (hazard ratio [95% confidence interval]: 0.72 [0.55, 0.94]; P=0.017) and IgG-p210native (hazard ratio [95% confidence interval]: 0.73 [0.56, 0.97]; P=0.029) had lower risk for incident coronary events after adjustment for cardiovascular risk factors in Cox proportional hazard regression models. Moreover, subjects with high levels of IgG-p210native were less likely to have carotid plaques as assessed by ultrasonography at baseline (odds ratio=0.81, 95% confidence interval 0.70-0.95, P=0.008 after adjustment for risk factors). CONCLUSIONS: This large prospective study demonstrates that subjects with high levels of apolipoprotein B-100 autoantibodies have a lower risk of coronary events supporting a protective role of these autoantibodies in cardiovascular disease.
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| 13. |
- Chyu, KY, et al.
(författare)
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Immunization using an Apo B-100 related epitope reduces atherosclerosis and plaque inflammation in hypercholesterolemic apo E(-/-) mice
- 2005
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 338:4, s. 1982-1989
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Tidskriftsartikel (refereegranskat)abstract
- Immune system modulates atherosclerosis and immunization using homologous LDL reduces atherosclerosis in hyperlipidemic animals. The nature of athero-protective antigenic epitopes in LDL remains unclear. We have recently identified nearly a 100 antigenic epilopes in human apo B-100 and in this study we evaluated the effects of immunization with two such epitopes on atherosclerosis in hypercholesterolemic apo E (-/-) mice. Male apo E (-/-) mice were immunized at 6-7 weeks of age with two different apo B-100 related peptide sequences using alum as adjuvant and mice immunized with alum alone served as controls. Peptide-2 immunization reduced aortic atherosclerosis by 40% and plaque inflammation by 80% compared to controls without a reduction in circulating cholesterol levels whereas Peptide-1 immunization had no effect. Peptide-2 immunization also reduced the progression of aortic lesions when mice were immunized at 16 weeks of age, suggesting the possibility of immuno-modulation in treating established atherosclerosis. The athero-protective effect of Peptide-2 immunization was absent in splenectomized mice but could be conveyed to non-immunized mice via adoptive transfer of splenocytes from peptide-2 immunized mice. In conclusion, immunization with a specific apo B-100 related peptide sequence reduces aortic atherosclerosis and plaque inflammation. Such acquired immunity and athero -protective effect appears to be mediated by splenocytes. These data demonstrate the feasibility of peptide based immunomodulating therapy for atherosclerosis.
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| 14. |
- Crisby, Milita, et al.
(författare)
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Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques - Implications for plaque stabilization
- 2001
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 1524-4539 .- 0009-7322. ; 103:7, s. 926-933
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Tidskriftsartikel (refereegranskat)abstract
- Background--The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Methods and Results--Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid Plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2 +/-8.4% versus 23.9 +/- 21.1% of the plaque area, P<0.05), less oxidized LDL immunoreactivity (13.33.6% versus 22.0 +/-6.5%, P<0.001), fewer macrophages (15.010.2% versus 25.3 +/- 12.5%, P<0.05), fewer T cells (11.29.3% versus 24.3 +/- 13.4%, P<0.05), less matrix metalloproteinase 2 (MMP-2) immunoreactivity (3.63.9% versus 8.4 +/-5.3%, P<0.05), greater tissue inhibitor of metalloproteinase 1 (TIMP-1) immunoreactivity (9.06.2% versus 3.1 +/-3.9%, P<0.05), and a higher collagen content by Sirius red staining (12.43.1% versus 7.5 +/-3.5%, P<0.005), Cell death by TUNEL staining was reduced in the pravastatin group (17.77.8% versus 32.0 +/- 12.6%, P<0.05). Conclusions--Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.
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| 15. |
- Dimayuga, Paul C, et al.
(författare)
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T Cell Modulation of Intimal Thickening After Vascular Injury. The Bimodal Role of IFN-{gamma} in Immune Deficiency.
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:Oct 13, s. 2528-2534
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Tidskriftsartikel (refereegranskat)abstract
- Background - Immune deficiency results in exuberant intimal thickening after arterial injury. The mechanisms involved are not well defined. We investigated the role of T cells and IFN-gamma in the response to injury in normal and immune-deficient Rag-1KO mice. Methods and Results - Carotid arterial injury was induced in wild-type (WT), Rag-1KO mice, and Rag-1KO mice reconstituted with T cell-enriched splenocytes. The exuberant intimal thickening in Rag-1KO mice compared with WT mice 21 days after injury was reduced by T cell transfer (P < 0.01). Exogenous IFN-gamma starting on the day of injury inhibited intimal thickening in Rag-1KO mice. However, antibody neutralization of endogenous IFN-gamma in Rag-1KO mice starting 7 days after injury decreased intimal thickening, indicating that late presence of IFN-gamma promoted intimal thickening in Rag-1KO mice. Results further suggest that the effect of late IFN-gamma in Rag-1KO mice is mediated in part by increased IRF-1 and iNOS expression, coupled with low SOCS1 expression. Conclusion - T cells inhibit intimal thickening in the early stages of the response to injury through basal IFN-gamma secretion. In the Rag-1KO mice, late IFN-gamma expression promotes intimal thickening. These findings add novel insight to conditions of immune deficiency that affect intimal thickening.
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| 16. |
- Dimayuga, Paul, et al.
(författare)
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Inhibitory effect on arterial injury-induced neointimal formation by adoptive B-cell transfer in Rag-1 knockout mice.
- 2002
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1524-4636 .- 1079-5642. ; 22:4, s. 644-649
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the effect of B-cell reconstitution in immune-deficient Rag-1 knockout (KO) mice subjected to arterial injury. After 21 days, injury induced a 4- to 5-fold increase in neointimal formation in Rag-1 KO mice fed normal chow compared with wild-type (WT) mice (0.020+/-0.0160 [n=8] versus 0.0049+/-0.0022 [n=8] mm(2), respectively; P<0.05) and in western-type diet-fed Rag-1 KO mice compared with WT mice (0.0312+/-0.0174 [n=7] versus 0.0050+/-0.0028 [n=6] mm(2), respectively; P<0.05). To investigate the role of B cells in response to injury, Rag-1 KO mice were reconstituted with B cells derived from the spleens of WT mice, with donors and recipients on the same diet. Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed normal chow) reduced neointimal formation compared with the effect in unreconstituted Rag-1 KO mice (0.0076+/-0.0039 [n=9] versus 0.020+/-0.0160 [n=8] mm(2), respectively; P<0.05). Reconstitution of Rag-1 KO mice with B cells from WT mice (both fed a western diet) reduced neointimal formation compared the effect in Rag-1 KO mice (0.0087+/-0.0037 [n=8] versus 0.0312+/-0.0174 [n=7] mm(2), respectively; P<0.05). Injured carotid arteries from reconstituted Rag-1 KO mice had detectable IgM and IgG, indicating viable transfer of B cells. The results suggest that B cells modulate the response to arterial injury.
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| 17. |
- Dunér, Pontus, et al.
(författare)
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Immune responses against aldehyde-modified laminin accelerate atherosclerosis in Apoe(-/-) mice.
- 2010
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 212:2, s. 457-465
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: LDL oxidation in the vascular wall is associated with aldehyde modification of surrounding extracellular matrix proteins that may target autoimmune responses against vascular tissues. Here we investigated the possible influence of immunity against a malondialdehyde (MDA)-modified form of the basement membrane protein laminin on atherosclerosis. METHODS AND RESULTS: IgM and IgG autoantibodies were present in human plasma and a prospective clinical study demonstrated that individuals who later suffered from acute cardiovascular events had lower levels of MDA-laminin antibodies compared to those in the control group. Immunohistochemical analysis of atherosclerotic plaques from Apoe(-/-) mice demonstrated co-localization between laminin and MDA epitopes, however MDA-laminin IgG was absent in mouse plasma. To determine the effect of MDA-laminin immunity, Apoe(-/-) mice were immunized with MDA-laminin. Analysis of circulating leukocytes at 12 weeks demonstrated increased T-cell activation, expansion of Th17 cells and a lower fraction of regulatory T cells (Tregs) in mice immunized with MDA-laminin. At 25 weeks, aortic atherosclerosis was increased by more than 60% in mice immunized with MDA-laminin, together with increased levels of MDA-laminin IgG1 and MDA-laminin-specific T-cells expressing IL-2, IL-4 and IL-6 in the spleen. CONCLUSION: The clinical observations suggest that immune responses against MDA-laminin may be involved in the development of cardiovascular disease in humans. Furthermore, observations in mice provide evidence for the presence of aldehyde-modified laminin in atherosclerotic lesions and demonstrate that induction of an immune response against these structures is associated with activation of Th17 cells, reduced fraction of Tregs and a more aggressive development of atherosclerosis.
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| 18. |
- Dunér, Pontus, et al.
(författare)
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Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease.
- 2009
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; Feb 14., s. 593-603
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Tidskriftsartikel (refereegranskat)abstract
- Abstract. Dunér P, To F, Alm R, Gonçalves I, Fredrikson GN, Hedblad B, Berglund G, Nilsson J, Bengtsson E (Malmö University Hospital, Lund University, Lund, Sweden). Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease. J Intern Med 2009; doi: 10.1111/j.1365-2796.2008.02067.xObjectives. Accumulation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. We have investigated the possibility that LDL oxidation results in release of aldehydes that modify surrounding matrix proteins and that this may target immune responses against the plaque extracellular matrix and modulate the disease progression. Results. Using custom-made ELISAs we demonstrate that human plasma contains autoantibodies against aldehyde-modified fibronectin (FN) and to a lesser extent also other extracellular matrix proteins including collagen type I, type III, and tenascin-C. Immunohistochemistry and western blot analysis showed that aldehyde-modified FN is present in human atherosclerotic plaques and that aldehydes generated by oxidation of LDL formed adducts with FN in vitro. We also demonstrate that aldehyde-modification of FN results in a loss of its ability to promote basal secretion of cytokines and growth factors from cultured macrophages without affecting the ability of the cells to respond to stimulation with LPS. A prospective clinical study demonstrated that subjects that subsequently developed acute myocardial infarction or sudden cardiac death had lower baseline levels of autoantibodies against aldehyde-modified FN than matched controls. Conclusions. These observations demonstrate that oxidation of LDL in the arterial wall may lead to aldehyde-modification of surrounding extracellular matrix proteins and that these modifications may affect macrophage function and activate autoimmune responses of pathophysiological importance for the development of atherosclerosis.
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| 19. |
- Dunér, Pontus, et al.
(författare)
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Immunization of apoE-/- mice with aldehyde-modified fibronectin inhibits the development of atherosclerosis.
- 2011
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 91, s. 528-536
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Tidskriftsartikel (refereegranskat)abstract
- Aims. Oxidation of LDL in the extracellular matrix of the arterial wall results in formation of malondialdehyde (MDA) that modifies surrounding matrix proteins. This is associated with activation of an immune response against modified extracellular matrix proteins present in atherosclerotic plaques. Clinical studies have revealed an inverse association between antibodies to MDA-modified fibronectin and risk for development of cardiovascular events. To determine the functional role of these immune responses in atherosclerosis we performed studies in which apoE-deficient mice were immunized with MDA-modified fibronectin. Methods and Results. Immunization of apoE-deficient mice with MDA-modified fibronectin resulted in a 70% decrease in plaque area and a less inflammatory phenotype of remaining plaques. Immunization shifted a weak naturally occurring Th1 antibody response against MDA-fibronectin into a Th2 antibody response. Cytokine expression and flow cytometry analyses of spleen cells from immunized mice showed an activation of regulatory T cells. Immunization with MDA-fibronectin was also found to reduce plasma fibronectin levels. Conclusions. Immunization with MDA-fibronectin significantly reduces the development of atherosclerosis in apoE-deficient mice suggesting that the immune response observed in humans may have a protective effect. MDA-fibronectin represents a possible novel target for immunomodulatory therapy in atherosclerosis.
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| 20. |
- Edsfeldt, Andreas, et al.
(författare)
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High Plasma Levels of Galectin-3 Are Associated with Increased Risk for Stroke after Carotid Endarterectomy.
- 2016
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Ingår i: Cerebrovascular Diseases. - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 41:3-4, s. 199-203
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-3 (Gal-3) has been suggested to have both pro- and anti-atherogenic properties. High plasma Gal-3 levels are associated with increased risk for cardiovascular (CV) death. However, it has so far not been investigated if plasma Gal-3 levels can predict the risk for future stroke in patients suffering from carotid atherosclerosis. The aim of this study was to investigate whether Gal-3 could be used as a marker to predict postoperative cerebrovascular ischemic events among patients who underwent carotid endarterectomy (CEA).
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| 21. |
- Engelbertsen, Daniel, et al.
(författare)
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High levels of IgM against methylglyoxal-modified apolipoprotein B100 is associated with less coronary artery calcification in patients with type 2 diabetes.
- 2012
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 271:1, s. 82-89
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Advanced glycation end products (AGE) have been implicated in diabetic vascular complications through activation of pro-inflammatory genes. AGE-modified proteins are also targeted by the immune system resulting in the generation of AGE-specific autoantibodies, but the association of these immune responses with diabetic vasculopathy remains to be fully elucidated. The aim of this study was to determine whether antibodies against apolipoprotein B100 modified by methylglyoxal (MGO-apoB100) are associated with coronary atherosclerosis in patients with type 2 diabetes. Methods. We measured antibodies against MGO-apoB100 in plasma from 497 type 2 diabetic patients without clinical signs of cardiovascular disease. Severity of coronary disease was assessed as coronary artery calcium (CAC) imaging. Immunoglobulin (Ig)M and IgG levels recognizing MGO-apoB100 were determined by enzyme-linked immunosorbent assay. Results. Anti-MGO-apoB100 IgM antibody levels were higher in subjects with a low to moderate CAC score (≤400 Agatston units) than in subjects with a high score (>400 Agatston units; 136.8 ± 4.4 vs. 101.6 ± 7.4 arbitrary units (AU), P < 0.0001) and in subjects demonstrating no progression of CAC during 30 months of follow-up (136.4 ± 5.7 vs. 113.9 ± 6.2 AU in subjects with progression, P < 0.0001). Subjects with a family history of premature myocardial infarction had lower levels of anti-MGO-apoB100 IgM. Female subjects had higher levels of anti-MGO-apoB100 antibodies and lower CAC than men. Accordingly, high levels of IgM against MGO-apoB100 are associated with less severe and a lower risk of progression of coronary disease in subjects with type 2 diabetes. Conclusions. Although conclusions regarding causal relationships based on epidemiological observations need to be made with caution, our findings suggest the possibility that anti-MGO-apoB100 IgM may be protective in diabetic vasculopathy.
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| 22. |
- Engelbertsen, Daniel, et al.
(författare)
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Low Levels of IgM Antibodies against an Advanced Glycation Endproduct-Modified Apolipoprotein B100 Peptide Predict Cardiovascular Events in Nondiabetic Subjects.
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 195:7, s. 3020-3025
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Tidskriftsartikel (refereegranskat)abstract
- Increased glucose levels are associated with the generation of advanced glycation endproduct (AGE) modifications. Interaction between AGE-modified plaque components and immune cells is believed to have an important role in the development of vascular complications in diabetes. Methylglyoxal (MGO) is one type of reactive aldehyde that gives rise to AGE modification. The present study analyzed whether autoantibodies against MGO-modified epitopes of the low-density lipoprotein apolipoprotein B (apoB) 100 predict cardiovascular events. A library consisting of 302 peptides comprising the complete apoB100 molecule was screened to identify peptides targeted by MGO-specific autoantibodies. Peptide (p) 220 (apoB amino acids 3286-3305) was identified as a major target. Baseline IgM and IgG against MGO-peptide 220 (p220) were measured in 700 individuals from the Malmö Diet and Cancer Cohort. A total of 139 cardiovascular events were registered during the 15-y follow-up period. Controlling for major cardiovascular risk factors demonstrated that subjects in the lowest tertile of MGO-p220 IgM had an increased risk for cardiovascular events (hazard ratio [95% confidence interval]: 2.07 [1.22-3.50]; ptrend = 0.004). Interestingly, the association between MGO-p220 IgM and cardiovascular events remained and even tended to become stronger when subjects with prevalent diabetes were excluded from the analysis (2.51 [1.37-4.61]; ptrend = 0.002). MGO-p220 IgM was inversely associated with blood glucose, but not with oxidized low-density lipoprotein. Finally, we demonstrate that anti-MGO-p220 IgM is produced by B1 cells. These data show that subjects with low levels of IgM recognizing MGO-modified p220 in apoB have an increased risk to develop cardiovascular events and that this association is present in nondiabetic subjects.
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| 23. |
- Fagerberg, Björn, 1943, et al.
(författare)
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Circulating Autoantibodies against the Apolipoprotein B-100 Peptides p45 and p210 in Relation to the Occurrence of Carotid Plaques in 64-Year-Old Women
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Immune responses against oxidized low density lipoprotein (LDL) play a key role in atherosclerosis. Previous studies have indicated inverse associations between autoantibodies to epitopes in oxidized LDL and cardiovascular disease. In this study we investigated the associations between autoantibodies against the apolipoprotein B-100 (apoB-100) peptides p45 and p210 and occurrence of carotid plaques. The study cohort consisted of a population-based sample of 64-year-old women with varying degrees of glucose tolerance (n=594). To identify and record the occurrence of carotid atherosclerotic plaques ultrasonography was used. Measurements of plasma IgM and IgG autoantibodies against the native and malondialdehyde (MDA)-modified apoB-100 peptides p45 and p210 were performed by ELISA. Women with carotid plaques were found to have lower levels of IgM MDA-p210 autoantibodies compared to plaque-free women. The number of carotid plaques in each subject and the total carotid plaque area correlated inversely with IgM MDA-p210 levels (r=-0.11, P=0.009 and r=-0.11, P=0.013, respectively). Furthermore, levels of IgM MDA-p210 above the lowest tertile were associated with an odds ratio of 0.55 (95% CI 0.38-0.79, P=0.001) for occurrence of carotid plaques, independently of other risk markers and statin treatment. Associations between apo-B100 peptide autoantibodies and cardiovascular risk factors were generally weak but subjects with impaired glucose tolerance had higher levels of IgM against MDA-p210. The present study demonstrates that high levels of IgM against MDA-p210 are associated with less severe carotid disease in women. These findings provide additional support for a role of immune responses against oxidized LDL in cardiovascular disease.
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| 24. |
- Goncalves, Isabel, et al.
(författare)
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Activator protein-1 in carotid plaques is related to cerebrovascular symptoms and cholesteryl ester content
- 2011
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Ingår i: Cardiovascular pathology. - : Elsevier. - 1054-8807 .- 1879-1336. ; 20:1, s. 36-43
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Tidskriftsartikel (refereegranskat)abstract
- Transcription factor activator protein-1 regulates genes involved in inflammation and repair. The aim of this study was to determine whether transcription factor activator protein-1 activity in carotid plaques is related to symptoms, lipid accumulation, or extracellular matrix composition. Methods: Twenty-eight atherosclerotic carotid plaques were removed by endarterectomy and divided into two groups based on the presence or absence of ipsilateral symptoms (b1 month ago). Activator protein-1 DNA binding activity was assessed, and subunit (c-Jun, JunD, JunB, c-Fos, FosB, Fra-1, Fra-2) protein levels analyzed by immunoblotting. Distribution of c-Jun in plaques was analyzed by immunohistochemistry. Results: Plaques associated with symptoms had increased activator protein-1 activity and increased expression of c-Jun and JunD, as compared to asymptomatic plaques. Fra-1 and Fra-2 were present in equal amounts in both groups, whereas JunB, FosB, and c-Fos were undetectable. Activator protein-1 activity correlated with cholesteryl ester and elastin in plaques and decreased with age. Activator protein-1 activity did not correlate with collagen, calcified tissue, or proteoglycan content. Conclusions: Activator protein-1 is increased in plaques associated with symptoms. The correlation between activator protein-1 and cholesteryl esters suggests that high activator protein-1 is a marker of plaque vulnerability. Activator protein-1 expression can also reflect the activation of repair processes.
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| 25. |
- Gonçalves, Isabel, et al.
(författare)
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Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes
- 2016
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 16:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. Methods: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). Results: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. Conclusions: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.
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| 26. |
- Goncalves, Isabel, et al.
(författare)
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Effects of simvastatin on circulating autoantibodies to oxidized LDL antigens : relation with immune stimulation markers
- 2009
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Ingår i: AUTOIMMUNITY. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 42:3, s. 203-208
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Tidskriftsartikel (refereegranskat)abstract
- Statins exert a number of anti-inflammatory and immunomodulatory effects in vitro. However, the immunomodulatory effects in vivo are less clarified. In the present study, we investigated whether simvastatin treatment changed the levels of autoantibodies against specific oxidized LDL (oxLDL) antigens as well as their association with leukocyte activation markers. Eighty volunteers with mild-to-moderate hypercholesterolemia were randomized to either simvastatin 40mg or placebo for 6 weeks. Autoantibodies against apo B peptide antigens, C-reactive protein (CRP) and interleukin (IL)-6 in plasma were determined by ELISA. Subsets of circulating B and T cells were studied by flow cytometry. Simvastatin significantly reduced CRP by 26%, whereas IL-6 remained unchanged. Levels of IgG against the apo B peptide P-240 (amino acids 3586-3605) increased by 16% (p=0.03) in the simvastatin group whereas autoantibody levels to other apo B peptides did not change. At baseline and after 6 weeks, the P-240 IgG levels were significantly correlated with the number of CD57+CD28-CD8+T cells but not to other lymphocyte subsets or inflammatory markers. The P-240 IgG levels after 6 weeks simvastatin therapy was strongly correlated to the relative increase in CD57+CD28-CD8+T cells (p=0.003). Simvastatin treatment induced an increase in autoantibodies against an oxLDL antigen. The effect was related to an expansion of a CD8+T cell subset and may involve an immunostimulation by simvastatin.
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| 27. |
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| 28. |
- Goncalves, Isabel, et al.
(författare)
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Elastin- and Collagen-Rich Human Carotid Plaques Have Increased Levels of the Cysteine Protease Inhibitor Cystatin C.
- 2008
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Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 45:5, s. 395-401
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cystatin C is a major inhibitor of the elastin- and collagen-degrading cysteine proteases and may therefore have an important role in preserving atherosclerotic plaque stability. In this study we analyzed the associations between human carotid plaque cystatin C expression and the plaque content of collagen and elastin. Methods: Thirty-one plaques were removed by endarterectomy and homogenized. Cystatin C levels were analyzed by densitometry of Western blots and elastin and collagen levels were determined colorimetrically. Results: The plaque content of cystatin C correlated with total elastin (r = 0.58, p = 0.001) and collagen (r = 0.50, p = 0.004), as well as with cross-linked forms of elastin (r = 0.42, p = 0.022) and collagen (r = 0.52, p = 0.003). Immunohistochemical analysis demonstrated that cystatin C colocalized with elastin and collagen. No correlation was seen between cystatin C and the amount of degraded elastin or collagen in plaques. Conclusion: The positive correlation between cystatin C levels and collagen and elastin levels in plaques supports the notion that cystatin C plays an important role in maintaining atherosclerotic plaque stability. Copyright (c) 2008 S. Karger AG, Basel.
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| 29. |
- Goncalves, Isabel, et al.
(författare)
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Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.
- 2015
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 35:7, s. 1723-1731
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.
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| 30. |
- Goncalves, Isabel, et al.
(författare)
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High levels of cathepsin D and cystatin B are associated with increased risk of coronary events.
- 2016
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Ingår i: Open Heart. - : BMJ. - 2053-3624. ; 3:1, s. 000353-000353
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Tidskriftsartikel (refereegranskat)abstract
- The majority of acute coronary syndromes are caused by plaque ruptures. Proteases secreted by macrophages play an important role in plaque ruptures by degrading extracellular matrix proteins in the fibrous cap. Matrix metalloproteinases have been shown to be markers for cardiovascular disease whereas the members of the cathepsin protease family are less studied.
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| 31. |
- Goncalves, Isabel, et al.
(författare)
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Humoral Immune Response Against Defined Oxidized Low-Density Lipoprotein Antigens Reflects Structure and Disease Activity of Carotid Plaques.
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:6, s. 1250-1255
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Tidskriftsartikel (refereegranskat)abstract
- Background - Immune responses against oxidized low- density lipoprotein ( LDL) play an important role in atherosclerosis. The aim of this study was to investigate if humoral immune response against specific oxidized LDL antigens, such as aldehyde- modified peptide sequences of apolipoprotein B- 100, reflects disease activity and structure of atherosclerotic plaques. Methods and Results - Plaques were obtained from 114 symptomatic subjects referred to carotid endarterectomy and characterized immunohistochemically and histologically. Plasma levels of IgG and IgM against aldehyde- modified apolipoprotein B- 100 amino acid sequences 661 to 680, 3136 to 3155 ( peptide 210), and 3661 to 3680 ( peptide 240) were determined by enzyme- linked immunosorbent assay. High levels of IgG against peptide 210 were associated with increased plaque content of lipids ( r = 0.24, P < 0.05) and hemorrhage ( r = 0.27, P = 0.005), with decreased content of fibrous tissue ( r = - 0.25, P = 0.01), but also with lower total plaque volume ( r = - 0.21, P < 0.05). In contrast, high levels of IgM against peptide 240 were associated with plaques with more fibrous tissue ( r = 0.35, P < 0.001), less lipids ( r = - 0.34, P < 0.001), and less macrophages ( r = - 0.24, P < 0.05). IgM against peptide 210 were found to be associated with plaque fibrous tissue ( r = 0.20, P < 0.05), less lipids ( r = - 0.21, P < 0.05), and less macrophages ( r = - 0.27, P = 0.01). Conclusion - These findings support the notion that immune responses against oxidized LDL epitopes are involved in atherosclerosis and that the level of circulating antibodies against these structures may reflect disease activity in the arterial wall.
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| 32. |
- Goncalves, Isabel, et al.
(författare)
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Identification of the target for therapeutic recombinant anti-apoB-100 peptide antibodies in human atherosclerotic lesions.
- 2009
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 205, s. 96-100
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Accumulation of oxidized LDL in the arterial wall is believed to play a key role in the development of atherosclerosis. Experimental studies have identified the presence of immune responses against epitopes in oxidized LDL that protects against atherosclerosis. We have produced human recombinant IgG against one of these epitopes (aldehyde-modified apoB-100 amino acids 661-680) and demonstrated that treatment with this human IgG1 2D03 antibody markedly reduces atherosclerosis in hypercholesterolemic mice. METHODS: In the present study, we screened a panel of 25 carotid plaques associated with clinical symptoms and 26 clinically silent plaques obtained at surgery for presence of the aldehyde-modified apoB-100 peptide defined by the 2D03 antibody and compared the expression of this epitope with other plaque constituents, plasma lipoproteins levels, plasma oxidized LDL and autoantibodies against apoB-100 peptides. RESULTS: We demonstrated that the epitope is commonly expressed in human atherosclerotic plaques and that plaques associated with clinical symptoms have an almost three-fold higher content of this epitope (8.6+/-4.9% versus 22.1+/-12.2% immunostaining of total plaque area, p<0.0005). There was also a significant association between 2D03 epitope staining and the plaque content of cholesterol esters (r=0.43, p<0.05), whereas there was no association with plasma oxidized LDL and autoantibodies against apoB-100 peptides. CONCLUSIONS: By demonstrating the presence of the 2D03 epitope in human atherosclerotic lesions our findings support the possibility that treatment with this antibody may have beneficial effects also in humans. Furthermore, they suggest the possibility to use these or other similar antibodies for diagnostic imaging of atherosclerotic plaques in humans.
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| 33. |
- Grönberg, Caitríona, et al.
(författare)
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Endarterectomy patients with elevated levels of circulating IL-16 have fewer cardiovascular events during follow-up
- 2016
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666. ; 85, s. 137-139
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Increased interleukin 16 (IL-16) levels in carotid plaques have been associated with reduced incidence of cardiovascular (CV) events during follow-up in patients who underwent carotid endarterectomy (CEA). In the present study we aimed to determine whether high circulating levels of IL-16 also are associated with a decreased risk of CV events after CEA. Methods Patients, who had their carotid plaques surgically removed (n = 473), were followed for a mean follow-up time of 3.1 years. Plasma levels of IL-16 the day before surgery were analyzed by proximity extension assay (PEA) and associated with the occurrence of CV events during follow-up (n = 98). Results High levels of circulating IL-16 were independently associated with a decreased risk of CV events when comparing the highest versus the lowest IL-16 tertile (hazard ratio [HR] 0.47; 95% CI 0.27–0.81; P = 0.007), as well as with CV deaths (HR 0.25; 95% CI 0.09–0.70; P = 0.008). Conclusion These present findings indicate an association between IL-16 and less clinical complications of atherosclerosis in a population with known advanced carotid disease.
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| 34. |
- Grönberg, Caitriona, et al.
(författare)
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Human Carotid Plaques With High Levels of Interleukin-16 Are Associated With Reduced Risk for Cardiovascular Events.
- 2015
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 46:10, s. 2748-2754
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-16 (IL-16) functions as a regulator of T-cell growth and acts as an inducer of cell migration. The aim of this study was to determine whether IL-16 measured in human carotid plaques was associated with symptoms (eg, stroke, transient ischemic attack, or amaurosis fugax), markers of plaque stability, and postoperative cardiovascular events.
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| 35. |
- Hammar, Oskar, et al.
(författare)
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Depletion of enteric gonadotropin-releasing hormone is found in a few patients suffering from severe gastrointestinal dysmotility.
- 2012
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 47:10, s. 1165-1173
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Many patients, especially women, suffer from severe gastrointestinal pain and dysmotility for several years without being diagnosed. Depletion of gonadotropin-releasing hormone (GnRH) in the enteric nervous system (ENS) has been described in some patients. The aim of this study was to examine the expression of GnRH in ENS and antibodies against GnRH in serum, in a dysmotility patient cohort of southern Sweden. Materials and methods: All consecutive patients (n = 35) referred for laparoscopic full-thickness biopsy because of symptoms or signs of severe dysmotility between 1998 and 2009, or patients with a severe dysmotility disorder having had a bowel resection within the time frame, were considered for inclusion. In 22 cases, representative biopsy material containing ganglia was available, and these patients were included. Medical records were scrutinized. The expression of GnRH was determined by immunohistochemistry in bowel biopsies from these patients and in patients with carcinoma or diverticulosis without ENS histopathology. Antibodies against GnRH in serum were determined by ELISA in patients and controls. Results: 14 patients were diagnosed with enteric dysmotility (ED) and 8 with chronic intestinal pseudo-obstruction due to varying etiology. Immunostained biopsies showed expression of GnRH in the ENS. A reduced expression of GnRH-containing neurons was found in 5 patients, as well as antibodies against GnRH in serum. 3 of these patients had a history of in vitro fertilization (IVF) using GnRH analogs. Conclusions: A subgroup of patients with severe dysmotility had a reduced expression of GnRH-containing neurons in the ENS and expressed antibodies against GnRH in serum.
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| 36. |
- Herbin, Olivier, et al.
(författare)
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Regulatory T-Cell Response to Apolipoprotein B100-Derived Peptides Reduces the Development and Progression of Atherosclerosis in Mice
- 2012
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 32:3, s. 144-605
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Tidskriftsartikel (refereegranskat)abstract
- Objective-The immunoinflammatory response plays a critical role in the development and progression of atherosclerosis. Recent studies suggested an important role for regulatory T (Treg) cells in the inhibition of disease-related vascular inflammation. We hypothesized that induction of a specific Treg cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance. Methods and Results-Young or old Apoe(-/-) mice were subcutaneously infused for 2 weeks with either a control ovalbumin (OVA) peptide or with apolipoprotein B100 (ApoB100)-derived peptides without adjuvant. Atherosclerosis development, progression and immunologic status were assessed at 8 weeks after the end of the infusion. Treatment with ApoB100 peptides led to significant reduction of lesion development in young Apoe(-/-) mice (P=0.001 versus OVA group) and abrogated atherosclerosis progression in old Apoe(-/-) mice with already established lesions (0% progression in ApoB100 versus 17% in OVA group, P<0.005). Limitation of plaque progression was associated with reduced vascular inflammation and increased collagen content, indicative of plaque stabilization. Infusion of ApoB100 peptides did not alter antibody production but promoted a specific Treg cell response, which was associated with a reduction of both T helper type 1-related and T helper type 2-related cytokines. Interestingly, depletion of CD4(+)CD25(+) Treg cells abrogated ApoB100 peptides-dependent immune modulation and atheroprotection. Conclusion-Subcutaneous infusion of adjuvant-free ApoB100-derived peptides to Apoe(-/-) mice reduces atherosclerosis through the induction of a specific Treg cell response. (Arterioscler Thromb Vasc Biol. 2012;32:605-612.)
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| 37. |
- Ketelhuth, D. F., et al.
(författare)
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Identification of a danger-associated peptide from apolipoprotein B100 (ApoBDS-1) that triggers innate proatherogenic responses
- 2011
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Ingår i: Circulation. - Stockholm : Karolinska Institutet, Dept of Medicine, Solna. - 1524-4539 .- 0009-7322. ; 124:22
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subendothelial deposited low-density lipoprotein particles are a known inflammatory factor in atherosclerosis. However, the causal components derived from low-density lipoprotein are still poorly defined. Apolipoprotein B100 (ApoB100) is the unexchangeable protein component of low-density lipoprotein, and the progression of atherosclerosis is associated with immune responses to ApoB100-derived peptides. In this study, we analyzed the proinflammatory activity of ApoB100 peptides in atherosclerosis. METHODS AND RESULTS: By screening a peptide library of ApoB100, we identified a distinct native peptide referred to as ApoB100 danger-associated signal 1 (ApoBDS-1), which shows sequence-specific bioactivity in stimulation of interleukin-8, CCL2, and interleukin-6. ApoBDS-1 activates mitogen-activated protein kinase and calcium signaling, thereby effecting the expression of interleukin-8 in innate immune cells. Ex vivo stimulation of carotid plaques with ApoBDS-1 enhances interleukin-8 and prostaglandin E release. Furthermore, we demonstrated that ApoBDS-1-positive peptide fragments are present in atherosclerotic lesions using immunoassays and that low-molecular-weight fractions isolated from plaque show ApoBDS-1 activity inducing interleukin-8 production. CONCLUSIONS: Our data show that ApoBDS-1 is a previously unrecognized peptide with robust proinflammatory activity, contributing to the disease-promoting effects of low-density lipoprotein in the pathogenesis of atherosclerosis.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Kolbus, Daniel, et al.
(författare)
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Association between CD8+ T-cell subsets and cardiovascular disease
- 2013
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796. ; 274:1, s. 41-51
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Tidskriftsartikel (refereegranskat)abstract
- Background The findings of experimental studies suggest that the immune system plays a key role in atherosclerosis, but the clinical importance of different immune cells in cardiovascular disease remains poorly characterized. In this study we investigated the association between CD8+ T cells and carotid disease as well as development of cardiovascular disease events. Methods The study cohort comprised 700 subjects from the cardiovascular arm of the Malmö Diet and Cancer Study. Peripheral blood mononuclear cells, obtained at the 1991–1994 baseline investigation and stored at −140 °C, were thawed and the different CD8+ T-cell populations analysed by flow cytometry. Baseline carotid intima–media thickness and stenosis were assessed by ultrasonography and clinical events were monitored through validated national registers. Results Subjects with a high fraction of CD8+ T cells were characterized by decreased cytokine release from activated leucocytes, metabolic signs of insulin resistance and increased incidence of coronary events; hazard ratios (95% confidence intervals) for the second and third tertiles of CD8+ T cells were 2.57 (1.16, 5.67) and 2.61 (1.19, 5,71), respectively, in a Cox proportional hazards regression model. Correlations were found between the fraction of CD8+CD25+ T cells and the degree of carotid stenosis (r = 0.11, P < 0.01), and between the CD8+CD56−IFN-γ+ T-cell fraction and the degree of stenosis (r = −0.18, P < 0.005). The association between CD8+CD56−IFN-γ+ T cells and carotid stenosis remained significant after controlling for major cardiovascular disease risk factors. Conclusion This study provides prospective clinical evidence for a role of CD8+ T cells in cardiovascular disease and suggests the existence of CD8+ T-cell subsets with different pathological functions.
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| 42. |
- Kolbus, Daniel, et al.
(författare)
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CD8+ T cell activation predominate early immune responses to hypercholesterolemia in Apoe-/- mice.
- 2010
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Ingår i: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- It is well established that adaptive immune responses induced by hypercholesterolemia play an important role in the development of atherosclerosis, but the pathways involved remain to be fully characterized. In the present study we assessed immune responses to hypercholesterolemia induced by feeding Apoe-/- mice a high-fat diet for 4 or 8 weeks.
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| 43. |
- Kolbus, Daniel, et al.
(författare)
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Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis.
- 2011
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Ingår i: Immunobiology. - : Elsevier BV. - 1878-3279 .- 0171-2985. ; 216, s. 663-669
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Tidskriftsartikel (refereegranskat)abstract
- Immune responses against modified self-antigens generated by hypercholesterolemia play an important role in atherosclerosis identifying the immune system as a possible novel target for prevention and treatment of cardiovascular disease. It has recently been shown that these immune responses can be modulated by subcutaneous injection of adjuvant. In the present study we immunized 25-week old ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis with adjuvant and two different concentrations of the carrier molecule cationized BSA (cBSA). Plasma levels of Th2-induced apolipoprotein B (apoB)/IgG1 immune complexes were increased in the cBSA immunized groups verifying induction of immunity against a self-antigen. Mice were sacrificed at 36 weeks of age and atherosclerosis was monitored by en face Oil red O staining of the aorta. Immunization with 100μg cBSA inhibited plaque progression, whereas the lower dose (50μg) did not. In addition, the higher dose induced a more stable plaque phenotype, indicated by a higher content of collagen and less macrophages and T cells in the plaques. Moreover, there was an increased ratio of Foxp3(+)/Foxp3(-) T cells in the circulation suggesting activation of a regulatory T cell response. In conclusion, we show that immunization with cBSA induces an immune response against apoB as well as an activation of Treg cells. This was associated with development of a more stable plaque phenotype and reduced atherosclerosis progression.
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| 44. |
- Kolbus, Daniel, et al.
(författare)
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TAP1-Deficiency Does Not Alter Atherosclerosis Development in Apoe−/− Mice
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 3:7
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Tidskriftsartikel (refereegranskat)abstract
- Antigen presenting cells (APC) have the ability to present both extra-cellular and intra-cellular antigens via MHC class I molecules to CD8+ T cells. The cross presentation of extra-cellular antigens is reduced in mice with deficient Antigen Peptide Transporter 1 (TAP1)-dependent MHC class I antigen presentation, and these mice are characterized by a diminished CD8+ T cell population. We have recently reported an increased activation of CD8+ T cells in hypercholesterolemic Apoe−/− mice. Therefore, this study included TAP1-deficient Apoe−/− mice (Apoe−/−Tap1−/−) to test the atherogenicity of CD8+ T cells and TAP1-dependent cross presentation in a hypercholesterolemic environment. As expected the CD8+ T cell numbers were low in Apoe−/−Tap1−/− mice in comparison to Apoe−/− mice, constituting ~1% of the lymphocyte population. In spite of this there were no differences in the extent of atherosclerosis as assessed by en face Oil Red O staining of the aorta and cross-sections of the aortic root between Apoe−/−Tap1−/− and Apoe−/− mice. Moreover, no differences were detected in lesion infiltration of macrophages or CD3+ T cells in Apoe−/−Tap1−/− compared to Apoe−/− mice. The CD3+CD4+ T cell fraction was increased in Apoe−/−Tap1−/− mice, suggesting a compensation for the decreased CD8+ T cell population. Interestingly, the fraction of CD8+ effector memory T cells was increased but this appeared to have little impact on the atherosclerosis development. In conclusion, Apoe−/−Tap1−/− mice develop atherosclerosis equal to Apoe−/− mice, indicating a minor role for CD8+ T cells and TAP1-dependent antigen presentation in the disease process.
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| 45. |
- Linninge, Caroline, et al.
(författare)
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Probiotic therapy to men with incipient arteriosclerosis initiates increased bacterial diversity in colon: A randomized controlled trial.
- 2010
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 208, s. 228-233
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study aimed to clarify the microbial change in the intestinal microbiota in patients, with cardiovascular disease, consuming a drink with high numbers of live Lactobacillus plantarum. METHODS: Sixteen males, with atherosclerotic plaque on the carotid wall, were randomly selected from a larger cohort and included in this double blind, placebo controlled study. Colonic biopsies, taken before and after four weeks of probiotic treatment, were analysed with Terminal Restriction Fragment Length Polymorphism, including digestion with MspI and HaeIII. Microbial diversity was calculated, short-chain fatty acids in faeces, and blood markers were analysed. RESULTS: Consumption of one probiotic strain of L. plantarum (DSM 9843) increased intestinal microbial diversity. The probiotic group had an increased diversity after consumption of the probiotic drink compared to the change in the placebo group when Shannon and Weaner diversity index (MspI and HaeIII, p=0.026) and Simpson index of diversity (MspI, p=0.044 and HaeIII, p=0.026) were calculated. The fermentation pattern of short-chain fatty acids in faeces were unaffected for most acids, but the probiotic group had decreased concentration of isovaleric acid (p=0.006) and valeric acid (p=0.029). Viable count of lactobacilli increased in the probiotic group (p=0.001), but no significant changes in blood markers were observed. CONCLUSION: Administration of a single-strain probiotic increases the bacterial diversity in the gut, and affects the concentration of some short-chain fatty acids. Consumption of the single strain L. plantarum DSM 9843 might be a strategy to favour a diverse intestinal microbiota, which is beneficial for the host.
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| 46. |
- Mantani, Polyxeni, et al.
(författare)
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Circulating CD40(+) and CD86(+) B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 34:1, s. 211-218
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Accumulating evidence shows that immune cells play an important role in atherosclerosis. Most attention has focused on the role of different T cell subsets, whereas the possible involvement of B cells has been less studied. In this study, we assessed the association of 2 different B cell subsets, CD19(+)CD40(+) and CD19(+)CD86(+) B cells, with risk for development of acute cardiovascular events. Approach and Results-The prospective study included 700 subjects randomly selected from the cardiovascular cohort of the Malmo Diet and Cancer study. Mononuclear leukocytes, stored at -140 degrees C at the baseline investigation in 1991-1994, were thawed and B cell subsets analyzed by flow cytometry. Cytokine release from CD3/CD28-stimulated mononuclear leukocytes was measured with multiplex ELISA. Baseline carotid intima-media thickness and stenosis were assessed by ultrasonography, and clinical events were monitored through validated national registers during a median/mean follow-up time of 15 years. The subjects in the highest tertile of CD19(+)CD40(+) B cells had a significantly lower risk of incident stroke after adjustment for other risk factors. In contrast, CD19(+)CD86(+) B cells were associated with higher risk for development of a stroke event and increased release of proinflammatory cytokines from mononuclear leukocytes. Conclusions-These observations provide evidence for an involvement of B cells in the incidence of stroke and suggest that both pathogenic and protective B cell subsets exist.
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| 47. |
- Mantani, Polyxeni, et al.
(författare)
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IL-25 Inhibits Atherosclerosis Development in Apolipoprotein E Deficient Mice
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective IL-25 has been implicated in the initiation of type 2 immunity and in the protection against autoimmune inflammatory diseases. Recent studies have identified the novel innate lymphoid type 2 cells (ILC2s) as an IL-25 target cell population. The purpose of this study was to evaluate if IL-25 has any influence on atherosclerosis development in mice. Methods and Results Administration of 1 mu g IL-25 per day for one week to atherosclerosis-prone apolipoprotein (apo) E deficient mice, had limited effect on the frequency of T cell populations, but resulted in a large expansion of ILC2s in the spleen. The expansion was accompanied by increased levels of anti-phosphorylcholine (PC) natural IgM antibodies in plasma and elevated levels of IL-5 in plasma and spleen. Transfer of ILC2s to apoE deficient mice elevated the natural antibody-producing B1a cell population in the spleen. Treatment of apoE/Rag-1 deficient mice with IL-25 was also associated with extensive expansion of splenic ILC2s and increased plasma IL-5, suggesting ILC2s to be the source of IL-5. Administration of IL-25 in IL-5 deficient mice resulted in an expanded ILC2 population, but did not stimulate generation of anti-PC IgM, indicating that IL-5 is not required for ILC2 expansion but for the downstream production of natural antibodies. Additionally, administration of 1 mu g IL-25 per day for 4 weeks in apoE deficient mice reduced atherosclerosis in the aorta both during initiation and progression of the disease. Conclusions The present findings demonstrate that IL-25 has a protective role in atherosclerosis mediated by innate responses, including ILC2 expansion, increased IL-5 secretion, B1a expansion and natural anti-PC IgM generation, rather than adaptive Th2 responses.
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| 48. |
- Mantani, Polyxeni T, et al.
(författare)
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ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions
- 2019
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Ingår i: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin-CD45+IL17RB+ICOS+IL7raintermediate) and address its direct role in experimental atherosclerosis by its adoptive transfer to hypercholesterolaemic apolipoprotein E deficient (apoE-/-) mice.RESULTS: Immunomagnetically enriched, FACS-sorted ILC2s from the spleens of IL-25 treated apoE-/- mice were stained for KLRG1 and ST2 directly upon cell obtainment or in vitro cell expansion for flow cytometric analysis. IL25-induced splenic ILC2s express high levels of both KLRG1 and ST2. However, both markers are downregulated upon in vitro cell expansion. In vitro expanded splenic ILC2s were intraperitoneally transferred to apoE-/- recipients on high fat diet. ApoE-/- mice that received in vitro expanded splenic ILC2s had decreased lipid content in subvalvular heart and brachiocephalic artery (BCA) plaques accompanied by increased peritoneal B1 cells, activated eosinophils and alternatively activated macrophages (AAMs) as well as anti-phosphorylcholine (PC) immunoglobulin (Ig) M in plasma.CONCLUSIONS: With the current data we designate the IL25-induced ILC2 population to decrease the lipid content of atherosclerotic lesions in apoE-/- mice and we directly link the induction of B1 cells and the atheroprotective anti-PC IgM antibodies with ILC2s.
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| 49. |
- Mantani, Polyxeni T., et al.
(författare)
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Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice
- 2018
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Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 293:18, s. 6791-6801
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is a chronic inflammatory disease characterized by the entrapment of apolipoprotein B– containing lipoproteins in the arterial intima, leading to local inflammation. T helper (Th) cell 1–mediated immune responses have been associated with atherosclerosis, and the cytokine interleukin-25 (IL-25 or IL-17E) has been reported to potentially regulate Th1 cell– and Th17 cell–related immune responses. In this study, we evaluated the effects of complete IL-25 deficiency or of a temporal IL-25 blockade on atherosclerosis development in apolipoprotein E– deficient (Apoe/) mice. Mice deficient in both apolipoprotein E and IL-25 (Apoe//IL-25/) had more Th1 cells in the spleen, along with elevated plasma levels of IL-17 and an increased release of splenic interferon- (INF-). In support of this observation, a 4-week-long treatment of young Apoe/ mice (at 10 –14 weeks of age) with an IL-25– blocking antibody increased the release of Th1/Th17-associated cytokines in the spleen. In both mouse models, these findings were associated with increased atherosclerotic plaque formation in the aortic arch. We conclude that complete IL-25 deficiency and a temporal IL-25 blockade during early plaque development aggravate atherosclerosis development in the aortic arch of Apoe/ mice, accompanied by an increase in Th1/Th17-mediated immune responses. Our finding that endogenous IL-25 has an atheroprotective role in the murine aortic arch has potential implications for atherosclerosis development and management in humans.
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| 50. |
- Mantani, Polyxeni T., et al.
(författare)
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Interleukin-25 reduces Th17 cells and inflammatory responses in human peripheral blood mononuclear cells
- 2018
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Ingår i: Human Immunology. - : Elsevier BV. - 0198-8859. ; 79:9, s. 685-692
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Tidskriftsartikel (refereegranskat)abstract
- Background: The absence of interleukin-25 (IL-25) favors the induction of Th1 and Th17 immune responses in mice. Th1 immune responses have been associated with the pathology of atherosclerosis, a lipid and inflammation driven disease of the arterial wall. Purpose of research: To evaluate the effect of IL-25 on human peripheral blood mononuclear cells (hPBMCs) in the presence and absence of oxidized low density lipoprotein (oxLDL), a key player in atherosclerosis development. Principal results: Human PBMCs were incubated with recombinant human IL-25 (rhIL-25) in the presence and absence of oxLDL and analyzed with flow cytometry while cytokine secretion was measured in cell culture supernatants. The IL-25 receptor, IL-17RB, was mostly expressed on T cells. Incubation of hPBMCs with IL-25 reduced the frequency of Th17 cells. Furthermore, IL-25 inhibited the release of the Th17-inducing cytokine IL-6 from dendritic cells isolated from hPBMCs indicating that the IL-25 mediated Th17 suppression may be indirect. Moreover, IL-25 reduced the secretion of the proinflammatory cytokine IFNγ from hPBMCs. OxLDL decreased IFNγ release from hPBMCs regardless of the presence or absence of IL-25. Conclusions: IL-25 reduces Th1 and Th17 immune responses in hPBMCs raising the interesting possibility that IL-25 could have a protective role in human atherosclerosis.
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