| 1. |
- 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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| 2. |
- Dunér, Pontus
(författare)
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Immune Responses Aginst Aldehyde Modified Extracellular Matrix in Atherosclerosis
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is a chronic inflammatory disease and the leading cause of myocardial infarction and stroke. Accumulation, aggregation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. The oxidation of LDL generates reactive aldehydes, including malondialdehyde (MDA) that modifies ApoB in LDL. Immune responses against MDA-modified epitopes on ApoB have been shown to be linked to atherosclerotic disease. This thesis is focused on the possibility that LDL oxidation result in the release of MDA that modified surrounding extracellular matrix (ECM) proteins. These modifications may subsequently target immune responses against the plaque ECM and influence the atherosclerotic process. Our studies provide evidence for the presence of MDA-modifications on ECM proteins during atherosclerosis. We also show that antibodies against several MDA-modified ECM proteins are present in human plasma. A prospective clinical study showed that subjects that later suffered from acute cardiovascular events had significantly lower IgG and IgM antibody levels against MDA-modified fibronectin. These epidemiological results indicate that immune responses against MDA-modified fibronectin may have protective effects in atherosclerotic disease. To investigate the functional role of immune responses against modified matrix proteins in atherosclerosis, we immunized Apoe-/- mice with two different MDA-modified matrix proteins to which we had found antibodies in human plasma. MDA-modified fibronectin immunization significantly decreased the atherosclerotic plaque development in both aorta and in subvalvular lesions, while MDA-modified laminin resulted in increased plaque development. Finally we show that injection of Alum, an adjuvant commonly used in vaccines, results in LDL oxidation and aldehyde generation at the injection site.
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| 3. |
- Nyström, Tobias, et al.
(författare)
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A constitutive endogenous osteopontin production is important for macrophage function and differentiation.
- 2007
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 313:6, s. 1149-1160
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Tidskriftsartikel (refereegranskat)abstract
- Macrophages are involved in the pathological process underlying atherosclerosis and constitutively express the multifunctional protein osteopontin which has important exogenous effects on these cells. However, the effect of the endogenous osteopontin expression on macrophage function has been sparsely studied. To shed light on the importance of the endogenous osteopontin expression, RAW 264.7 macrophage-like cells were silenced in osteopontin expression using RNAi. The cells were analysed for basic functions including attachment, migration, apoptosis and for the expression of macrophage differentiation markers and cytokines. The macrophages with silenced osteopontin expression showed impaired migration and an increased rate of serum starvation-induced apoptosis as compared to osteopontin-producing control cells. Furthermore, the cells with silence osteopontin expression had an altered phenotype with monocyte-like characteristics, including decreased expression of macrophage scavenger receptor A type 1. The altered phenotype of these cells could not be reversed by presence of extracellular osteopontin. In addition the cells with silenced osteopontin expression had a lower expression of IL-12 mRNA and the anti-apoptotic Flip mRNA. We conclude that a constitutive endogenous osteopontin production is important for proper basic functions of macrophages and our study indicates that the constitutive osteopontin production is involved in maintaining macrophages in a differentiated phenotype.
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| 4. |
- Wigren, Maria, et al.
(författare)
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Atheroprotective effects of Alum are associated with capture of oxidized LDL antigens and activation of regulatory T cells
- 2009
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Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 104:12, s. e62-70
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Tidskriftsartikel (refereegranskat)abstract
- The immune system represents a promising novel target for prevention of atherosclerosis. Several pilot vaccines that reduce atherosclerosis in experimental animals have been developed. The aluminum hydroxide adjuvant Alum has been shown to have antiatherogenic properties in itself, suggesting that it may be a suitable adjuvant in possible future atherosclerosis vaccines. To characterize the immune pathways mediating this protection, we treated wild-type C57BL/6 and Apoe(-)(/)(-) mice with Alum or PBS. Analyses of splenocytes isolated from 12-week-old mice demonstrated that Alum increased the presence of CD4(+)CD25(+)FoxP3(+) regulatory T cells and downregulated the expression of T cell activation markers CD28 and ICOS in Apoe(-)(/)(-) mice but not in C57BL/6 wild-type mice. A similar immunosuppressive phenotype was found also in 25-week-old Apoe(-)(/)(-) mice and was associated with reduced atherosclerosis. Alum precipitates recovered from the injection site of Apoe(-)(/)(-) mice contained antigens derived from oxidized LDL. These findings demonstrate that treatment of Apoe(-)(/)(-) mice with Alum results in an increase of regulatory T cells and suggest that these are activated by tolerogenic antigen-presenting cells presenting oxidized LDL antigens. Our findings provide improved mechanistic understanding of the atheroprotective properties of aluminum hydroxide adjuvants but also point to the importance of determining if hypercholesterolemia may compromise the efficacy of Alum-containing vaccines used clinically today.
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