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Atherosclerosis and Lipoproteins |
From the Research Department, Kantonal Hospital St Gallen, St Gallen, Switzerland.
Correspondence to Burkhard Ludewig, Research Department, Kantonsspital St Gallen, Rorschacherstrasse 95, CH-9007 St Gallen, Switzerland. E-mail burkhard.ludewig{at}kssg.ch
| Abstract |
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Methods and Results— To distinguish between the effects of systemic activation and cognate immune reactivity against a pathogen-derived persisting antigen in the vasculature, we used hypercholesterolemic transgenic mice constitutively expressing the β-galactosidase (β-gal) transgene in the cardiovascular system (apoE–/–xSM-LacZ). After infection with β-gal–recombinant MCMV-LacZ, apoE–/–, and apoE–/–xSM-LacZ mice mounted comparable cellular immune responses against the virus. β-gal–specific CD8+ T cells expanded rapidly and remained detectable for at least 100 days in both mouse strains. However, compared with apoE–/– mice, apoE–/–xSM-LacZ mice developed drastically accelerated atherosclerosis. Moreover, atherosclerotic lesions in MCMV-LacZ–infected apoE–/–xSM-LacZ but not apoE–/– mice were associated with pronounced inflammatory infiltrates.
Conclusions— Taken together, our data indicate that chronic immune reactivity against pathogen-derived antigens persisting in the vasculature significantly exacerbates atherogenesis.
This study demonstrates that T cell responses directed against persisting microbial antigen within the vasculature favor the development of an inflammatory environment that is important for the acceleration of atherosclerotic lesion development.
Key Words: cytomegalovirus atherosclerosis inflammation immunopathology coronary heart disease
| Introduction |
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In addition, various infection-associated immunopathological mechanisms impinge on the atherosclerotic process.11 Molecular similarities ("mimicry") between microbial and host proteins, as found in the structurally related human and chlamydial heat shock proteins (HSP60/65), precipitate inflammatory reactions in atherosclerotic lesions.12 General immune activation with systemic ("bystander") effects on the vascular wall can be triggered by a MCMV infection-associated increase in IFN
serum levels leading to the secretion of proinflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1) by endothelial cells.13 It is possible that such processes foster the recruitment of monocytes/macrophages and T cells to atherosclerotic lesions.14 It has been argued that the transient induction of bystander cytokines during the first 2 weeks after MCMV infection of apoE–/– mice may be crucial for MCMV-mediated acceleration of atherosclerosis.15,16 However, systemic immune activation by generalized herpesvirus simplex virus 1 infection seems not to be sufficient to aggravate lesion formation in hypercholesterolemic apoE–/– mice.17 It appears that it is rather the specific tropism of herpesviruses for cells of the vascular wall that determines the enhancement of atherogenesis in apoE–/– mice after herpesvirus infection.17,18 Therefore, an issue central to the role of murine and human cytomegaloviruses in atherogenesis is the relative contribution of the different immunopathological mechanisms ("bystander activation" versus "reactivity against persisting antigens") during the development of atherosclerotic lesions.
In the present study we used a well-defined mouse model of cardiovascular immunopathology19 to distinguish between MCMV infection-associated systemic immune activation and specific immune reactivity directed against a persisting viral antigen in the vasculature. In SM-LacZ mice, the β-galactosidase (β-gal) antigen is expressed in arterial smooth muscle cells.20 The peripherally expressed antigen is ignored by T cells unless the antigen is efficiently presented in secondary lymphoid organs.21 During infection with β-gal recombinant MCMV (MCMV-LacZ) the vascular β-gal transgene in SM-LacZ mice functions therefore as a pathogen-derived antigen that persists in the arterial wall. Infection of hypercholesterolemic apoE–/–x SM-LacZ mice with MCMV-LacZ revealed that virus-induced T cell responses directed against the transgenic β-gal antigen within the vasculature favor the development of an inflammatory environment that is important for the acceleration of atherosclerotic lesion development.
| Materials and Methods |
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Immunohistology
Freshly removed organs were immersed in HBSS and snap-frozen in liquid nitrogen (LN2). Frozen tissue sections were cut in a cryostat and fixed in acetone for 10 minutes. Sections were incubated with antibodies against β-gal (MP Biomedicals,), CD8 (clone YTS169.4.2), CD4 (YTS191.1.2), or F4/80 (Biomedicals AG, clone BM8) followed by goat anti-rat Ig (Caltag Labs) and alkaline phosphatase-labeled donkey anti-goat Ig (Jackson ImmunoResearch Labs). Alkaline phophatase was visualized by using AS-BI phosphate/New Fuchsin, and sections were counterstained with hemalum. For the quantitative evaluation of atherosclerotic lesions, 5 to 10 serial cross-sections through the aortic origin, beginning with the appearance of all 3 valve cusps, were stained with Sudan Red, counterstained with hemalum, and measured by using a Leica DM R microscope, Leica DC300 FX camera and Leica IM1000 (version 1.20) computer-aided morphometry software. The average lesion size for each mouse was calculated.
For semiquantitative assessment of inflammatory alterations in atherosclerotic lesions, sections were evaluated in a blinded fashion by 2 observers using the following criteria: grade 0, no infiltration; grade 1, confined minor infiltration (foci of <20 cells) in the perivascular space; grade 2, confined major infiltration (foci of >20 cells) in the perivascular space and/or within the intimal lesion; grade 3, multiple clusters of inflammatory cells (>100 cells) in the perivascular space; grade 4:, multiple clusters of inflammatory cells (>100 cells) in the perivascular space and within the intimal lesion. Average severity has been calculated for MCMV-LacZ–infected hypercholesterolemic mice. Infiltration with CD8+ T cells was enumerated on 3 sections per mouse covering the area of the coronary artery bifurcations.
For β-gal staining in whole tissue mounts, aortic arches were prepared from C57BL/6 and SM-lacZ mice and immersed in PBS 2 mmol/L MgCl2. After fixation in PBS containing 0.5% glutaraldehyde and 2 mmol/L MgCL2 for 1 hour, tissues were rinsed in PBS. β-gal activity was revealed by incubation for 2 to 4 hour at 37°C in X-Gal buffer (5 mmol/L potassium ferrocyanide, 5 mmol/L potassium ferricyanide, 2 mmol/L MgCl2 and 1 mg/mL X-Gal in PBS).
Please see supplemental materials, available online at http://atvb.ahajournals.org, for additional Materials and Methods.
| Results |
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(Figure 1B). Recognition of SMC by MCMV-induced CTL could be enhanced by exogenous pulsing with β-gal497–504 peptide. Furthermore, SMC lacking the Fas death receptor and Fas-competent C57BL/6 SMC could only be lysed by perforin-competent CTL (Figure 1C). These data indicate that (1) SMC expressing a protein shared by a cytomegalovirus can be lysed by virus-specific CTL, and (2) that CTL-mediated death of SMC is mainly mediated via perforin-dependent lysis.
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The adaptive immune response against MCMV is dominated by CD8+ T cells that are required for the termination of the productive infection and the establishment of latency.22 MCMV-specific memory CTL responses may show differences in their expansion and contraction patterns, eg, a rapid expansion can be followed by a pronounced contraction phase or by the continuous increase of IFN
producing memory CTL.23,24 We therefore tested in a first set of experiments, the CTL responses directed against the β-gal497–504 epitope and the immunodominant MCMV M45985–993 epitope of MCMV. Analysis with MHC class I tetramers on days 6, 50 and 100 post infection revealed that both β-gal497–504- and M45985–993-specific CD8+ T cells followed a similar pattern in normo- and hypercholesterolemic mice with maximal expansion during the acute response, a pronounced contraction and subsequent establishment of a stable long-term memory cell population (Figure 2A).
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Based on the finding that IFN
permits recognition of aortic SMC by MCMV-induced CTL (Figure 1B) and because IFN
accelerates atherosclerotic lesion development,25 we determined the ability of virus-specific CD8+ T cells to produce IFN
using intracellular cytokine staining (Figure 2B) and ELISPOT assays (Figure 2C and 2D). The ELISPOT assays were used for measurement of IFN
-secreting cells in the memory phase because this assay provides a better resolution and accuracy at lower T cell frequencies. These analyses revealed that neither hypercholesterolemia nor the presence of the β-gal-transgene had a significant impact on the peak expansion of β-gal497–504- and M45985–993-specific IFN
-secreting CD8+ T cells (Figure 2B). Furthermore, both β-gal497–504- and M45985–993-specific memory CTL were able to secrete IFN
following in vitro restimulation (Figure 2C and 2D). Again, the activity of anti-MCMV CD8+ T cells was not significantly different between hypercholesterolemic and normocholesterolemic mice, and there was no indication that the β-gal transgene in the vasculature had an influence on MCMV-induced CTL responses (Figure 2C and 2D). Taken together, the presented transgenic model provides the means to quantify and to phenotypically characterize virus-specific CD8+ T cells which recognize a persisting vascular antigen both under normo- and hypercholesterolemic conditions.
Virus Replication and Lipid Metabolism
It has been described previously that hypercholesterolemia may negatively influence immune reactivity and consequently alters the host-pathogen interaction with delayed clearance of viruses,26 bacteria,27 or fungi.28 We therefore assessed whether hypercholesterolemia in apoE–/– and apoE–/–xSM-LacZ mice influences initial replication and distribution of MCMV in comparison to normocholesterolemic C57BL/6 and SM-LacZ mice. Polymerase chain reaction (PCR)-based quantification of MCMV genome equivalents revealed that spleens and salivary glands were equally well infected in the four mouse strains (Figure 3A). Furthermore and in contrast to previous studies in mice,29 we could not observe a modulation of cholesterol levels in the course of MCMV infection in normo- or hypercholesterolemic mice (Figure 3B). Of particular importance for this study is that apoE–/– and apoE–/–xSM-LacZ mice are only distinguishable by constitutive β-gal expression in the cardiovascular system, all other MCMV infection-associated parameters such as T cell responses, viral distribution, and total cholesterol values were comparable.
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Accelerated Atherogenesis in MCMV-Infected ApoE–/–xSM-LacZ Mice
The impact of infection with β-gal recombinant MCMV-LacZ on atherosclerotic lesion development was assessed in the aortic sinus. The most striking observation was the nearly 200% increase of atherosclerotic lesion formation in apoE–/–xSM-LacZ versus apoE–/– control mice on day 50 after infection (Figure 4A and 4B). The acceleration of atherogenesis attributable to chronic virus-driven immune reactivity against the vascular β-gal antigen was less pronounced on day 100 after infection (Figure 4A and 4B). However, in accordance with a previous report from Epstein and colleagues,30 we found only a mild enhancement of atherosclerosis through infection of apoE–/– mice with MCMV on day 100 after infection (Figure 4B). These data indicate that it is mainly the chronic immune reactivity against the persisting MCMV antigen in the vasculature that exacerbates atherosclerotic lesion formation.
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In addition to the accelerated lesion formation, MCMV-LacZ–infected apoE–/–xSM-LacZ mice showed significant mononuclear infiltrations both in the neointima (Figure 4A, asterisks) and in the perivascular tissue underlying the atherosclerotic lesions (Figure 4A, arrow heads). Immunohistological characterization of the vascular inflammatory infiltrates revealed the presence of macrophages and T cells, with a predominance of CD8+ T cells (Figure 5). Semiquantitative in situ analysis revealed that MCMV-LacZ–infected apoE–/–xSM-LacZ showed significantly stronger inflammatory infiltration compared with apoE–/– mice, both on day 50 (1.8±0.5 versus 0.6±0.2; P<0.05) and on day 100 (2.1±0.3 versus 1.1±0.3; P<0.05) after infection. Furthermore, enumeration of CD8 T cells infiltrating neointima and perivascular space revealed that MCMV-LacZ infection of apoE–/–xSM-LacZ mice elicited a more pronounced recruitment of these cells compared with infected apoE–/– mice; both on day 50 (CD8 T cells per slide: 20.9±8.1 (n=13) versus 6.4±1.6 (n=9); P<0.05) and on day 100 (40.1±6.6 (n=8) versus 12.9±4.7 (n=11); P<0.01) after infection. It is thus conceivable that the abundant CD8+ T cells in and around the atherosclerotic lesions in apoE–/–xSM-LacZ mice were recruited to this location as a consequence of the ongoing immune activation during the persistent MCMV infection.
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| Discussion |
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can be produced by virus-specific NK and Th cells.34 It is possible that IFN
that is generated in the course of virus infection, either systemically or locally within the inflamed tissue, could promote CTL-mediated SMC lysis by virus-specific CTL through upregulation of MHC I molecules. In human SMC, for example, cytomegalovirus infection can lead to an increased MHC class I expression in smooth muscle cells, hence modulating their immunogenicity.35 Nevertheless, the results of this investigation demonstrate that chronic immune reactivity against a persisting microbial antigen in the arterial wall is a dominant immunopathological factor during MCMV-accelerated atherosclerosis in hypercholesterolemic apoE–/– mice.
Evidence from experimental and natural infections with herpesviruses supports the notion that general immune activation by a viral infection is less important for the inflammatory processes in the vascular wall. For example,
-herpesvirus infection of large arteries is associated with an acute lymphoid panarteritis and chronic obliterating arteriosclerosis in chicken36 and cattle.37 Furthermore, murine
-herpesvirus 68 (
HV68) exhibits a prominent tropism for medial smooth muscle cells of great elastic arteries38 and, consequently, enhances atherogenesis in apoE–/– mice.17,18 In MCMV infection, viral antigens have been reported to be expressed in endothelial and smooth muscle cells of the aorta.29 However, the presence of MCMV in the aorta is limited to a few weeks after infection15; a condition under which MCMV only mildly aggravates atherosclerosis in apoE–/– mice. Thus, accumulation of inflammatory cells in the perivascular space and increased development of atherosclerotic lesions heavily infiltrated with inflammatory cells, depends probably on prolonged antigen presentation within the vessel wall, as it is the case in apoE–/–xSM-LacZ mice. Likewise, factors that favor MCMV persistence in the vasculature lead to increased vascular inflammation39 and atherosclerosis.29
Activated T cells are a major fraction of the cellular components in human atherosclerotic plaques.40 Immunohistological analysis revealed that in advanced plaques of apoE–/– mice, CD4+ T cells are prominent in the fibrous cap and subendothelially, whereas CD8+ T cells are sparse.41 The importance of CD4+ T cells in the amplification of atherogenesis has been demonstrated in adoptive transfer studies where CD4+ T cells from apoE–/– transferred to immunodeficient apoE–/–xscid/scid mice accelerated lesion formation.42 CD4 T cells are activated during MCMV infection and help to maintain long-term control of MCMV in certain cell types within salivary gland tissues.43 It is likely that not only CD8+ but also CD4+ MCMV-specific T cells have contributed to the observed amplification of atherosclerotic lesions in apoE–/–xSM-LacZ mice. Furthermore, it may well be that the recently described dendritic cell network present in atherosclerosis-prone sites of the aorta32 locally presents viral antigens to both CD4+ and CD8+ T cells.
Infections are an important risk factor in atherosclerosis-related diseases such as coronary artery disease or stroke. It is striking that in particular those infectious agents which possess a pronounced tropism for cells of the vascular wall (HCMV or Chlamydia pneumoniae) are the most prominent in the list of infectious agents that contribute to the "infectious burden".4,44,45 Taken together with the data presented in this study, it is most likely that long-lasting immune reactivity against antigens of vascular-tropic infectious agents significantly amplifies inflammatory reactions within atherosclerotic lesions. Thus, treatment strategies against atherosclerosis should aim at reducing exaggerated immune reactivity within the atherosclerotic lesion without impairing general immune defense mechanisms against the persisting pathogen.
| Acknowledgments |
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Sources of Funding
The project received support from the Swiss National Science Foundation, the Fritz Thyssen Stiftung, the Novartis Foundation for Biomedical Research and the Jubiläumsstiftung Rentenanstalt.
Disclosures
None.
| Footnotes |
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