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Originally published online as doi:10.1189/jlb.1203605 on March 23, 2004

Published online before print March 23, 2004
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(Journal of Leukocyte Biology. 2004;76:300-306.)
© 2004 by Society for Leukocyte Biology

Immunopathogenesis of atherosclerosis

Burkhard Ludewig1, Philippe Krebs and Elke Scandella

Research Department, Kantonal Hospital St. Gallen, Switzerland

1Correspondence: Research Department, Kantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland. E-mail: Burkhard.Ludewig{at}kssg.ch


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE ROLE OF INFECTIOUS...
 INFECTION-ASSOCIATED VASCULAR...
 CONCLUSIONS-EXPANDING TREATMENT...
 REFERENCES
 
Recent clinical studies indicate that the number of microbial infections (the "pathogen burden") critically determines the development and progression of atherosclerotic disease. Viruses or bacteria with a specific tropism for cells of the vascular wall may contribute to the initial vascular injury via direct cytopathic effects or via the induction of genuine autoimmune responses. Immunopathological processes such as molecular mimicry, epitope spreading, or bystander activation of self-reactive lymphocytes most likely fuel the chronic inflammatory process in the vascular wall. Recognition of atherogenesis as a pathogen-driven, immunopathological process makes this disease amenable to new treatment strategies such as vaccination or immunomodulation.

Key Words: immunopathology • bystander activation • molecular mimicry • transgenic mouse model


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE ROLE OF INFECTIOUS...
 INFECTION-ASSOCIATED VASCULAR...
 CONCLUSIONS-EXPANDING TREATMENT...
 REFERENCES
 
Cardiovascular and cerebrovascular diseases including coronary heart disease and stroke are still the major causes of mortality in the Western world [1 ]. Chronic progression of atherosclerotic lesions in the arterial wall is the underlying pathological principle of these diseases. A strong association between elevated blood cholesterol levels and atherosclerosis had led to the classification of atherosclerosis as a lipid storage disease. Indeed, patients with familial hypercholesterolemia, a rare genetic disease with defects in the low-density lipoprotein receptor (LDLR), suffer from strongly elevated blood cholesterol [2 ] and may develop myocardial infarction at a young age. However, strongly elevated cholesterol levels, even in genetically predisposed individuals, do not necessarily precipitate lethal cardiovascular disease [3 ]. Hypercholesterolemia is clearly an important factor for the progression of atherosclerotic lesions, but other factors critically impinge on the initiation of the vascular lesion and on the overall damage that is caused by the disease. For example, severely hypercholesterolemic mice lacking apolipoprotein E (apoE) or LDLR-deficient mice fed a cholesterol-rich diet do not develop lethal myocardial infarction, despite pronounced cholesterol-induced fatty-streak formation [4 , 5 ]. The high resistance against cholesterol-induced myocardial infarction, at least in mice, is shown by the fact that mice lacking LDLR and apoE showed only a rather mild form of myocardial infarction, even after 8 months of a high cholesterol diet [6 ]. Additional factors such as hypoxia or mental stress were required for severe hypercholesterolemia-induced myocardial damage to develop in this particular experimental setting [6 ].

A large body of evidence indicates now that inflammatory processes in the vascular wall are the decisive factors that account for the rate of lesion formation and clinical development in patients. Longitudinal angiographic studies show that atherosclerosis starts already in childhood and proceeds in steps, whereby episodes of vascular alteration are followed by incomplete healing [7 ]. Intimal thickening may be associated with systemic infections already during the first years of life [8 ]. In adults, progression of atherosclerotic disease is associated with an increase of inflammatory markers in serum such as C-reactive protein, interleukin-6 (IL-6), and cell adhesion molecules [9 , 10 ]. This state of chronic inflammation is most likely maintained by repeated and/or chronic infection with multiple pathogens, an observation that has been first made by Epstein and colleagues [11 ]. A more recent, prospective study investigated the relationship among infectious burden, extent of atherosclerosis, and clinical prognosis. Seroreactivity against Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 2 (HSV-2) was significantly associated with advanced atherosclerosis. Furthermore, the risk for future death from cardiovascular disease was increased in patients chronically infected with multiple pathogens [12 ]. These and other clinical studies [13 , 14 ] suggest that the "infectious burden" is not only a predictor of coronary artery disease, which is mainly a result of plaque rupture or thrombosis, but may as well be associated with initiation and development of the atherosclerotic lesion. In this review, we discuss the contribution of inflammatory conditions, infectious and/or autoimmune, to atherogenesis and assess the role of different immunopathological mechanisms that may be involved in the disease process.


   THE ROLE OF INFECTIOUS DISEASES IN ATHEROGENESIS
TOP
 ABSTRACT
 INTRODUCTION
 THE ROLE OF INFECTIOUS...
INFECTION-ASSOCIATED VASCULAR...
 CONCLUSIONS-EXPANDING TREATMENT...
 REFERENCES
 
As outlined above, there is strong clinical evidence that the simultaneous or subsequent infection with several pathogens is a major factor involved in the pathogenesis of atherosclerosis. In the following section, we will briefly summarize the epidemiological linkage of the main infectious agents, C. pneumoniae, H. pylori, and cytomegalovirus, with coronary artery disease and atherosclerosis, and discuss the potential, direct pathological effects mediated by infection of cells of the vascular wall with these infectious agents.

C. pneumoniae
C. pneunomiae is a common human respiratory pathogen. Infection with this intracellular bacterium is not only associated with cardiovascular disease but also implicated in a number of chronic, degenerative diseases including multiple sclerosis [15 ] and Alzheimer’s disease [16 ]. C. pneumoniae can infect the principal cell types that are involved in the process of atherosclerosis in vitro [17 ]. In patients, C. pneunoniae antigen and DNA can be detected in atheromatous lesions [18 ], and viable organisms have been cultivated from atherosclerotic lesions obtained from endarterectomy and restenotic bypass samples [19 ]. C. pneumoniae infection of vascular wall cells is most likely not directly cytopathic. However, infection of endothelial cells with C. pneumoniae may stimulate production of soluble factors that elicit proliferation of smooth muscle cells [20 ]. Furthermore, macrophages infected with C. pneumoniae show accelerated uptake of LDL and transformation into foam cells [21 ].

The linkage of C. pneumoniae infection with atherosclerotic disease has been observed first by Saikku et al. [22 ], who determined C. pneumoniae-specific immunoglobulin G (IgG) antibody in patients with acute or chronic coronary artery disease [22 ]. More recent seroepidemiological surveys, including meta-analysis of previously published studies [23 , 24 ], found only a very weak association between C. pneumoniae IgG seroprevalence and concomitant cardiovascular disease. It appears that C. pneumoniae serology is a rather poor predictor for the presence of C. pneumoniae in atherosclerotic lesions [25 ]. However, pathology-based studies clearly show that C. pneumoniae DNA is more common in atherosclerotic lesions than in undiseased arteries [18 , 26 ]. Furthermore, a meta-analysis of Smieja and colleagues [27 ] indicates that detection of C. pneumoniae DNA in peripheral blood mononuclear cells by polymerase chain rection is a reliable instrument for prospective studies assessing the contribution of C. pneumoniae in atherosclerotic disease. Overall, C. pneumoniae, present in the diseased vessel wall, is most likely not an "innocent bystander"; however, the (immuno-)pathological consequences of this infection still remain to be fully elucidated.

H. pylori
This gram-negative bacterium typically infects human gastric epithelium and can be occasionally detected in atherosclerotic plaques [28 ]. Several serological studies indicate a significant association of H. pylori with atherosclerotic disease, even after adjustment for risk factors [12 , 13 ]. However, not all seroepidemiological studies were conclusive [29 ], most likely, as H. pylori is widely distributed in the population. More recent data suggest that virulence factors, such as the cytotoxin-associated gene A, determine the pathogenicitiy of H. pylori in the context of atherosclerosis [30 , 31 ]. The exact mechanisms as to how the increased pathogenicity of certain H. pylori strains impacts on plaque formation directly are still unknown. Nevertheless, it is likely that the presence of this pathogen in atherosclerotic lesions suffices to provoke and to maintain the inflammatory milieu in the vessel wall.

Cytomegalovirus
Human cytomegalovirus belongs to the group of ß-herpesviruses and infects 50–100% of the human population during early childhood. Several members of the herpesvirus family possess a strong tropism for cells of the cardiovascular system. Fabricant and colleagues [32 ] have provided the first evidence that herpesvirus infection alone is sufficient to cause acute arteritis and chronic atherosclerotic changes in the vascular wall. It is important that vaccination can prevent atherosclerosis induced by Marek’s disease virus infection of cells in the arterial wall of chicken [33 ]. A second {gamma}-herpesvirus, the ovine herpesvirus 2, elicits an often-lethal vascular syndrome in heifers, which is characterized by acute lymphoid panarteritis and chronic obliterating arteriosclerosis [34 ]. Human {gamma}-herpesvirus infection is usually not associated with arterial inflammation [35 ]. In contrast, human cytomegalovirus (HCMV) infection is frequently linked with human vasculitides and atherosclerosis. This has been shown in several seroepidemiological studies [36 , 37 ] and the frequent detection of DNA from HCMV in arteries of patients with inflammatory abdominal aortic aneuryms [38 ] as well as in atherosclerotic lesions of patients with coronary artery disease [18 , 39 ]. Moreover, a recent study shows the association of HCMV seropositivity with impaired vascular function in asymptomatic human individuals [40 ], suggesting that human HCMV infection is an early event in the chronological development of cardiovascular disease.

HCMV can infect all cell types in the vascular wall including endothelial cells and smooth muscle cells. HCMV infection of vascular endothelial may be lytic or result in viral latency [41 ]. Infection of arterial smooth muscle cells with HCMV leads to the generation of reactive oxygen species and nuclear factor-{kappa}B activation, which in turn, may result in the synthesis of atherogenic chemokines and cytokines [42 ]. In addition, the US28 gene product of HCMV, a viral chemokine receptor, enhances the migration of smooth muscle cells in response to the inflammatory chemokines RANTES (regulated on activation, normal T expressed and secreted) and MCP (monocyte chemoattractant protein-1) [43 ]. The US28-mediated effect represents a molecular mechanism as to how HCMV infection may contribute directly to neointima formation and thereby to the acceleration of vascular disease.


   INFECTION-ASSOCIATED VASCULAR INFLAMMATION AND IMMUNOPATHOLOGY
TOP
 ABSTRACT
 INTRODUCTION
 THE ROLE OF INFECTIOUS...
 INFECTION-ASSOCIATED VASCULAR...
CONCLUSIONS-EXPANDING TREATMENT...
 REFERENCES
 
The critical involvement of adaptive and innate immune mechanisms in the atherosclerotic process has been demonstrated in mice with genetically determined hypercholesterolemia. Crossing apoE–/– mice with recombination-activating gene-deficient mice lacking T and B cells resulted in a 40–80% reduction in early lesion formation [44 45 46 ]. Similarly, apoE–/– mice crossed with severe combined immunodeficiency mice showed 70% fewer lesions; however, transfer of CD4 T cells from apoE-deficient mice into the immunodeficient apoE–/–/severe combined immunodeficiency (scid)/scid mice increased the severity of atherosclerosis to levels similar to that of immunocompetent controls [47 ]. On the molecular level, production of interferon-{gamma} (IFN-{gamma}) and the activation of the adaptive immune system via CD40–CD154 interaction appear to be of prime importance for the development of atherosclerosis in hypercholesteremic mice [48 , 49 ].

Whereas immunodeficiency usually reduces atherosclerosis in hypercholesterolemic mice, vascular infection-associated inflammation may, on the other hand, accelerate the atherosclerotic process significantly. For example, mouse cytomegalovirus (CMV) [50 ] and murine {gamma}-herpesvirus-68 infection [51 ] potentiate the spontaneous lesion formation in apoE–/– mice. Systemic infection with HSV-1, which lacks a specific tropism for cells of the vascular wall, however, did not enhance atherogenesis in apoE–/– mice [52 ]. Similar observations have been made in high cholesterol diet-fed LDLR-deficient mice infected with C. pneumoniae or the Chlamydia trachomatis mouse pneumonitis strain. Only mice infected with C. pneumoniae showed accelerated lesion development [53 ]. The atherosclerosis-promoting role of C. pneumoniae in apoE–/– mice, however, is more contradictory, as illustrated by different studies showing acceleration [54 , 55 ] or no effect on lesion development [56 ]. Overall, these and other animal studies (reviewed in ref. [57 ]) indicate that specific infection parameters and/or pathogen-associated immune mechanisms determine whether and how particular infections impinge on the atherosclerotic process.

Molecular mimicry
Infection of cells in the vascular wall may initiate a cascade of inflammatory reactions and may lead to the destruction of cells via direct cytopathicity (Fig. 1a ). Inflammatory chemokines may recruit monocytes to the site, and up-regulation of adhesion molecules on endothelial cells may facilitate rapid transmigration and accumulation of monocytes and lymphocytes in the vessel wall. Indeed, atherosclerosis in hypercholesteroemic LDLR mice is significantly reduced in the absence of MCP-1 [58 ] or the combined absence of P- and E-selectins [59 ]. Although fatty-streak formation in hypercholesterolemic mice may also occur in the absence of pathogens, i.e., under germ-free housing conditions [60 ], it is most likely that pathogen-driven, innate inflammatory mechanisms significantly participate in the initiation and progression of human atherosclerosis.



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  		Figure 1. Immunopathological mechanisms involved in atherosclerosis. (a) Microbial infections of cells in the vascular wall may initiate immunopathological processes as a result of their direct cytopathicity. Pathogens or pathogen-derived antigens reach secondary lymphoid organs leading to the induction of T and B cell responses. (b) Activation of cross-reactive T or B cells that recognize pathogen- and self-antigens has been termed "molecular mimicry". Locally activated B cells may secret cytotoxic antibodies. T helper (Th) cells, which are activated by tissue-resident antigen-presenting cells (APC), secret cytokines and chemokines that recruit and activate monocytes and macrophages, which may damage the vessel wall through various effector pathways. (c) Release of self-antigens from endothelial or smooth muscle cells and their subsequent uptake and transport to secondary lymphoid organs elicit genuine autoimmune responses. Epitope spreading may lead to perpetuation of the inflammatory response by formation of antigen-antibody complexes and local activation of self-reactive Th cells. Macrophages activated by immune complexes and/or Th cell-derived soluble factors may secrete oxidative intermediates, cytokines, or metallo-matrix proteases (MMPs). (d) Chemokines and cytokines secreted by pathogen-specific Th cells attract and may stimulate self-reactive "bystander" Th cells in a T cell receptor-independent manner. IFN-{gamma}, producing autoimmune Th cells and activated macrophages, contributes to the perpetuation of the local inflammatory response. DC, Dendritic cells; NO, nitric oxide.

 
Pathogen-specific immune responses are induced when the infectious agent or its antigens reach secondary lymphoid organs [61 ]. Cross-reactive Th cells recognizing microbial and self-antigens may be generated during viral and bacterial infections, a process that has been termed molecular mimicry [62 ]. The peripheral activation of pathogen-induced Th cells, recognizing self-antigens presented by tissue-resident APC, may result in the release of cytokines such as IFN-{gamma} and chemokines, which attract further T cells and macrophages to the vascular lesion (Fig. 1b) . Molecular mimicry may play an important role in atherogenesis, as structurally related human and chlamydial heat shock proteins (HSP60/65) can be found in atherosclerotic lesions [63 ]. It has been shown, for example, that immunization of mice with recombinant bacterial HSP65 enhanced early lesion in mice fed a high cholesterol diet [64 ] and that HSP65-specific T cells or antibodies can promote fatty-streak formation in LDLR-deficient mice [65 ]. Furthermore, increased anti-HSP60 antibody titers are associated with atherosclerosis [66 ], and autoantibodies against HSP60 may exert endothelial cytotoxicity [67 ]. Cross-reactive T cells [68 ] and the direct macrophage-stimulatory function of HSP60 [63 ] may lead to the secretion of cytokine, MMPs, and NO by macrophages, thereby fueling inflammatory reactions in the atherosclerotic lesion.

The detrimental consequences of chronic T cell-mediated inflammatory responses in the vascular wall can be demonstrated in a transgenic mouse model of inducible cardiovascular immunopathology. In SM-LacZ mice, the microbial ß-galactosidase antigen is expressed exclusively in cardiomyocytes of the right heart and in arterial smooth muscle cells [69 ]. The transgene thus functions as a self-antigen, mimicking a bacterial antigen that persists in the cardiovascular system. It is interesting that T cells ignore the peripherally expressed antigen until the antigen is efficiently presented in secondary lymphoid organs. For example, immunization with DC presenting ß-galactosidase peptide elicits arteritis and myocarditis [70 ]. By crossing SM-LacZ mice onto the hypercholesterolemic apoE–/– background, it was possible to determine the influence of hypercholesterolemia in the development of immune-mediated arterial inflammation and to evaluate the significance of immune-mediated arteritis in the chronological process of cholesterol-induced atherosclerosis. Hypercholesterolemia enhanced and perpetuated T cell-mediated arterial inflammation, and arterial inflammation significantly increased the susceptibility of the arterial wall to cholesterol-induced atherosclerosis [71 ]. Such mutual detrimental effects of vascular immunopathology and hypercholesterolemia have been observed in other experimental systems. For example, the number of IFN-{gamma}-producing Th1 cells infiltrating atherosclerotic lesions decreases under severe hypercholesterolemic conditions, and the subsequent Th1-to-Th2 switch results in the formation of IgG1 autoantibodies directed against oxidized LDL [72 ]. In addition, C. pneumoniae infection was shown to aggravate diet-induced atherosclerosis in normal C57BL/6 mice [73 ]. Overall, these data support the notion that the mutual perpetuation of pathogen- or autoimmunity-driven arterial inflammation and cholesterol-induced atherosclerosis may favor the vicious circle of chronic vascular injury.

Epitope spreading and bystander activation
Infection-associated autoimmune diseases such as multiple sclerosis are characterized by strong antibody and Th cell responses against self-antigens [74 ]. For example, in the model of Theiler’s virus-induced demyeliniating disease, Th cell responses against a set of tissue-specific antigens arise in a distinct chronological order after the initial virus infection and correlate with the clinical severity of the disease. Intra- and intermolecular epitope spreading can be observed in this particular experimental model [75 ]. Epitope spreading also appears to be a major immunopathological mechanism in the pathogenesis of multiple sclerosis [74 ], and there is evidence that pathogen-induced diversification of Th and B cell responses may play a role in atherogenesis [76 ] (Fig. 1c) .

An extensive collection of data support the notion that the oxidized form of LDL (oxLDL) is a major autoantigen involved in atherosclerosis (reviewed in ref. [77 ]). oxLDL and anti-oxLDL antibodies are present in atherosclerotic lesions [78 , 79 ], and immune complexes consisting of oxLDL and anti-oxLDL may be ingested by tissue macrophages via Fc-{gamma} receptors, leading to activation of the phagocytes with release of inflammatory cytokines, oxygen-activated radicals, and MMPs [80 ]. However, LDL-specific antibodies may also exert protective effects. For example, immunization of LDLR-deficient rabbits or mice with homologous malondialdehyde-modified or native LDL significantly inhibited the development of atheromatous lesions [81 , 82 ]. In light of these somewhat contradictory findings, it remains to be clarified under which conditions antibodies directed against the LDL molecule and its modifications protect against or favor the development of atherosclerosis.

Nevertheless, the finding that Th cells recognize oxLDL [83 ] provides further evidence that oxLDL-driven immune responses contribute significantly to the chronic inflammatory reaction in the atherosclerotic plaque. Infectious agents may foster this immunopathological process. For example, herpesviruses may alter the general cholesterol metabolism [84 , 85 ], and local oxidation of LDL by C. pneumoniae has been described [21 ]. It is interesting to note that the atherogenic effect of C. pneumoniae depends on elevated serum cholesterol levels [53 ].

Infection-associated inflammation involves the release of cytokines and chemokines, which attract further pathogen-specific effector cells and lymphocytes of other specificities. This bystander effect can suffice to activate lymphocytes directed against self-antigens, leading to initiation and/or exacerbation of autoimmune disease. For instance, virus-induced "bystander activation" of self-reactive T cells appears to be the major immunopathological mechanism in insulin-dependent diabetes [86 ]. In atherosclerosis, it may well be that persistent infection of cells in the vessel wall results in increased release of the prototypic atherogenic cytokines. Indeed, C. pneumoniae of aortic smooth muscle cells induces proinflammatory cytokine responses with release of IL-6 and IL-8 [87 ]. Chlamydia-induced inflammation may as well be mediated by release of tumor necrosis factor and IL-1ß from monocytes/macrophages, which are activated through the Toll-like receptor 2 [88 ]. Similarly, CMV may contribute to the atherogenetic process by interacting with monocytes and inflammatory cytokines/chemokines, which are expressed in cells of the vascular wall [43 , 89 ]. Acceleration of inflammatory responses by pathogens is thus most likely a critical event in the initiation and progression of atherosclerotic lesions.


   CONCLUSIONS–EXPANDING TREATMENT OPTIONS
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 ABSTRACT
 INTRODUCTION
 THE ROLE OF INFECTIOUS...
 INFECTION-ASSOCIATED VASCULAR...
 CONCLUSIONS-EXPANDING TREATMENT...
REFERENCES
 
During the recent years, our understanding of the mechanisms underlying the development and progression of atherosclerotic lesions has rapidly advanced. Atherosclerosis is now seen as the consequence of an inflammatory cascade that is most likely promoted by microbial infections of the vessel wall and is enhanced under certain conditions such as hypercholesterolemia or hypertension. It is noteworthy that the new insights into the immunopathogenesis of atherosclerosis have opened up new treatment options. For example, therapeutic intervention using statins, which inhibit the key enzyme in the cholesterol metabolism, 3-hydroxyl-3-methylglutaryl CoA reductase, significantly reduces mortality rates in patients with coronary heart disease [90 ]. It is important that statins not only lower cholesterol levels but also affect the general immune responsiveness, for example, by acting as direct inhibitors of IFN-{gamma}-induced major histocompatiblity complex class II expression on endothelial cells by suppressing Th cell activation [91 ].

Whereas statins or other immune-modulating compounds may be used to treat more advanced atherosclerotic disease, preventive strategies may be used to impact on early atherosclerosis. Infections with C. pneumoniae, which most likely cause repeated acute inflammatory reactions in early arterial disease, can be treated with antibiotics in experimental animals [55 , 92 ]. It is important that treatment of C. pneumoniae seropositive, but not seronegative patients with the macrolide antibiotic roxithromycin, has been shown to delay the atherosclerotic process [93 ]. Furthermore, a recent prospective, double-blind, placebo-controlled trial in 40 male patients with coronary artery disease revealed that the macrolide antibiotic azithromycin has a favorable effect on endothelial function [94 ]. Likewise, antibiotic treatment can significantly reduce adverse cardiac events in patients presenting with acute coronary syndromes [95 ] or acute non-Q-wave coronary syndrome [96 ]. It is important to note that a positive impact of antibiotic therapy on coronary heart disease is not necessarily linked to C. pneumoniae seropositivity [95 , 97 ], further supporting the notion that multiple infections most likely contribute to the progression of atherosclerosis.

Infections and autoimmune diseases may not only be treated with antibiotics or immunosuppressive drugs but are also amenable to vaccination. Several C. pneumoniae antigens have been identified that induce protective immunity in a mouse model of acute C. pneumniae infection [98 ]. Furthermore, vaccination approaches using autoantigens such as oxLDL [82 , 99 ] or HSP60/65 [100 ] in experimental animals showed some beneficial effects. The great challenge for the future is thus to translate the results from the encouraging experimental stage into clinical studies.


   ACKNOWLEDGEMENTS
 
The Swiss National Science Foundation, the Fritz-Thyssen-Foundation, and the Kanton of St. Gallen supported this work.

Received December 1, 2003; revised February 12, 2004; accepted February 16, 2004.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 THE ROLE OF INFECTIOUS...
 INFECTION-ASSOCIATED VASCULAR...
 CONCLUSIONS-EXPANDING TREATMENT...
 REFERENCES
 

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