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Molecular Cell Biology of Atherosclerosis

Göran K. Hansson*Department of Medicine and Center for Molecular Medicine, Karolinska University Hospital Solna, KarolinskaInstitutet, Stockholm, Sweden

Abstract

Atherosclerosis is a chronic inflammatory disease elicited by the accumulation of cholesterol-richlipoproteins in the artery wall. This review outlines its pathogenesis, with a focus on molecularmechanisms mediating immune-metabolic interactions, vascular inflammation, formation ofatherothrombi, and triggering of clinical ischemic events.

Glossary of Terms

Adaptive immunity Adaptive immunity is a highly specific system for the recognitionand neutralization of pathogens; it is initiated when antigenicfragments bound to MHC proteins on cell surfaces are recognizedby unique T-cell receptors (TCR). Downstream thereof highlyspecific antibodies as well as cell-mediated responses contribute toantigen elimination, cell death, and inflammation.

C-reactive protein (CRP) C-reactive protein (CRP) is a complement-binding proteinproduced in the liver in the acute phase response initiated byinterleukin-6.

Chemokines Chemokines are proteins that mediate the migration of cells towarda concentration gradient.

Eicosanoids Eicosanoids are lipid mediators and include prostaglandins andleukotrienes

E-selectin and VCAM-1 E-selectin and VCAM-1 are leukocyte adhesion molecules whoseexpression on the endothelial surface mediates the binding ofdifferent types of leukocytes to the vessel wall.

High-density lipoprotein(HDL)

High-density lipoprotein (HDL) is a set of particles transportingcholesterol from peripheral tissues to the liver.

Low-density lipoprotein(LDL)

Low-density lipoprotein (LDL) is the major cholesterol-transporting particle in blood that delivers cholesterol from theliver to other tissues for membrane formation, steroid hormonesynthesis, etc.

NF-kB and KLF2 NF-kB and KLF2 are transcription factors regulating geneexpression.

Major histocompatibilitycomplex (MHC)

Major histocompatibility complex (MHC) proteins andcostimulatory factors are crucial in the initiation of adaptiveimmunity.

*Email: [email protected]

PanVascular MedicineDOI 10.1007/978-3-642-37393-0_6-1# Springer-Verlag Berlin Heidelberg 2014

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Pattern recognitionreceptors

Pattern recognition receptors bind macromolecules and particlesbased on pattern recognition rather than recognition of highlyspecific molecular structures; they play important roles in innateimmunity.

Introduction

Atherosclerosis is a chronic inflammatory response to the accumulation of lipid in the artery wall(Hansson 2005; Hansson and Hamsten 2012; Libby et al. 2011) (Fig. 1). It is characterized byclinically silent intimal plaques that develop in arteries for years and even decades (Fogelstrand andBoren 2012; Libby et al. 2013). Fissuring or erosion of atherosclerotic plaques triggers the formationof a thrombus that accumulates over seconds to minutes to cause acute ischemia of the end organ.This ischemia, in turn, results in the dramatic clinical manifestations. It is estimated that approxi-mately 90 % of cases of myocardial infarction, 60 % of strokes, most cases of heart failure, and up toone-third of all cases of dementia are due to atherosclerosis. Therefore, atherosclerosis and itscomplications represent a major burden on society, with regard to demography, economics, andhuman suffering.

The major risk factors that promote the development of atherosclerosis are an elevated low-density lipoprotein (LDL) cholesterol level, cigarette smoking, type 2 diabetes, hypertension, andgenetic predisposition (Hansson and Hamsten 2012). Other conditions thought to increase the risk ofatherosclerotic disease include a low high-density lipoprotein (HDL) level, abdominal obesity,hypertriglyceridemia, high plasma levels of lipoprotein (a) [Lp(a)], hyperfibrinogenemia, theinflammatory marker C-reactive protein (CRP), and physical inactivity. Other potential risk factorsinclude uric acid, psychosocial stress, and elevation of plasma homocysteine.

An atherogenic lipoprotein phenotype has been defined as the presence of a predominance ofsmall, dense LDL particles, hypertriglyceridemia, and low plasma HDL cholesterol concentration(Sniderman et al. 2010). This lipoprotein phenotype, which is strongly linked to obesity, insulinresistance, hypertension, and abnormalities in postprandial lipoprotein metabolism, is similar to theso-called metabolic syndrome, in that both are associated with a cluster of atherogenic andthrombotic risk factors – raised plasma levels of fibrinogen, plasminogen activator inhibitor-1(PAI-1), and coagulation factor VII, as well as platelet hyperactivity.

The inflammatory biomarker, CRP, has gained much interest as a predictor of cardiovascularevents (Kaptoge et al. 2012; Libby et al. 2011). Since it is not causatively related to atherosclerosis,CRP reflects ongoing inflammation in atherosclerotic lesions as well as inflammatory conditionselsewhere that may accelerate the atherosclerotic process.

Hemodynamics, Endothelial Phenotype, and Lesion Formation

Atherosclerosis preferentially occurs at sites of disturbed flow in large- and medium-sized arteries.Such sites include bifurcations, branches, and curvatures. Here, the normal orientation of theendothelial cells along the direction of the blood flow is changed to a less organized pattern, andtheir transcriptome displays increased expression of the NF-kB signal transduction pathwayand reduced expression of “vasculo-protective” genes including endothelial nitric oxide synthase


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and a set of genes induced by Kr€uppel-like factors (KLF) 2 and 4 (Davies et al. 2013; Gimbrone andGarcia-Cardena 2013). Endoplasmic reticulum (ER) stress in these regions triggers an unfoldedprotein response with the upregulation of antioxidant proteins and chaperones.

A set of molecular species derived from the underlying arterial intima can also activate endothelialcells. These molecules include a set of phospholipids generated upon lipoprotein oxidation, such aslysophosphatidylcholine and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine(Ox-PAPC), and also 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL), which is a quorumsensing molecule produced by certain bacterial pathogens (Kim et al. 2011). These molecules triggera kinase cascade in endothelial cells that results in the expression of leukocyte adhesion moleculessuch as E-selectin and VCAM-1, several chemokines, and enzymes involved in handling oxygenradicals. They also modulate the expression of cyclooxygenase-2, an enzyme involved in theproduction both of proinflammatory PGE-type prostaglandins and in antithrombotic prostacyclin(Tang et al. 2014).

Downstream consequences of endothelial activation include increased transendothelial perme-ability and vascular contractility, as well as recruitment of monocytes and T cells to the arterialintima.

LDL Accumulation Initiates Atherosclerosis

The accumulation of cholesterol-containing low-density lipoprotein (LDL) particles in the vascularintima is thought to be the initiating event in atherosclerosis. Arterial endothelial cells expressadhesion molecules that capture leukocytes on their surfaces when subjected to irritative stimuli

Fig. 1 Formation and growth of atherosclerotic lesions. (a) Macrophages and T cells are recruited to sites of LDLaccumulation in the arterial intima. (b) The atherosclerotic lesion contains a core region with foam cells, extracellularcholesterol, and dead cells, covered by a fibrous cap consisting of vascular smooth muscle cells and collagen fibers andin turn covered by the endothelial cell layer. In the “shoulder region” of the lesion, activated macrophages and T cellsproduce cytokines, eicosanoids, and other bioactive mediators that promote growth of the lesion. In advanced stages ofdisease, a periadventitial reaction is observed, with organized tertiary lymphoid structures of B cells, T cells, macro-phages, and dendritic cells (From Hansson and Hermansson 2011)


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such as dyslipidemia, hypertension, or proinflammatory mediators. Parallel changes in endothelialpermeability and the composition of the extracellular matrix beneath the endothelium promote theentry and retention of LDL in the artery wall.

Small, dense LDL particles are particularly prone to accumulate in the intima, where theyassociate with proteoglycans of the extracellular matrix (Fogelstrand and Boren 2012). Lipoproteinlipase produced locally in the artery can bridge LDL to the extracellular matrix, and phospholipaseand sphingomyelinase actions may contribute to the entrapment of LDL. Once trapped in the arterywall, LDL particles can be attacked by enzymes such as myeloperoxidase and NADPH oxidases;they may also be modified by nonenzymatic oxidation. During oxidative modification of LDL,certain biologically active oxidized phospholipid species are released and activate endothelial cellsand macrophages. Such activation leads to the production of chemokines such as MCP-1 (CCL2),RANTES (CCL5), and fractalkine (CX3CL1) and to the expression of leukocyte adhesion mole-cules including VCAM-1 and ICAM-1 on the endothelial surface. Together, these moleculesinstigate recruitment of monocytes and T cells to the intima.

Monocyte-Derived Macrophages Develop into Foam Cells

Monocytes entering the tunica intima differentiate into macrophages upon stimulation by mediatorssuch as monocyte-colony-stimulating factor (M-CSF), which is produced locally (Clintonet al. 1992). The accumulation of mononuclear phagocytes in the atherosclerotic lesion dependsnot only on their influx, mediated by adhesion molecules and chemoattractants, but also on retentionwithin the plaque. Netrin-1, a molecule implicated in neuronal guidance, appears to be an importantretention promoting factor (van Gils et al. 2012).

After initiating an atherogenic diet, the blood of hypercholesterolemic mice shows a dramaticincrease in a subtype of monocytes that expresses high levels of the surface protein, Ly6c (Robbinset al. 2012). This Ly6chi monocyte subpopulation exhibits a series of functions that would renderthem particularly pathogenic in the context of a chronic inflammatory disease such as atheroscle-rosis. For example, these cells bind with high avidity to activated endothelial monolayers. Theyexpress higher levels of proinflammatory cytokines and proteases implicated in the pathogenesis ofatherosclerosis than their Ly6clo counterparts. These proinflammatory monocytes arise fromextramedullary hematopoiesis in the spleen.

Proinflammatory monocytes of splenic origin comprise up to a quarter of the mononuclearphagocytes in mouse atheromata (Robbins et al. 2012). Endoplasmic reticulum stress related tointracellular lipid accumulation, as well as production of the hematopoietic cytokines, IL-3 andGM-CSF, may contribute to extramedullary hematopoiesis in the spleen of hypercholesterolemicmice. Cells from this population home to sites of acute injury, such as infarcts of the heart or brain, aswell as to sites of chronic inflammation, such as atheroma in mice (Dutta et al. 2012). The humanmonocyte population that corresponds to the Ly6chi population in mice remains controversial, butthe CD14+ CD16� population in humans may subserve this function.

Atherosclerotic lesions are dominated by the M1 subpopulation of macrophages (Johnson andNewby 2009). These classically activated macrophages can arise from monocytes in response to thecytokine interferon (IFN)-g combined with a TLR stimulus and elaborate mediators associated withthe progression and complication of atherosclerosis. Their less inflammatory counterparts, the M2macrophages, may in contrast elaborate mediators that mitigate atherosclerosis. Whether the Ly6chi

population of monocytes preferentially give rise to M1 macrophages remains incompletely sub-stantiated. The polarization between monocyte and macrophage subtypes in humans appears much


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hazier in humans than in mice, raising a note of caution in facile extrapolations from murineatherosclerosis to the human disease.

Macrophage differentiation associates with increases in scavenger receptors (SRs) on the cells.These pattern recognition receptors (PRRs) include SR-A (CD204), CD36, MARCO, and LOX-1(OLR-1), which mediate internalization of a broad range of molecules and particles such asendotoxins, apoptotic bodies, parasite components, and LDL particles (Lundberg and Hansson2010). SRs can bind these particles after they undergo oxidative modification locally in the arterialwall. Eventually, cholesterol entry can overwhelm the cell’s capacity for eliminating these mole-cules, and cholesterol starts to accumulate as cholesteryl ester droplets in the cytosol. With time, themacrophages become overloaded with cholesteryl ester droplets, taking on the characteristic “foamcell” appearance. Many of these lipid-engorged phagocytes eventually die, leading to the accumu-lation of apoptotic bodies and necrotic debris in the lesion. A “necrotic” core forms in the evolvingatheromatous lesion. Components of this detritus can promote plaque progression and areprothrombotic. Therefore, impaired clearance of such apoptotic debris (impaired efferocytosis)may contribute to thrombotic complications of atherosclerotic lesions (Van Vre et al. 2012).

Cholesterol Accumulation Activates the Inflammasome

When cholesterol accumulates in macrophages, intracellular microcrystals can form (Fig. 2). Cho-lesterol crystal formation in macrophages depends on the uptake, the intracellular balance betweenfree cholesterol and cholesterol ester, and the cholesterol efflux to extracellular HDL or HDL-typeapolipoproteins. Such intracellular microcrystals can activate a member of the cytosolic nucleotide-binding domain and leucine-rich repeat gene family (NLRP3), triggering its associatedinflammasome to process the proform of interleukin-1b (IL-1binto a bioactive cytokine (Duewellet al. 2010; Rajamaki et al. 2010). Just as uric acid crystals in joints can cause gout, cholesterolcrystals in plaques can incite inflammation in the artery wall. Genetic targeting of either IL-1b ora component in the NLRP3 inflammasome reduces atherosclerosis in mice, supporting a pathogenicrole for this pathway of inflammatory activation (Duewell et al. 2010). Thus inflammasomeactivation provides a possible pathogenic pathway that links cholesterol accumulation to the chronicinflammatory process of atherosclerosis.

Pattern Recognition Receptor Activation in Atherosclerosis

Several types of pattern recognition receptors (PRRs) may participate in atherogenesis (Lundbergand Hansson 2010) (Fig. 2). Beyond cytosolic NOD-like receptors, cells in human atheromataexpress Toll-like receptor (TLR) family members (Edfeldt et al. 2002). Several experiments usinggene-targeted mice have addressed the role of TLRs in atherogenesis, yielding rather complexresults (Lundberg and Hansson 2010). TLR2 and TLR4 appear proatherogenic, while TLR3, TLR7,and TLR9may protect against atherosclerosis in mice. The situation for TLR2 presents a particularlycomplex situation, as its expression on vascular endothelium appears to promote atherosclerosis,whereas TLR2 has protective effects when expressed by myeloid cells (Mullick et al. 2008). It isnoteworthy that cell surface-exposed TLR2 and TLR4 are proatherogenic, while TLRs bound tointracellular membranes, including TLR3, TLR7, and TLR9, protect against experimental athero-sclerosis (Lundberg and Hansson 2010).


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MyD88 functions as an adaptor protein for several TLRs and for the IL-1 signaling receptor. Theactivation of MyD88 via TLR ligation triggers the NF-kB pathway, leading to the production ofmany inflammatory agonists implicated in atherogenesis. Targeted deletion of MyD88 showsa much more pronounced effect of MyD88 on atherosclerosis than interruption of TLR4 itself(Bjorkbacka et al. 2004; Michelsen et al. 2004). This result implies that TLR4-independentpathways for MyD88 activation contribute at least as important for atherogenesis as TLR4 ligation.

The distinct effects of different TLRsmay relate to their roles in host defense. Several molecules andparticles present in the extracellular spacemay ligate TLR4, including oxidized LDL particles and heatshock protein-60 (Bae et al. 2009; Cohen-Sfady et al. 2005). The ligands of intracellular TLRs includeendogenous and pathogen-derived nucleic acids and certain lipids implicated in atherogenesis. Geneticstudies of PRR gene polymorphism as a potential risk factor for coronary artery disease have yieldedcontradictory results (Edfeldt et al. 2003). Therefore, the importance for human atherosclerosis ofinnate immune activation through TLR, NLRP, or other PRRs remains unclear.

Mast Cells in Atherosclerosis

Mast cells accumulate in human atheromata, particularly at sites of plaque rupture. These cellsexhibit several functions that could contribute to atherogenesis in vitro (Kovanen 2007). Bothpharmacologic and genetic approaches support a contribution of mast cells to experimental athero-sclerosis in mice (Sun et al. 2007; Bot et al. 2007). In mice with genetic deficiency of mast cells,adoptive transfer experiments of mast cell populations point to proatherogenic roles of mast cell-derived IFN-g and IL-6 in the pathogenesis of atherosclerosis. The signature proteinases of mastcells including chymase and tryptase may also participate in aspects of the disease.

Fig. 2 Innate immune activation of macrophages in atherosclerosis. Pattern recognition receptors of macrophagesinclude internalizing scavenger receptors and signaling Toll-like receptors as well as NOD-like receptors of theinflammasome. Signaling through these receptors leads to secretion of proinflammatory cytokines, chemokines, pro-teases, costimulatory factors, reactive oxygen and nitrogen species, and eicosanoids (From Hansson and Hermansson2011)


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Platelets as a Source of Inflammatory Mediators

Ample experimental and clinical data demonstrate a key role for platelets in atherothrombosis. Theseparticles may also contribute to inflammation prior to plaque rupture and thrombosis, as they containabundant preformed proinflammatory mediators including CD40 ligand (CD154), RANTES, andIL-6 as well as anti-inflammatory TGF-beta (Croce and Libby 2007; Toma and McCaffrey 2012).Upon activation, platelets release these mediator proteins in huge amounts; this likely impactssubstantially on local inflammation at sites of thrombus formation. In addition, platelets modulateT-cell activation and may therefore also impact adaptive immunity in atherosclerotic lesions (Gerdeset al. 2011).

Dendritic Cells Link Innate and Adaptive Immunity

Dendritic cells (DCs) derived from the myeloid lineage express many different PRRs and populatemost tissues where they serve as sentinels of infection and injury. The intima and adventitia ofnormal mouse and human arteries contain DCs, and their numbers increase in atherosclerotic lesions(Angeli 2004; Bobryshev 2010). DCs can internalize oxLDL and become foam cells in vivo, andthese cells therefore likely participate in inflammatory responses in early lesions (Fig. 3). DCsactivated as part of an innate immune response in tissues increase the expression of the CCR7chemokine receptor, as well as major histocompatibility complex (MHC) and costimulatorymolecules – changes that favor their migration into lymphoid tissues and presentation of peptideantigens to naïve T cells. Therefore, the recognition of PRR ligands primes DCs to initiate T-cellresponses. In the absence of innate stimuli, so-called “immature” tissue DCs likely migrate consti-tutively at low levels to lymphoid tissues and present healthy tissue antigens for recognition by naïverecirculating self-antigen-specific T cells. The encounter of naïve T cells with these immature DCs,which express only low levels of costimulators, leads to T-cell death, anergy, or skewed differen-tiation toward a regulatory program – all consequences that promote T-cell tolerance to self. Giventhe potential catastrophic consequences of active T-cell responses to antigens (self or foreign) in thearterial wall, vascular DCs likely normally promote tolerance to vascular wall antigens (Choiet al. 2011). Atheroprotective effects of DC can be further enhanced when a tolerogenic phenotypeis induced by treatment with IL-10 during differentiation (Hermansson et al. 2011).

Adaptive Immunity in Atherosclerosis

Several lines of evidence show that adaptive immunity is activated in human atherosclerosis.Plaques contain T cells, including some that bear markers of activation (Hansson and Jonasson2009; Jonasson et al. 1985, 1986), and autoantibodies to LDL circulate in atherosclerotic patients(Hartvigsen et al. 2009). The rapid occurrence of arteriopathy in human hearts transplanted acrossmajor histocompatibility barriers, sometimes in the absence of classical risk factors for atheroscle-rosis, underscores the potential of allogeneic immune responses to produce an arterial disease inhumans that recapitulates many features of atherosclerosis (Salomon 1991; Michell 2007). Suchobservations led to the hypothesis that components of adaptive immunity aggravate and modulatedisease development. Subsequent studies in animals, in particular the gene-targeted mouse, supportthis hypothesis and offer insights into an intricate and nuanced network of immune regulation inatherogenesis (Hansson and Hermansson 2011; Lahoute et al. 2011).


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Atherosclerosis as a T-Cell-Driven Disease

The advanced human atherosclerotic plaque contains Tcells, largely effector-memory cells of whicha substantial proportion display signs of activation. About two-thirds of human plaque T cells bearCD4 and the balance CD8, whereas CD4+ Tcells dominate in atherosclerotic mice. T cells of humanlesions exhibit a T helper-1 (Th1) cell-associated cytokine secretion pattern, including IFN-g andtumor necrosis factor (TNF), and mouse experiments have demonstrated important proatherogeniceffects of Th1 cells and their cytokines (Frostegard et al. 1999). As in other conditions, T cells ofhuman atherosclerotic plaques do not show the same degree of polarization as those of inbred mousestrains, but Th1 cytokines do prevail and arise from a larger number of Tcells in human plaques thando T helper-2 (Th2) cell effector cytokines such as IL-4.

The signature Th1 cytokine, IFN-g, promotes atherogenesis in mice. Thus, targeted deletion ofIFN-g or its receptor leads to reduced disease, whereas administration of recombinant cytokineprotein aggravates atherosclerosis in hypercholesterolemic mice (Gupta et al. 1997; Whitmanet al. 2000). Interference with IFN-g signaling also blocks allograft arteriopathy in mice (Naganoet al. 1997). Several molecular targets may contribute to such an effect of IFN-g. It inhibitsproliferation and collagen production by vascular smooth muscle cells (SMCs), thus impairingrepair processes in the vessel wall and possibly reducing plaque stability (Amento et al. 1991;Hansson et al. 1989). Furthermore, IFN-g hampers cholesterol efflux from macrophages and affectsscavenger receptor expression. Interestingly, this cytokine also promotes hyperglycemia andincreases fat inflammation, conditions thought to enhance the risk of atherosclerotic cardiovasculardisease (Rocha et al. 2008).

The role of Th17 cells in atherosclerosis is the topic of ongoing research in several laboratories.Several studies show that Th17 overproduction leads to the formation of large lesions. However, thismay be due to a fibrogenic effect of the signature cytokine, IL-17A, resulting in large but fibrotic andpresumably stable lesions (Gistera et al. 2013).

In humans, a CD28 null subset of CD4+ T cells expands in the setting of chronic inflammatorydiseases, cytomegalovirus infection, or advanced age. These cells elaborate many proinflammatorycytokines and exhibit cytotoxicity. CD28 null CD4+ T cells localize in unstable human lesions, andafter MI, these cells increase in peripheral blood (Liuzzo 2007).

Natural killer T (NKT) cells have particular interest for atherosclerosis, as they recognize lipidantigen and localize in lesions both in mice and in humans (albeit at much lower levels). Theinvariant NKT cell undergoes activation when lipid antigens bound to CD1d ligate its Vbeta14+

TCR. Human atheromata contain cells that display CD1 (Melian et al. 1999). The activation of NKTcells with a model antigen, alpha-galactosylceramide, significantly increases early atherosclerosis inhypercholesterolemic mice (Tupin et al. 2004). The production of a set of proinflammatory cyto-kines that include IFN-g and TNF and the expression of MHC molecules and leukocyte adhesionmolecules in lesions accompany this aggravation of atherosclerosis. Interestingly, CD1d deficiencyresults in reduced disease in atherosclerosis-prone mice. In accordance with these findings, CD1d-deficient mice display reduced atherosclerosis (Tupin et al. 2004) – suggesting that endogenous lipidantigens, or possibly those derived from the host microbiome, promote atherosclerosis via recog-nition by NKT cells.


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Counterbalancing Factors in Adaptive Immune Responses inAtherosclerosis

Two anti-inflammatory cytokines, IL-10 and transforming growth factor-b (TGF-b), modulateatherogenesis in hypercholesterolemic mice (Caligiuri et al. 2003; Lutgens et al. 2002). Thesecytokines are produced by several cell types, including regulatory T cells (Treg) that are activatedby cognate antigens. Eliminating TGF-b signaling to T cells dramatically accelerated experimentalatherosclerosis (Robertson et al. 2003), pointing to regulatory T cells (Treg), which use TGF-beta tocontrol effector T cells, as an important atheroprotective cell population (Ait-Oufella et al. 2006). Insupport of this notion, the transfer of isolated CD4+CD25+ cells containing natural Treg cell reducedatherosclerosis and counteracted the pro-atherosclerotic effect of Treg cell deficiency (Ait-Oufellaet al. 2006). Treg cells may not only affect the artery wall, as Treg cell elimination also impactsplasma lipoprotein metabolism, leading to delayed clearance of cholesterol-rich lipoproteins andelevated plasma cholesterol levels (Klingenberg et al. 2013).

The limited data available for human atherosclerosis supports a pro-atherosclerotic role for Th1cells and supports the operation of atheroprotective adaptive immune mechanisms, but we lackdetailed knowledge in this regard (Hansson and Hermansson 2011).

B Cells and Humoral Immunity in Atherogenesis

Initial studies on the role of B cells showed that splenectomy accelerates atherosclerosis inhyperlipidemic mice atherosclerosis, and adoptive transfer of B cells protected splenectomizedmice from severe disease (Caligiuri et al. 2002) Nonselective B-cell depletion achieved by admin-istration of an anti-CD20 antibody, however, reduces murine atherosclerosis (Ait-Oufellaet al. 2010). Subsequent studies using interruption of B-cell-activating factor (BAFF) signalingpoint to a role for the B2 subpopulation of lymphocytes in promoting atherogenesis in mice (Sageet al. 2012). Current experimental evidence suggests that natural antibody derived from B1lymphocytes mutes experimental atherogenesis, while B2 cells aggravate this process. Thus, as inthe case of T lymphocytes, distinct subpopulations of B lymphocytes exert opposite effects onexperimental atherosclerosis. Although human atheromata do contain some B lymphocytes, theapplicability of the burgeoning results on B-cell biology in mouse lesions to the human situationremains uncertain.

Vaccination Against Atherosclerosis: Science Fiction or Future Reality?

The identification of autoantigens led to the proposal that immunization against themmight alleviatedisease. The first immunization studies with oxLDL showed a remarkable, protective effect againstatherosclerosis in hypercholesterolemic rabbits (Ameli et al. 1996; Palinski et al. 1995). This findingwas repeated in several other studies of rabbits and mice, with data implicating both cell-mediatedand humoral effects in the observed atheroprotection.

The LDL particle contains multiple lipid species andmay bear other apoproteins besides ApoB. Inaddition, LDL can transport other hydrophobic or amphipathic molecules, such as endotoxins. Theidentification of the key antigens associated with the particle could spur the development ofvaccination strategies. A screen of LDL-derived peptides for immunogenicity has identified a setof peptides useful for immunization and characterized T- and B-cell responses to these epitopes


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(Fredrikson et al. 2003; Hermansson et al. 2010). Studies are evaluating different adjuvants andadministration routes, such as mucosal immunization, subcutaneous administration with variousadjuvants, and DC-based immunization (Klingenberg et al. 2010; Wigren et al. 2009). The lack ofhuman leukocyte antigen (HLA) restriction for atherosclerotic CVD in humans presentsa conceptual challenge, as T-cell epitopes may vary depending on the HLA alleles in each individual.Therefore, an anti-atherosclerosis vaccine may have to contain a combination of immunogenicpeptides in a suitable adjuvant .

Smooth Muscle Cells, Matrix, and the Fibrous Cap

The vascular smooth muscle cell (VSMC) constitutes the quantitatively largest cellular componentof the advanced atherosclerotic lesion (Jonasson et al. 1986). It is recruited largely from the VSMCpopulation of the underlying tunica media (Bentzon et al. 2007); whether a significant proportion ofplaque VSMC is derived from circulating stem cells remains unclear.

VSMC are pluripotent, versatile cells that maintain several functions usually associated withfibroblasts, including the production of the components of intercellular matrix (Alexander andOwens 2012). In contrast, plaque VSMC are unlikely to impact on vascular tone by contractileactivity. The platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) speciesrecruit VSMC to the intimal site of lesion formation; they also modulate VSMC phenotype in sucha way that migrating and dividing cells enter the lesion and organize themselves into cap-likestructures. Once there, they develop a synthetic phenotype specialized in the production of fibrillar

T cell recognition of nativeLD helps the productionof antibodies:

- anti-LDL

- anti-ApoB100

- anti-MDA-ApoB100

- anti-PC

- anti-oxPC

Cytokinesinducing macrophageactivation

Macrophage

TRAV_XTRBV31

oxLDL LDL

APC

T

T

TB

B plasma cell

Fig. 3 Recognition of LDL fragments as autoantigens activates adaptive immunity. After uptake and processing inantigen-presenting dendritic cells and macrophages, peptide fragments of LDL protein are presented on MHC class IImolecules for recognition by antigen-specific T cells. When activated, such cells help B cells to make antibodies toa broad range of LDL-associated molecules. They also promote macrophage activation and inflammation (FromHermansson et al. 2010)


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collagen. As discussed below, the collagen cap formed by VSMC and their collagen fiber productsserves as a major protective device against plaque rupture and thrombosis.

VSMC phenotype is regulated by several factors, in a pattern that overlaps substantially withthose regulating endothelial cell phenotype (Hellberg et al. 2010; Spin et al. 2012). Proinflammatorystimuli produced in atheromata are powerful inhibitors of VSMC. Thus, interferon-gamma inhibitsVSMC proliferation, differentiation, and collagen gene expression (Amento et al. 1991; Hanssonet al. 1989), whereas the TNF superfamily member, RANKL, inhibits collagen cross-linking(Ovchinnikova et al. 2009). The RANKL antagonist, osteoprotegerin, therefore promotes fibrouscap formation, as does interleukin-17A (see above) (Gistera et al. 2013).

Growth, Death, and Progression of Disease

Early atherosclerotic lesions grow by the accumulation of cholesterol; the infiltration of inflamma-tory cells; the activation, proliferation, and death of such cells; and the gradual development of a corethat contains cellular debris and lipids (Hansson 2005; Libby et al. 2011). As a tissue response to thisprocess, smooth muscle cells form a subendothelial cap structure dominated by collagen fibers thatare produced by these cells. The collagen cap stabilizes the plaque mechanically and creates a barrierbetween the hemostatic components of the blood and the thrombogenic material of the plaque. Untilthe plaque is far advanced, compensatory enlargement (“remodeling”) of the arterial wall prevents itfrom significantly protruding into the arterial lumen. However, after the plaque has enlarged toa sufficient size, the lumen narrows as the plaque grows, and the artery remodels inward, oftenaccompanied by exaggerated or paradoxical vasoconstriction.

Plaque Activation, Thrombosis, and Infarction

Atherosclerosis proceeds as a silent process for months, years, and even decades, and it may neverresult in clinical manifestations. However, if and when the plaque’s surface is damaged, thromboticocclusion of the artery may ensue (Hansson 2005; Libby et al. 2011) (Fig. 4). Surface continuity maybe damaged by fissuring (so-called plaque rupture, observed in 60–80 % of cases of acute coronarysyndrome) or surface erosion (present in 20–40 % of cases with coronary thrombosis, especiallywomen and young victims of sudden coronary death). Fissures and erosions triggeratherothrombosis by exposing thrombogenic material inside the plaque, such as phospholipids,tissue factor, and matrix molecules, to platelets and coagulation factors. Platelet aggregates formingon these exposed surfaces are stabilized by fibrin networks. Tissue factor, expressed in vascularsmooth muscle cells and macrophages of the atherosclerotic plaque, is the primary cellular initiatorof the blood coagulation cascade that leads to fibrin formation (Wilcox et al. 1989). Atherothrombiexpand rapidly and can fill the lumen within minutes, thereby leading to ischemia and infarction.

A range of factors may contribute to atherothrombosis (Loeffen et al. 2012; Malarstig andHamsten 2010). The disturbance of the balance between prothrombotic and fibrinolytic activityon the plaque surface likely plays an important role for the precipitation of the thrombotic event, butthe precise sequence of events that operate in vivo is not yet known.

The cause of plaque rupture also remains unclear. Clinical studies have associated ischemicatherothrombotic events such as myocardial infarction and stroke with infections and stressfulevents. Histopathologic analysis shows increased inflammation with infiltration of macrophages,activated T cells, dendritic cells, and mast cells, as well as reduced thickness of the fibrous cap and


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increased neovascularity at sites of plaque rupture and thrombosis (Falk et al. 2013). Rupturedplaques also tend to have a large necrotic lipid core. In contrast, plaques underlying erosions do nothave a large lipid core and show less inflammation compared with ruptured plaques. Plaque rupturefrequently occurs without clinical manifestations, possibly reflecting variation in the thromboticresponse depending on the thrombogenicity of exposed plaque constituents, local hemorheology,shear-induced platelet activation, systemic clotting activity, fibrinolytic function, and the sensitivityof the end organ to ischemia.

Cell death may be an important trigger of plaque rupture. Apoptotic cells contained in the plaqueare usually removed by efferocytosis (Van Vre et al. 2012). If this process fails, secondary necrosisensues, leading to reduced mechanical integrity and accumulation of prothrombotic material fromdead cells.

Fig. 4 Plaque rupture caused by inflammatory activation triggers atherothrombosis (From Hansson 2005)


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Several members of the matrix metalloproteinase and cysteine proteinase families that areproduced by macrophages are found at sites of plaque rupture and have been implicated in plaquerupture, but their effects on the composition and size of lesions are complex (Back et al. 2010). Inaddition, interferon-g released from activated T cells inhibits collagen fiber formation and smoothmuscle proliferation (Hansson and Hermansson 2011).

Although significant progress has been made lately, the triggers of atherothrombosisremain enigmatic. Improved imaging techniques, biomarkers, and experimental models will beneeded to elucidate the pathogenesis of this condition and develop new therapeutic strategies(Libby et al. 2011).

Acknowledgment

The author gratefully acknowledges grant support from the Swedish Research Council (project grantand Linnaeus support), the Swedish Heart-Lung Foundation, the Foundation for Strategic Research,the Stockholm County Council, and the European Commission.

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