hansson et al the immune response in atherosclerosis
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Atherosclerosis is an inflammatory disease characterizedby intense immunological activity, which increasinglythreatens human health worldwide1. Atherosclerosisinvolves the formation in the arteries of lesions thatare characterized by inflammation, lipid accumula-tion, cell death and fibrosis. Over time, these lesions,which are known as atherosclerotic plaques, mature andgain new characteristics. Although clinical complica-tions of atherosclerosis can arise from plaques causingflow-limiting stenoses, the most severe clinical eventsfollow the rupture of a plaque, which exposes the pro-thrombotic material in the plaque to the blood andcauses sudden thrombotic occlusion of the artery atthe site of disruption. In the heart, atherosclerosis canlead to myocardial infarction and heart failure; whereas inthe arteries that perfuse the brain, it can cause ischaemicstroke and transient ischaemic attacks. If atherosclero-sis affects other arterial branches, it can result in renalimpairment, hypertension, abdominal aortic aneurysms
and critical limb ischaemia. As our knowledge of thisdisease increases, we increasingly recognize that there isno simple answer to the question of whether the immuneresponse promotes or retards atherogenesis. Indeed, thetwo arms of the immune response can either promoteor attenuate aspects of atherosclerosis and its complica-tions. This Review summarizes our current understand-ing of the role of adaptive immunity in atherosclerosisand, in particular, weighs the evidence regarding theyin and yang of the immune response at various placesand times in the evolution of this lengthy and complexdisease. We do not discuss the arteriosclerosis of allo-grafted transplants, which is a distinct disease with a
unique pathogenesis, although it might represent anextreme case of immune-driven arteriopathy.
Immunological features of atherosclerosis
In humans, atherosclerotic plaques contain blood-borneinflammatory and immune cells (mainly macrophagesand T cells), as well as vascular endothelial cells, smoothmuscle cells, extracellular matrix, lipids and acellularlipid-rich debris2. These lesions typically present asasymmetrical focal thickenings of the intima, which isthe innermost layer of the artery(FIG. 1). Accumulationof immune cells and lipid droplets in the intima occursduring the f irst stage of plaque formation. Lipid-ladenmacrophages, known as foam cells, outnumber othercells in early plaques (which are known as fatty streaks),but these nascent plaques also contain T cells. Fattystreaks are prevalent in young individuals, never causesymptoms, and can progress into mature atheroscleroticplaques or disappear with time.
Mature plaques (also known as atheromas) have amore complex structure than fatty streaks (FIG. 1). Inthe centre of a plaque, foam cells and extracellular lipiddroplets form a core region that is surrounded by a capof smooth muscle cells and a collagen-rich matrix2.Other cell types present in plaques include dendritic cells(DCs)3, mast cells4, a few B cells2 and probably naturalkiller T (NKT) cells. The shoulder region of the plaque,which is where it grows, and the interface between thecap and the core have particularly abundant accumu-lations of T cells and macrophages2. Many of theseimmune cells show signs of activation and produce pro-inflammatory cytokines such as interferon-(IFN) and
*Center for Molecular
Medicine, Department
of Medicine, Karolinska
University Hospital,
Karolinska Institute,
Stockholm, SE-17176,
Sweden.Leducq Transatlantic
Network of Excellence in
Cardiovascular Research,
Brigham and Womens
Hospital and Harvard
Medical School, Boston,Massachusetts, USA.Donald W. Reynolds
Cardiovascular Clinical
Research Center, Department
of Medicine, Brigham
and Womens Hospital and
Harvard Medical School,
Boston, Massachusetts
02115, USA.
Correspondence to P.L.
e-mail:
doi:10.1038/nri1882
Published online
16 June 2006
Plaque
An atherosclerotic lesion
consisting of a fibrotic cap
surrounding a lipid-rich core.
The lesion is the site of
inflammation, lipid
accumulation and cell death.Also known as an atheroma.
The immune response inatherosclerosis: a double-edged swordGran K. Hansson* and Peter Libby
Abstract | Immune responses participate in every phase of atherosclerosis. There is
increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis.
Although improved treatment of hyperlipidaemia reduces the risk for cardiac and cerebral
complications of atherosclerosis, these remain among the most prevalent of diseases
and will probably become the most common cause of death globally within 15 years.This Review focuses on the role of immune mechanisms in the formation and activation of
atherosclerotic plaques, and also includes a discussion of the use of inflammatory markers
for predicting cardiovascular events. We also outline possible future targets for prevention,
diagnosis and treatment of atherosclerosis.
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Cellular debrisand cholesterol
Shoulder
Media
Blood-vessel lumen
Endothelial cell
Normal artery
Elastic laminaIntima
Media
Foam cell T cellMacrophage Mast cell MonocyteCholesterol Dendritic cellDead cellSmoothmuscle cell
Myocardial infarction
An episode of acute cardiac
ischaemia that leads to death
of heart muscle cells. It is
usually caused by a thrombotic
atherosclerotic plaque.
Ischaemic stroke
An episode of acute regional
ischaemia in the brain leading
to nerve-cell death. It is usually
caused by thrombi or emboli
from atherosclerotic plaques.
Aneurysm
The local dilatation of an artery
caused by weakening of the
artery wall. Some, but not all,
aneurysms are caused by
atherosclerosis.
Intima
The innermost layer of anartery, which consists of loose
connective tissue and is
covered by a monolayer of
endothelium. Atherosclerotic
plaques form in the intima.
Fibrous cap
A structure composed of a
dense collagen-rich
extracellular matrix with
occasional smooth muscle
cells, macrophages and T cells
that typically overlies the
characteristic central lipid core
of plaques.
tumour-necrosis factor (TNF)5. With time, the plaquecan progress into an even more complex lesion, thelipid core of which has become a paucicellular pool ofcholesterol deposits surrounded by a fibrous cap of vary-ing thickness. The fibrous cap prevents contact betweenthe blood and the pro-thrombotic material in the lesion(FIG. 1). Disruption of the cap can lead to thrombosis andmany of the adverse clinical outcomes associated withatherosclerosis.
Models of atherogenesis in mutant mice
Direct analysis of the early phases of human atherosclerosispresents obvious obstacles. Therefore, systematic inves-tigation of the mechanisms that initiate atherosclerosisrelies on animal models of the disease. The availableobservations indicate that there is substantial overlapbetween disease development in these animal models andthe human disease. Two strains of genetically altered micehave been particularly fruitful in this regard. Apoe/
mice lack apolipoprotein E (APOE; which is a keycomponent in cholesterol metabolism), and developspontaneous hypercholesterolaemia and atheroscleroticdisease (which is exacerbated by an atherogenic diet)that progresses to myocardial infarction and stroke 6,7.Low-density-lipoprotein receptor (LDLR)-deficient micerespond to being fed with fat by developing hypercholes-terolaemia and atherosclerotic plaques8. The crossbreed-ing of these mice with mice that carry deletions in genesencoding crucial components of the immune systemhas provided important information on the role of theimmune system in the pathogenesis of atherosclerosis. Inaddition, bone-marrow transplantation of, and spleen-cell
transfer to,Apoe/ or Ldlr/ mice has offered insights intothe role of specific populations of bone-marrow-derivedcells in disease development.
Immune-cell recruitment initiates atherosclerotic-plaque formation. In experimental animals, endothelialcells in the arteries express leukocyte adhesion mol-ecules, in particular vascular cell-adhesion molecule 1(VCAM1), as part of the initial vascular response tocholesterol accumulation in the intima9(FIG. 2a). Thepatchy distribution of adhesion-molecule expressioncorresponds to the subsequent position at which fattystreaks form10. This patchy pattern of expression prob-ably reflects haemodynamic factors, because the shearstresses and disturbed fluid flows vary over the arterialbed in a similar way to the predilection sites for athero-sclerosis. Interestingly, exposing cultured endothelialcells to oscillatory shear stress that mimics arterialblood flow increases the expression of several leukocyte
adhesion molecules11.Shortly after VCAM1 induction, monocytes and
T cells enter the arterial intima (FIG. 2a). Under the influ-ence of macrophage colony-stimulating factor (M-CSF)produced by endothelial cells and smooth muscle cells12,the monocytes differentiate into macrophages13(FIG. 2b)and T cells can undergo antigen-dependent activation(FIG. 2c;see later). Interestingly, VCAM1 expression bythe endothelium ceases after a few weeks, but smoothmuscle cells begin to express this adhesion molecule14.Expression of VCAM1 and other adhesion molecules bysmooth muscle cells might promote the recruitment andretention of mononuclear cells in the arterial intima.
Figure 1 | Cellular composition of atherosclerotic plaques. The atherosclerotic plaque has a core containing lipids
(which include esterified cholesterol and cholesterol crystals) and debris from dead cells. Surrounding it, a fibrous cap
containing smooth muscle cells and collagen fibres stabilizes the plaque. Immune cells including macrophages, T cells
and mast cells populate the plaque, and are frequently in an activated state. They produce cytokines, proteases, pro-
thrombotic molecules and vasoactive substances, all of which can affect plaque inflammation and vascular function.
Until complications occur, an intact endothelium covers the plaque.
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Endothelialcell
MHC class II
TCR
APC
Scavengerreceptor
VLA4VCAM1
Blood-vessellumen
LDL
oxLDL
Monocyte
MacrophageMonocyte
Foam cell
Chemokinereceptor Chemokine
M-CSF
T cell
TLR T cell Endothelial cell
LPS, HSP60or oxLDL
Pro-inflammatory cytokinesProteasesProcoagulantsPro-apoptotic factors
Increased adhesion moleculesIncreased permeabilityIncreased propensity forthrombus formation
Decreased collagen productionDecreased proliferation
CD4+ T cell
TH1 cell
IL-12IL-15IL-18
b
c
oxLDL
TH1 cell
Smoothmuscle cell
MHC class IITCR
IFNTNF
CD40L CD40
Macrophage
ProteasesPro-inflammatorymediators
Decreasedinflammation
TH1 cell
TH2 cell orregulatoryT cell
Smoothmuscle cell
TGF
TGF
IL-10
e
Macrophage
a d
T cell Endothelial cellT cell Endothelial cell
T cell Endothelial cell
Figure 2 | Recruitment and activation of immune cells in atherosclerotic plaques. a |Low-density lipoprotein (LDL)
diffuses from the blood into the innermost layer of the artery, where LDL particles can associate with proteoglycans of the
extracellular matrix. The LDL of this extracellular pool is modified by enzymes and oxygen radicals to form molecules such
as oxidized LDL (oxLDL). Biologically active lipids are released and induce endothelial cells to express leukocyte adhesion
molecules, such as vascular cell-adhesion molecule 1 (VCAM1). Monocytes and T cells bind to VCAM1-expressing
endothelial cells through very late antigen 4 (VLA4) and respond to locally produced chemokines by migrating into the
arterial tissue. b | Monocytes differentiate into macrophages in response to local macrophage colony-stimulating factor
(M-CSF) and other stimuli. Expression of many pattern-recognition receptors increases, including scavenger receptors
and Toll-like receptors (TLRs). Scavenger receptors mediate macrophage uptake of oxLDL particles, which leads tointracellular cholesterol accumulation and the formation of foam cells. TLRs bind lipopolysaccharide (LPS), heat-shock
protein 60 (HSP60), oxLDL and other ligands, which instigates the production of many pro-inflammatory molecules by
macrophages.c | T cells undergo activation after interacting with antigen-presenting cells (APCs), such as macrophages
or dendritic cells, both of which process and present local antigens including oxLDL, HSP60 and possibly components
of local microorganisms. A T helper 1 (TH1)-cell-dominated response ensues, possibly owing to the local production of
interleukin-12 (IL-12), IL-18 and other cytokines. Antigen presentation and TH1-cell differentiation might also occur in
regional lymph nodes. d | TH1 cells produce inflammatory cytokines including interferon-(IFN) and tumour-necrosis
factor (TNF) and express CD40 ligand (CD40L). These messengers prompt macrophage activation, production of
proteases and other pro-inflammatory mediators, activate endothelial cells, increase adhesion-molecule expression
and the propensity for thrombus formation, and inhibit smooth-muscle-cell proliferation and collagen production.
e | Plaque inflammation might be attenuated in response to the anti-inflammatory cytokines IL-10 and transforming
growth factor- (TGF), which are produced by several cell types including regulatory T cells, macrophages, and for TGF,also vascular cells and platelets. TCR, T-cell receptor.
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Scavenger receptors
Cell-membrane proteins that
take up oxidatively or
otherwise modified low-density
lipoproteins.
Experiments using genetically altered mice showthat leukocyte adhesion molecules participate in theinitiation of atherosclerosis.Apoe/ mice that are alsodeficient for both endothelial-cell selectin (E-selectin)and platelet selectin (P-selectin) have reduced severityof atherosclerosis15. Similarly, Ldlr/ mice that expressa truncated form of VCAM1 with impaired func-tion develop less severe disease than those expressingwild-type VCAM1 (REF. 16). Such studies use truncatedVCAM1 because complete VCAM1 deficiency is lethalat the embryonic stage.
In addition to the expression of adhesion molecules,several chemokines produced by vascular cells guidethe recruitment of immune cells (FIG. 2a). Data obtainedusing knockout mice show a key role for CC-chemokineligand 2 (CCL2; also known as MCP1) and its receptor,CC-chemokine receptor 2 (CCR2), in the initiation ofatherosclerosis17,18. Indeed, absence of CCL2 or CCR2limits the entry of monocytes and T cells into the arte-rial intima and inhibits atherogenesis. Macrophagesand vascular cells of the forming plaque also produce
the T-cell attractants CCL5 (also known as RANTES),CXC-chemokine ligand 10 (CXCL10; also known asIP10) and CXCL11 (also known as ITAC)19, the mast-cell attractant CCL11(also known as eotaxin)20 and alsothe Janus molecule CXCL16, which can function as botha scavenger receptor and a chemokine21. Administrationof a blocking form of CCL5 attenuates atherogenesisin mice22.
Atherosclerotic plaques in humans and mice alsoexpress another chemokine, the cell-surface anchoredCX
3-chemokine ligand 1 (CX
3CL1; also known as
fractalkine), which is a transmembrane protein pref-erentially expressed by smooth muscle cells. CX
3CL1
that is shed by proteolysis can engage CX3
-chemokinereceptor 1 (CX
3CR1), which is expressed by monocytes
and macrophages. Ligation of CX3CR1 on blood-borne
monocytesstimulates their migration to the artery walland contributes to atherogenesis, as indicated by stud-ies using mice deficient for both APOE and CX
3CR1
(REFS 23,24).
Innate immunity and lipid accumulation
Monocyte-derived macrophages abound in plaques andare outnumbered only by vascular smooth muscle cellsin some plaques. Several phenotypes of macrophage arefound in plaques, including inflammatory macrophagesand also foam cells, which develop when cholesteryl
esters accumulate in the cytosol of intimal macrophages(FIG. 2b). Cholesterol derives from lipoproteins that haveundergone oxidation or enzymatic modification in thetissue. This renders the lipoprotein particle amenableto uptake by macrophages that express scavenger recep-tors25, a family of proteins that includes CD36, CD68,CXCL16, lectin-type oxidized low-density lipoproteinreceptor 1 (LOX1), scavenger receptor A (SR-A) andSR-B1 . Scavenger receptors are pattern-recognitionreceptors (PRRs) that mediate internalization andlysosomal degradation of modified lipoprotein parti-cles, lipopolysaccharide, fragments of malaria parasitesand apoptotic bodies26. Uptake by scavenger receptors
does not lead directly to inflammation but can lead toMHC-class-II-restricted antigen presentation of inter-nalized material, thereby linking innate and adaptiveimmunity27.
Considering their role in the formation of foamcells, one would expect scavenger receptors to have animportant, if not crucial, role in atherogenesis. However,recent results showing increased, rather than decreased,atherosclerosis in mice lacking CD36, CXCL16 or SR-Ahave cast doubt on this conclusion28. This might bebecause receptor-mediated internalization of modifiedlipoproteins by macrophages can facilitate the eventualelimination of these particles from plaques throughhigh-density-lipoprotein-dependent mechanisms29.If, as a result of the absence of foam cells, this clear-ance of modified lipoprotein did not occur, removal ofsuch lipids from plaques would be less efficient and theaccumulation of extracellular cholesterol in the lipidpool might be more detrimental than the presence offoam cells.
Whereas scavenger receptors mediate internaliza-
tion, degradation and antigen presentation of ligands,Toll-like receptors (TLRs) can elicit inflammatoryresponses directly30. The many TLR-family membersthat can be detected in plaques are expressed mainly bymacrophages and endothelial cells31. By contrast, in thenormal artery wall, only TLR2 and TLR4 are expressedby endothelial cells and the underlying smooth musclecells do not express TLRs. Therefore, plaque forma-tion causes a considerable increase in the repertoireof PRRs expressed by the artery wall. A broad range ofpathogen-associated molecular patterns can ligate thedifferent TLRs30. Among them, microbial components,heat-shock proteins (HSPs) and unmethylated CpGDNA might be directly relevant to atherogenesis becauseseveral microorganisms are associated with atheroscle-rosis. In addition, some data indicate that endogenousHSP60 and oxidized LDL (oxLDL) bind TLR4CD14complexes and elicit inflammatory responses3234.
Following ligation, TLRs activate nuclear factor-B(NF-B) and mitogen-activated protein kinaseactivator protein 1 signalling pathways30,32. Directimmunohistochemical analysis has shown that a largeproportion of the TLR4-expressing cells in humanplaques have nuclear translocation of NF-B, which isconsistent with a role for TLR4 ligation in inflammatoryactivation in the plaques31. The response downstreamof TLR ligation in the plaque probably involves the
secretion of pro-inflammatory cytokines and matrixmetalloproteinases (MMPs), as well as the productionof low-molecular-weight inflammatory mediators suchas nitric oxide and endothelin-1 (REF. 30). Genetic defi-ciency of TLR4 or its signal-transducing adaptor mol-ecule myeloid differentiation primary-response gene 88(MyD88) reduces plaques in mice35,36.
T cells promote atherogenesis
Human atherosclerotic plaques contain numerousT cells. In a plaque, ~40% of the cells express macro-phage markers, ~10% are CD3+ T cells and most of theremainder have the characteristics of smooth muscle
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Vasa vasorum
Small nutrient vessels in the
normal adventitia and outer
media of the artery wall,
which can also give rise to
microvessels in the plaque.
cells2. Small populations of mast cells, B cells and DCsoccur in plaques and, together with T cells, monocytesand macrophages, might traffic between the blood inthe arterial lumina, the lesioned artery wall, the vasavasorum microvessels that penetrate the artery andthe regional lymph nodes.
The ratio of CD4+ to CD8+ T cells in advancedplaques resembles that found in peripheral blood2. MostT cells are T cells, but there is also a small propor-tion of T cells. Lesions of early stages of experimentalatherosclerosis contain oligoclonal expansions of CD4+cells expressing an T-cell receptor (TCR)37, indi-cating activation in response to a limited set of localantigens (FIG. 2c). The CD4+ T cells that are isolatedfrom human plaques are mostly CD45RO-expressingmemory and/or effector T cells38. An initial round ofT-cell activation in response to athero-antigens mightoccur in the regional lymph nodes, possibly after anti-gen presentation by DCs trafficking from the plaqueto the lymph node39. After entering the blood, previ-ously activated memory and/or effector T cells bind
cell-surface adhesion molecules that are expressed byendothelial cells at the plaque surface and/or in the vasa
vasorum, and then enter the plaque. Macrophages inthe plaque expressing MHC class II molecules mightthen present antigen to these T cells, leading to furtherrounds of activation.
Very recently,Ath1, which is an atherosclerosis sus-ceptibility locus on mouse chromosome 1, was mappedto the gene encoding OX40 ligand (OX40L; also knownas TNFSF4), which is a co-stimulatory factor for T-cellactivation40. Reduced expression of this protein was asso-ciated with reduced atherosclerosis in inbred strains thatdiffer in their Tnfsf4 alleles and also in mice carrying atargeted deletion of this gene40. Polymorphisms in humanTNFSF4 were found to be associated with coronaryatherosclerosis and with an increased risk for myocar-dial infarction in a human genetic epidemiology study40.These data re-emphasize the importance ofimmuneactivation in atherosclerosis and its complications41.
Plaque antigens activate local cellular adaptive immu-
nity. Cloning T cells from surgically removed humanplaques has identified several cell-mediated, local adap-tive immune reactions. CD4+ T-cell clones derived fromplaques recognize oxLDL, with other clones recognizingHSP60 or other antigens derived from certain pathogenicmicroorganisms, such as Chlamydia pneumoniae 42,43
(FIG. 2c). In all of these cases, antigen recognition wasrestricted by HLA-DR and involved TCR+ CD4+T cells42,44,45.
Antigen-presenting cells selectively internalizeoxLDL particles through the scavenger-receptor path-way. After proteolytic processing, fragments of theprotein component of LDL, APOB, bind nascent MHCclass II molecules and traffic to the cell surface. Indeed,APOB fragments are among the peptides displayed mostfrequently by HLA-DR molecules in cultured humanlymphoblastoid cells46. Therefore, receptor-mediatedendocytosis and the antigen-presentation pathway facili-tate MHC class II presentation of LDL-derived peptides
to CD4+ T cells. As expected, no T cells react with nativeLDL components. However, oxidative modificationof LDL breaks tolerance and oxLDL-reactive T cells local-ize in plaques, lymph nodes, and in the blood of patientswith atherosclerosis and experimental animals42,47.OxLDL-reactive CD4+ T cells probably recognizeAPOB-derived oligopeptides carrying adducts formedduring oxidation48; whereas oxLDL-specific antibodiesreact with oxidized phospholipids such as phosphoryl-choline49,50, as well as aldehyde-peptide epitopes includingmalondialdehyde-lysine42,44,45.
Most oxLDL-reactive CD4+ T cells have a T helper 1(T
H1)-cell phenotype42,47. Because T
H1 cytokines (such as
IFN) generally stimulate pro-atherosclerotic processes(see later), these T cells probably promote atherogenesis,a conclusion supported by adoptive-transfer studies insevere combined immunodeficient (SCID) mice lack-ing APOE51. As expected, these mice show substantiallyreduced atherosclerotic plaques compared with immuno-competentApoe/ mice. Transfer of CD4+ T cells fromimmunocompetentApoe/ mice to SCID mice lacking
ApoE increases the atherogenesis found in immuno-deficient mice, to almost the same level as that foundin fully immunocompetentApoe/ mice. Therefore, thenet effect of CD4+ T cells is to increase atherogenesis inmice susceptible to atherosclerotic disease. Obviously,this finding does not preclude the existence of T-cellsubsets that might mitigate disease.
Recent studies have identified transcripts encodingV14J281-containing TCR -chains in plaques ofhypercholesterolaemic mice, indicating the presenceof NKT cells52. The abundance of CD1 molecules inplaques53 indicates that CD1-mediated NKT-cell acti-
vation takes place, but the absence of specific markersfor NKT cells has hampered direct immunohistologicaldemonstration of NKT cells in plaques. However, admin-istration of ligands that specifically activate NKT cells toApoe/ mice shows that NKT-cell activation increasesearly atherosclerotic plaque development concomitantlywith increased local expression of pro-inflammatorycytokines, whereas abrogation of CD1-mediated antigenpresentation reduces disease52,54. Therefore, NKT cellscontribute to atherosclerosis, probably by antigen-specific activation in response to lipid antigens presentin plaques.
A role for TH
1/TH
2-cytokine balance?Analyses ofcell-surface-marker expression and cytokine secretion
indicate activation of a remarkably large proportionof T cells in plaques38. T
H1-type cytokines dominate
in mouse models of atherosclerosis and in humanplaques. For example, human plaques contain cellsproducing IFN, interleukin-12 (IL-12), IL-15, IL-18and TNF, but few cells producing the T
H2-type cytokine
IL-4 (REFS 42,55,56). Together with the histopatho-logical features of accumulation of macrophages andT cells, the predominance of T
H1-type cytokines indi-
cates that atherosclerosis is a TH
1-cell-driven disease(FIG. 2d). This hypothesis is supported by studies ingenetically altered mice that show that there is reducedatherosclerosis in hypercholesterolaemic mice lacking
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Tissue factor
A procoagulant that stimulates
thrombus formation, when in
contact with blood, by
accelerating the action of
factors VIIa and Xa.
IFNor its receptor57,58, IL-12 (REF. 59), IL-18 (REF. 60),TNF61 or the T
H1-cell-inducing transcription factor
T-bet62. Administration of recombinant IFN63 orthe T
H1-cell-inhibiting drug pentoxifyllin64 to hyper-
cholesterolaemic mice led to increased and decreasedatherosclerosis, respectively, lending further supportto this hypothesis64.
If TH
1 cytokines stimulate plaque formation andT
H2 cytokines inhibit T
H1-cell responses, can T
H2-cell
responses protect against atherosclerosis? In supportof this proposition, C57BL/6 mice (which are proneto T
H1-type immune responses) develop fatty streaks
if fed a high-cholesterol diet, whereas BALB/c mice(which are prone to T
H2-type immune responses)
are resistant to atherogenesis65,66. Targeted deletionof the gene encoding signal transducer and activa-tor of transcription 6 (STAT6), a transcription factorthat is essential for the differentiation of T
H2 cells,
renders BALB/c mice susceptible to atherogenesis andthis occurs in parallel with a switch from T
H2-cell to
TH1-cell responses66.
Although these studies of the development offatty streaks indicate opposing roles for T
H1 and T
H2
cells in disease development, mice that develop moreadvanced plaques show a more complicated picture.Pharmacological inhibition of T
H1 cells using pentoxi-
fyllin or IL-18-binding protein inhibits atherosclerosisinApoe/ mice64,67, and administration of recombinantT
H1 cytokines (recombinant IL-18 and IFN) exacer-
bates disease63,68. However, data for IL-4, which isthe prototypic T
H2 cytokine, are inconclusive. Some
studies have shown that IL-4 has a protective effect,whereas others found reduced disease in the absenceof IL-4 (REFS 59,69). These divergent findings, underdifferent experimental conditions, might reflect thecomplex range of biological activities found for IL-4,including stimulation of scavenger-receptor expres-sion and the induction of elastin degrading MMP12,which can lead to aneurysm formation70. Defining therole of T
H2 cells in atherosclerosis, therefore, requires
further study.
Pro-atherosclerotic action of TH1 cells.How can T
H1
cells promote disease development? IL-12 and IL-18,which are produced by macrophages and smooth mus-cle cells in plaques, can indirectly affect the develop-ment of plaques by promoting T
H1-cell differentiation.
By contrast, IFNand TNF directly accelerate disease
through their actions on macrophages and vascularcells (FIG. 2c,d). IFNactivates macrophages, therebyincreasing their production of nitric oxide, pro-inflam-matory cytokines, and pro-thrombotic and vasoactivemediators. Additionally,IFNinhibits endothelial-cellproliferation71, the proliferation and differentiationof vascular smooth muscle cells72, and also decreasescollagen production by these smooth muscle cells73.Decreasing the cell and collagen content of the fibrouscap might reduce the stability of the plaque. Therefore,the combined effects of IFNon cells of the formingplaque promote inflammation and extracellular-matrixdestabilization.
The pro-inflammatory cytokine TNF triggers vascu-lar inflammation through the NF-B pathway, inducingthe production of reactive oxygen and nitrogen species,proteolytic enzymes and pro-thrombotic tissue factor byendothelial cells, and modulates the fibrinolytic capacityof the cells7476. TNF also has profound metabolic effectsthat include the suppression of lipoprotein lipase, whichleads to the accumulation of triglyceride-rich lipopro-teins in the blood. Such lipoproteins, and the TNF levels,have been associated with heart disease in clinical stud-ies7779. Genetic loss-of-function studies also support theidea that TNF has a pro-atherogenic role61.
CD40 and CD40L: a co-stimulatory dyad with pro-atherogenic action.The cell-surface proteins CD40 andCD40 ligand (CD40L; also known as CD154) have sev-eral similarities to soluble pro-inflammatory cytokines.CD40 ligation on cells found in plaques triggers aninflammatory response similar to that elicited by TNF,that is, secretion of other cytokines and MMPs, andexpression of adhesion molecules80. Importantly, CD40
ligation causes expression of the procoagulant tissuefactor by human macrophages, something that solublepro-inflammatory cytokines do not do. Macrophages andT cells express CD40 and CD40L, as do vascular endothe-lial cells, smooth muscle cells and platelets81,82. Therefore,CD40 ligation propagates inflammatory activation in allthe main cell types involved in atherogenesis. Inhibitionof CD40 ligation andinactivation of the gene encodingCD40L reduces atherosclerotic plaques in hypercholes-terolaemic mice83,84. Unfortunately, CD40 blockade inhumans can promote platelet aggregation and thrombosis,which is an obstacle to its clinical application.
Anti-atherogenic immunity
Anti-inflammatory cytokines.Although local cellularimmunity predominantly promotes atherosclerosisthrough the action of cell-surface molecules (such asCD40CD40L) and cytokines (such as IFNand TNF),counterbalancing factors can function to dampen dis-ease activity(FIG. 2e). Two anti-inflammatory cytokines,IL-10 and transforming growth factor- (TGF), provideparticularly important atheroprotective signals.
Two groups have reported previously that IL-10-deficient C57BL/6 mice that consume a fatty diet developan increased quantity of fatty streaks compared withwild-type mice85,86. By contrast, Il10 transgenic C57BL/6mice do not develop fatty streaks, thereby providing evi-
dence of a protective role for IL-10 in atherosclerosis85,86.The mouse model used in these early studies mimickedthe initial stage of atherogenesis, but the mice didnot develop lesions similar to human clinical disease.However, subsequent experiments usingApoe/ mice,which develop atherosclerotic lesions that are more simi-lar to those found in humans, also show an atheroprotec-tive role for IL-10 (REF. 87). Interestingly, IL-10 promotesarteriopathy in transplanted hearts, indicating a morecomplex picture.
The pluripotent cytokine TGF has many effects on adiverse range of cell types and can inhibit atherosclerosisat least as well as IL-10. For example, TGF promotes
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collagen production, which could increase plaquestability. Treatment with tamoxifen, which is a TGF-stimulating oestrogen-receptor agonist, reduces theformation of fatty streaks in C57BL/6 mice fed withfat88, whereas administration of TGF-specific block-ing antibodies or decoy receptors for TGF reducesatherosclerotic plaque formation in Ldlr/ mice89,90.However, these studies did not identify the mechanismof action of TGF.
Two more-recent studies show that TGF exerts itsatheroprotective effects by modulating T-cell activation.In the first study, crossbreeding mice carrying dominant-negative TGF receptors (that were expressed underthe control of the Cd4 promoter) with Apoe/ miceled to a fivefold increase in plaque size and advancedplaques were found in the proximal aorta of 12-week-old crossbred mice91. Notably, the plaques showed signsof increased inflammation and had fewer interstitialcollagen fibres, a characteristic of human plaques thatcause thrombosis (see later). In the second study, bonemarrow from mice that expressed a dominant-negative
form of the type II TGF receptor (that was expressedunder the control of the Cd2 promoter) was transplantedto irradiated Ldlr/ mice92. Again, plaques showed signsof substantial inflammation and a poorly developedcollagenous matrix. These studies show the importantatheroprotective effects of TGF that occur through thedampening of T-cell activity.
Several cell types can produce TGF and IL-10,including platelets, macrophages, endothelial cells,smooth muscle cells and regulatory T cells. Activationof regulatory T cells could therefore offer a means ofantigen-specific atheroprotection (FIG. 2e). A recent studysupports this idea by showing that the transfer of naturalCD4+CD25+ regulatory T (T
Reg
) cells reduces athero-sclerosis, whereas depletion of CD25+ cells increases dis-ease inApoe/ mice93. Depletion of CD25+ cells in micelacking functional TGF receptors on T cells did not alterplaque size, indicating that this cytokine mediates theatheroprotective effect of regulatory T cells93.
Humoral immunity. In addition to innate immunityand T cells, antibodies with different specificities canparticipate in atherosclerosis. Humans and experimen-tal animals with disease have antibodies specific foroxLDL particles44. B-cell epitopes in oxLDL includeamino-acid residues of APOB that are modified bylipid peroxidation products, such as malondialdehyde
and 4-hydroxynonenal. Although some clinical and epi-demiological studies have found positive correlationsbetween the presence of antibodies specific for oxLDLand the progression of atherosclerosis94,95, other studieshave not detected any correlation. Interestingly, anti-bodies specific for oxLDL, mainly of the IgM isotype,also circulate in asymptomatic humans96 and crossreactwith apoptotic bodies49. These antibodies bind theoxidized phospholipids in oxLDL and also recognizephosphorylcholine in the cell wall ofStreptococcuspneumoniae49. Phosphorylcholine-specific IgM con-sists of germline-encoded antibodies of the T15 typethat are produced by B1 cells49. Therefore, expansion
of B-cell clones that produce T15-type antibodies, forexample during a pneumococcal infection, might affectthe development of plaques. Indeed, immunization ofLdlr/ mice with a pneumococcal vaccine reduced theextent of atherosclerosis50.
Molecular mimicry could explain the crossreactiv-ity between the humoral immune responses to oxLDL,apoptotic bodies and pneumococci. This mechanismmight also apply to HSP60, another antigen associatedwith atherosclerosis97. HSP60 is a chaperone moleculethat is involved in protein folding and can be detectedin plaques. Antibodies specific for HSP60 are found inexperimental animals that have atherosclerosis and havebeen correlated with disease progression in a humancohort study98. Present in prokaryotes and eukaryotes,HSP60 has shown remarkable sequence conservation dur-ing evolution. As antibodies specific for HSP60 crossreactbetween microbial and eukaryotic HSP60, antibodiesthat react to human HSP60 can be generated in responseto infection with microbes that express HSP60, such asC. pneumoniae99.
Several further experimental, and some human, stud-ies show that humoral immunity can protect againstatherosclerosis. Splenectomy increases atherosclerosis inbothApoe/ mice and humans100. InApoe/ mice, trans-fer of splenic B cells from atherosclerotic animals intosplenectomized recipients protects against disease, pos-sibly because of the production of protective antibodiesby B cells100.
Immunization experiments identify oxLDL andHSP60 as important antigens that can induce protective,as well as detrimental, immune responses (TABLE 1; seealso later). A tentative conclusion from these studies is thatT
H1-type immune responses promote disease; whereas
humoral immunity has protective effects, possibly byeliminating antigens before they reach plaques.
Adaptive immunity disrupts plaques
In general, the gravest clinical complications of athero-sclerosis result from the sudden thrombotic occlusion ofan artery101. The sudden onset of myocardial infarction,as well as many strokes and episodes of acute limb ischae-mia, is caused by thrombi that arise from atheroscleroticplaques that do not necessarily tightly narrow the artery.Therefore, many episodes of damage to the heart muscle,brain or lower extremities can occur without warning, alltoo often with devastating consequences.
Physical disruption of a plaque is the most frequent
cause of thrombotic occlusions. Indeed, the most fre-quent patho-anatomical substrate for sudden coronarythrombosis is rupture of the fibrous cap that overlies thelipid core of the plaque101(FIG. 3). Fibres of interstitial col-lagens (types I and III) normally confer biomechanicalstability on the fibrous cap of the plaque. As discussedearlier, the T
H1-cytokine IFNstrongly inhibits the
production of interstitial collagens by vascular smoothmuscle cells, which are the main source in the arterialwall of this extracellular-matrix macromolecule73. IFNcan also inhibit the proliferation of smooth musclecells, thereby reducing the stabilizing and collagen-synthesizing cellular component of the plaque72. Also,
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Angina pectoris
A reversible attack of chest
discomfort, usually caused by
an imbalance between the
oxygen demand of the working
heart muscle and the
insufficient supply through
narrow, atheroscleroticcoronary arteries.
Angioplasty
A percutaneous catheter
procedure that inflates a
balloon in areas of narrowing
(stenosis) in arteries.
Statins
A class of drugs that inhibit the
rate-limiting enzyme (3-
hydroxy-3-methylglutaryl
coenzyme A reductase) in the
pathway of cholesterol
biosynthesis.
proteases elaborated mainly from activated macrophagesin plaques can degrade collagen102,103. In addition, liga-tion of CD40 expressed by macrophages increases theproduction of matrix-degrading proteases that include
the interstitial collagenases of the MMP family, MMP1,MMP8 and MMP13 (REF. 104). Therefore, T
H1 cells
probably have an essential role in regulating the func-tions of smooth muscle cells (collagen-fibre formation)and macrophages (collagen degradation) that cruciallyregulate the integrity of the fibrous cap of the plaqueand therefore its susceptibility to rupture and provokethrombosis.
Once coagulation factors in the blood gain accessto the lipid core of the plaque following rupture of thefibrous cap, thrombosis commonly ensues. Tissue factor,the potent procoagulant expressed by a subpopulationof macrophages in the lipid core of the plaque, triggersthese thromboses101. As noted earlier, ligation of CD40expressed by macrophages strongly induces expressionof tissue factor80. Indeed, T cells expressing CD40L local-ize in the vicinity of macrophages that are expressing tis-sue factor in the lipid core of human plaques105. Becauseplatelets can also express CD40L82 when activated, positivefeedback can amplify the local inflammatory response,once a thrombus begins to form, because of generation ofthe protease thrombin induced by tissue factor and plate-let activation induced by thrombin. Therefore, althoughT cells could orchestrate the pathophysiology of plaquedisruption, dysregulated antigen-nonspecific pathwaysprobablyamplify and sustain the formation of thrombi.Modulation of immunity in atherosclerosisImmunopharmacological intervention against sympto-matic atherosclerosis.Although thrombi cause most ofthe acute complications of atherosclerosis, the gradualformation of stenoses that impede blood flow causesmany of the chronic symptoms of atherosclerotic disease,such as angina pectoris (chest discomfort precipitatedtypically by physical or emotional stress). Recent decadeshave witnessed important advances in the ability of inter-
ventions, particularly percutaneous procedures, to relievestenoses and reduce ischaemia. Until recently, however,the long-term success of mechanical procedures, suchas the deployment of arterial stents (metal scaffolds to
hold arteries open) and balloon angioplasty (inflationof miniature balloons in blocked segments of arter-ies to expand the arterial lumen), has been limitedby re-growth of intimal tissue which is known as
in-stent stenosis and restenosis, respectively. Thisfibro-proliferative response of the injured artery canre-occlude the lumen within months in a substantialminority of patients.
Recently, the coating of stents with immunosup-pressive agents, for example sirolimus (Rapamycin),has shown striking effectiveness at reducing in-stentstenosis106. This advance has markedly improved clinicaloutcomes in patients undergoing percutaneous interven-tion. Early preclinical studies provided the experimentalbasis for this important therapeutic advance by show-ing that another immunosuppressant, cyclosporin,reduces intimal-cell proliferation in response to arterialinjury107.
The use ofstatins has shown striking clinical benefitin preventing atherosclerotic complications during thepast decade. Numerous clinical trials have establishedthat 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (drugs of the statin family)can reduce various atherosclerotic complications108.The lowering of LDL cholesterol concentrations in theblood doubtless accounts for much of this remarkableclinical benefit.However,recent data indicate that partof the clinical benefit of statins occurs because of ananti-inflammatory effect that is apparently not relatedto LDL reduction109. (See REF. 110 for a detailed discus-sion of non-LDL-lowering effects of statins).
By blocking HMG-CoA reductase, statins preventthe formation of lipids that control the function ofseveral intracellular proteins111. By acting on the MHCclass II transactivator (CIITA), statins can interfere withthe transcriptional induction of MHC class II mol-ecules, which would decrease immune activation in theplaque112. Statins can also limit the accelerated arterio-sclerosis (sclerosis of the arterial walls)that complicatessolid-organ transplantation, a disease that often occursin the absence of increased concentrations of LDL113.They also seem to reduce disease activity in patients withrheumatoid arthritis114 and in mice with experimentalautoimmune encephalomyelitis115. All these results lend
Table 1 | Immunization against atherosclerosis in experimental models
Antigen Route Animal model Effect on atherosclerosis References
MDA-LDL Subcutaneous WHHL rabbits Reduced 124
oxLDL Subcutaneous Fat-fed NZW rabbits Reduced 125
MDA-LDL Subcutaneous Apoe/ mice Reduced 47,126
MDA-LDL Subcutaneous Ldlr/ mice Reduced 127
APOB-peptides Subcutaneous Apoe/ mice Reduced 95,128
MDA-LDL Subcutaneous Cd4/Apoe/ mice Reduced 129
HSP65 Subcutaneous Ldlr/ mice Increased 130
HSP65 Peroral/nasal Ldlr/ mice Reduced 131,132
2-GPI Subcutaneous Ldlr/ mice Increased 133
APO, apolipoprotein; GPI, glycoprotein I; HSP65, heat-shock protein 65; LDL, low-density lipoprotein; LDLR, LDL receptor; MDA-LDL,malondialdehyde-modified LDL; NZW, New Zealand white; oxLDL, oxidized LDL; WHHL, Watanabe hereditably hyperlipidaemic.
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Blood-vessel lumen
Endothelial cell
Elasticlamina
Cellular debrisand cholesterol
Rupture
Thrombus
Platelet
Erythrocyte
Fibrin
Foam cell T cellMacrophage Mast cell MonocyteCholesterol Dendritic cellDead cellSmoothmuscle cell
Peroxisome-proliferator-
activated receptors
Nuclear receptors that
participate in the regulation
of cellular metabolism and
differentiation.
Thiazolidinedione
A class of medication, used
to treat diabetes, that binds
peroxisome-proliferator-
activated receptor-.
support to the idea that the immunomodulatory actionsof statins also contribute to their effects in patients withatherosclerosis.
Recent studies have establishedthat another categoryof anti-atherosclerotic drugs, the ligands for a group ofnuclear transcription factors known as peroxisome-proliferator-activated receptors (PPARs), can inhibit T-cellactivation in vitro. Activators of both PPAR
(members
of the fibrate class of drugs) and PPAR(members ofthe thiazolidinedione family of drugs) can reduce T-cellactivation, as was shown by decreased production ofIFN, TNF and IL-2 (REF. 116). PPAR agonists alsoinhibit inflammatory activation of vascular smooth
muscle cells117. Therefore, activation of PPAR or PPARmight also affect atherosclerosis in a beneficial mannerby blunting the adaptive and innate immune responses.
Nonspecific anti-inflammatory therapies, such asnon-steroidal anti-inflammatory drugs (NSAIDs), havenot improved the cardiovascular outcome. Indeed, treat-ment with NSAIDs selective for cyclooxygenase-2 seemsto increase the risk of thrombotic complications118,119.Despite their marked anti-inflammatory properties,glucocorticosteroids themselves probably increase,rather than decrease, atherogenesis, as chronic admin-istration of these agents adversely affects plasma lipopro-teins, promotes insulin resistance and sodium retention,
Figure 3 | Plaque activation, rupture and thrombosis. When activated, immune cells including macrophages, T cells
and mast cells can release pro-inflammatory cytokines, which reduce collagen formation and induce the expression of
tissue factor. Proteases that attack the collagenous cap are also released by activated immune cells. The weakened plaque
might fissure when subjected to the forces of arterial blood pressure. Exposure of subendothelial structures and
procoagulants such as tissue factor promotes platelet aggregation and thrombosis. A thrombus forms and might occlude
the lumen of the artery, leading to acute ischaemia.
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C-reactive protein
An acute-phase reactant
protein, the plasma
concentration of which
increases in inflammatory
states.
and inhibits collagen and elastin formation. It thereforedoes not offer a reasonable therapeutic alternative in thechronic phases of atherosclerosis.
Vaccination against atherosclerosis?Parenteral immu-nization with malondialdehyde-modified LDL (thatis, LDL with a defined oxidative modification) ormalondialdehyde-modified peptides derived from theLDL protein apolipoprotein inhibits atherosclerosis andthis occurs in parallel with increased titres of antibodyspecific for the immunogen (TABLE 1). Interestingly, pro-tection through this route does not require CD4+ T-cellhelp120. Therefore, protection seems to depend mostlyon humoral immunity, at least in this model.
By contrast, the outcomes after immunization withHSP60 or its mycobacterial homologue HSP65 arecomplex (TABLE 1). Parenteral immunization in C57BL/6mice fed with fat, as well as Ldlr/ mice, aggravatesdisease, whereas oral or nasal immunization elicitsprotective immunity. Induction of mucosal immunityinvolves activation of regulatory T cells that produce
anti-inflammatory cytokines and also high titres ofspecific antibodies. Therefore, the precise mechanismby which mucosal immunization leads to reducedatherosclerosis remains to be clarified.
Although several questions remain, the immuniza-tion experiments with malondialdehyde-modified LDLand HSP60 indicate that it is possible that a vaccina-tion strategy might protect against atherosclerosis andits complications. Obviously, many obstacles remain,rendering the success of this approach unpredictable,particularly in humans.
Conclusion
The evidence reviewed in this article supports theinvolvement of the immune response in atherosclerosisfrom its initiation through to its thrombotic complica-tions. The concept that adaptive immunity pivotallyregulates atherogenesis has already been clinically useful.Markers of the acute-phase response, notablyC-reactiveprotein (CRP), predict the prognosis of patients whohave already sustained a cardiovascular event121. Lesserelevations of CRP concentration, measured with a highlysensitive assay and previously considered in the normalrange, can be used to predict cardiovascular events inapparently well populations109,122,123. Markers of height-ened innate immune responses, such as CRP, correlatewith worse outcomes in individuals with acute coronarysyndromes121.
Systemic administration of non-selective immuno-suppressive drugs will probably not be useful for thetreatment of atherosclerosis, at least during its longasymptomatic phase, because of the need for prolongedtherapy and the potential toxicities of such treatments.
However, the immune system in its full complexity offersmuch more subtle targets for therapeutic manipulation.As more details emerge of the specific pathways involvedin the immune response and the inflammation thatoccur in atherosclerosis, more selective interventionsmight prove appropriate for long-term anti-atheroscle-rotic therapy. Also, as our ability to gauge the risk ofacute complications improves, we might be able to targetin a much more selective manner those therapies thatwould otherwise impair host defences if administeredon a long-term basis.
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AcknowledgementsWe regret that we have not been able to cite many important
papers owing to space limitations. Our research is supported
by grants from the Swedish Research Council, Heart-Lung
Foundation, European Community, US National Institutes of
Health and Leducq Foundation.
Competing interests statementThe authors declare no competing financial interests.
DATABASESThe following terms in this article are linked online to:
Entrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
APOE | CCL2 | CD14 | CD40 | CD40L | CD68 | CX3CR1 |
HSP60 | IFN | IL-4 | LDLR | MMP1 | PPAR | PPAR | TLR4 | TNF |VCAM1
FURTHER INFORMATIONPeter Libbys homepage:
http://reynolds.brighamandwomens.org/faculty/libby.asp
Gran K. Hanssons homepage:
http://www.ki.se/medicin/medicine_ks/experimental_
cardiovascular_research_unit/index_en.html
Access to this links box is available online.
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