arterioscler thromb vasc biol 2001 hansson 1876 90
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Gran K. Hansson
Immune Mechanisms in Atherosclerosis
Print ISSN: 1079-5642. Online ISSN: 1524-4636Copyright 2001 American Heart Association, Inc. All rights reserved.
Greenville Avenue, Dallas, TX 75231is published by the American Heart Association, 7272Arteriosclerosis, Thrombosis, and Vascular Biology
doi: 10.1161/hq1201.1002202001;21:1876-1890Arterioscler Thromb Vasc Biol.
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Immune Mechanisms in Atherosclerosis
Gran K. Hansson
AbstractAtherosclerosis is an inflammatory disease. Its lesions are filled with immune cells that can orchestrate andeffect inflammatory responses. In fact, the first lesions of atherosclerosis consist of macrophages and T cells. Unstableplaques are particularly rich in activated immune cells, suggesting that they may initiate plaque activation. We have seena rapid increase in the understanding of the mechanisms that govern the recruitment, differentiation, and activation ofimmune cells in atherosclerosis. Experimental research has identified several candidate antigens, and there areencouraging data suggesting that immune modulation as well as immunization can reduce the progression of the disease.This review provides an overview of our current understanding of the role of immune mechanisms in atherosclerosis.(Arterioscler Thromb Vasc Biol. 2001;21:1876-1890.)
Key Words:atherosclerosis pathophysiology cell biology cytokines
The atherosclerotic lesion contains large numbers of im-
mune cells, particularly macrophages and T cells. Fur-thermore, the disease is associated with systemic immuneresponses and signs of inflammation. Histopathological andclinical investigations point to inflammatory/immune activa-tion of plaques as a cause of acute coronary syndromes, andseroepidemiological studies have suggested links betweenatherosclerosis and microbial infections. During recent years,experiments in gene-targeted mice have provided mechanisticevidence in support of the hypothesis that immune mecha-nisms are involved in atherosclerosis. This review willprovide an update on immune mechanisms in atherosclerosis,with particular focus on mechanistic studies.
Immune Cells in the Lesions of AtherosclerosisAdaptive (ie, antigen-specific) immune reactions are initiatedwhen a macrophage (or a dendritic cell of the macrophagelineage) displays a surface complex consisting of an antigenicpeptide bound to a major histocompatibility complex (MHC)protein to a neighbor T cell. This can elicit T-cell activation,cytokine secretion, cytotoxicity, antibody production, andmany other components of an immune reaction. There is nowgood evidence that atherosclerosis is associated with immunereactions and that antigen presentation occurs in atheroscle-rotic lesions. The cellular composition of an atheroma isillustrated in Figure 1. It has been known for many years that
monocyte-derived macrophages are present in large numbersin atherosclerotic lesions.17 The discovery of the scavengerreceptor pathway for uptake of modified lipoproteins810
provided an explanation for the finding that most foam cellsbear macrophage differentiation markers.
The other main immune cell of atherosclerotic lesions, theT cell, remained undetected for a long time. It was observed
that many vascular smooth muscle cells (SMCs) in human
lesions express human leukocyte antigen (HLA)-DR, a cellsurface protein that is induced by the T-cell cytokineinterferon- (IFN-).11 By using T-cellspecific CD3 anti-bodies, it could be established that T cells are abundant inhuman plaques.12 A large proportion of them are in anactivated state1316; ie, they express adhesion molecules andother surface molecules, secrete cytokines, and may prolifer-ate. The activation of T cells and macrophages leads to acascade of cytokines that induce an inflammatory state. Withthe cDNA cloning and production of recombinant cytokines,it became possible to study their effects in the context ofvascular biology. Such studies revealed that vascular endo-
thelial cells and SMCs are important targets for inflammatorycytokines and that they are capable of producing significantamounts of cytokines themselves on stimulation.17,18
Studies during the last decade have identified other types ofimmune cells in atherosclerotic plaques. Among them, dendriticcells are professional antigen-presenting cells that may beparticularly important in the initiation of immune responses toplaque antigens.19 Mast cells are immune effector cells with acapacity to modify lipoproteins and digest matrix components;they could be important in plaque activation and rupture.20 Allthese different cells may be involved in the initiation, progres-sion, and/or development of complications to atherosclerosis. Atpresent, there is evidence for pathogenic roles of monocyte-
derived macrophages and T cells.
Recruitment of Immune Cells to the Vessel Wall
Leukocyte Adhesion to the EndotheliumDuring the initiation of atherosclerosis, mononuclear leuko-cytes, ie, monocytes and T cells, are recruited to the vesselwall across an intact endothelium. This requires activation of
Received May 21, 2001; revision accepted October 2, 2001.From the Center for Molecular Medicine and the Department of Medicine at Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.Correspondence to Gran K. Hansson, Center for Molecular Medicine and Department of Medicine, Karolinska Hospital, Karolinska Institute,
SE-17176, Stockholm, Sweden. E-mail Goran.Hansson@cmm.ki.se
2001 American Heart Association, Inc.Arterioscler Thromb Vasc Biol.is available at http://www.atvbaha.org
1876
Brief Reviews
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the endothelium to express leukocyte adhesion molecules.
These cell surface proteins are mainly regulated transcription-
ally in a process that involves nuclear factor (NF)-B,21 a
transcription factor that is transactivated when proinflamma-
tory cytokines ligate their receptors on the endothelial sur-
face. Both E-selectin and 2 imunoglobulin-like adhesionmolecules, intercellular adhesion molecule-1 (ICAM-1) and
vascular cell adhesion molecule-1 (VCAM-1), can be induced
in this way.
VCAM-1 can be induced not only on cytokine stimulation
but also in response to other proinflammatory macromole-
cules. Lipopolysaccharides of Gram-negative bacteria acti-
vate NF-B by ligating toll-like receptors (TLRs), which
transduce NF-B activation through a kinase cascade similar
to the one initiated by interleukin-1 (IL-1). In addition,
lysophosphatidylcholine and other oxidized phospholipids
can induce VCAM-1 expression in endothelial cells.22,23
Interestingly, such phospholipid species are generated during
lipoprotein oxidation. Their activity may explain the in-creased adhesive properties of endothelial cells exposed to
oxidized LDL (oxLDL)24 (Figure 2). In vivo studies have
shown that hypercholesterolemia rapidly leads not only to
lipoprotein deposition and oxidation in the intima but also to
VCAM-1 expression on the luminal aortic endothelium.25,26
This provides a direct link between hypercholesterolemia and
inflammatory activation of the vessel wall.
ICAM-1 is induced in endothelial cells through a cytokine-
dependent pathway, but its expression is also promoted by
hemodynamic stress. The latter seems to be due to activation
of the shear stress response element in its promoter.27 This
probably explains the finding of ICAM-1 expression in aortic
regions where the endothelium is exposed to variations in
shear stress caused by blood flow.2729 It is likely that the
disturbed flow encountered during hypertension can increase
ICAM-1 expression. Thus, both hypercholesterolemia andhypertension, 2 major risk factors for atherosclerosis, in-
crease the recruitment of leukocytes to the artery.
Adhesion is a multistep process that starts with leukocyte
rolling on the endothelial surface. This is due to selectin
ligation, whereas the subsequent firm adhesion depends on
interactions between immunoglobulin-like molecules
(VCAM-1, ICAM-1, and others) on the endothelium and
integrins on the leukocyte surface.30 Very lateactivationantigen-4 (VLA-4), a major counterreceptor for VCAM-1, is
expressed by monocytes and lymphocytes but not by granu-
locytes.31 This explains the selective recruitment of mononu-
clear cells to the arterial intima during early atherosclerosis.32
Immunopharmacological blockade of ICAM-1 and VCAM-1has been shown to inhibit fatty streak development33 (Table
1). The importance of selectin interactions is illustrated by the
finding that mice deficient in E-selectin and P-selectin de-
Figure 1. Immune cells in atheroma. Macrophages (MPh) and Tcells are common components of lesions, which may also con-tain mast cells and occasional B cells. T cells are activated bylocal antigens presented by antigen-presenting macrophagesand dendritic cells. Activation leads to production of interferon-(IFNg), which not only primes macrophages for activation but
also regulates smooth muscle and endothelial functions. Acti-vated macrophages produce proinflammatory cytokines such astumor necrosis factor- (TNFa) and IL-1, which can induce pro-coagulant (Coag), fibrinolytic (fibr.), and adhesive properties onendothelial cells (EC). Macrophages also make matrix metallo-proteinases (MMP), and both T cells and macrophages producecytotoxic factors, which contribute to apoptosis. See text forexplanation of other abbreviations.
TABLE 1. Animal Studies Demonstrating Important Roles for Leukocyte Adhesion and Migration
in Atherosclerosis
Molecule Function Experiment Atherosclerosis Model Result Reference No.
P-, E-selectin Rolling (PMN, MC, Ly) KO ApoE-KO 2 Fatty streaks 34
P-selectin Rolling (PMN, MC, Ly) KO ApoE-KO 2 Atheroma 35
VCAM-1 Firm adhesion (MC, Ly) Ab Rabbit 2 Postinjury lesion 213
MCP-1 Chemoattractant (MC, Ly) KO LDLR-KO, apoE-KO, apoB-Tg 2 Atheroma 44, 46
CCR-2 MCP-1 rec (MC, Ly) KO LDLR, apoE-KO 2 Atheroma 45
CCR-2 indicates C-C chemokine receptor-2; PMN, polymorphonuclear leukocytes; MC, monocytes; Ly, lymphocytes; rec, receptor;
and Tg, transgenic. See text for explanation of other abbreviations.
Figure 2. Hypercholesterolemia leads to recruitment of immunecells to the vessel wall. LDL accumulates in the arterial intima.Lipid products of LDL oxidation induce VCAM-1 in endothelialcells. Monocytes and T cells adhere through their VLA-4 recep-tors. Their subsequent migration through the endothelial layer isstimulated by chemokines such as MCP-1 and also by comple-ment activation products (Cpt), which can be generated by oxi-dized cholesterol aggregates. See text for explanation of otherabbreviations.
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addition, IFN- induces expression of secretory phospho-lipase A2, which can lead to production of inflammatory lipid
mediators such as eicosanoids, lysophosphatidylcholine, and
PAF.71
In vivo studies in rats have shown that the proliferative
response of SMCs after arterial injury is inhibited by IFN-,72
which also inhibits smooth muscle contractility and collagen
synthesis.70,73 It was therefore proposed that IFN-produc-ing T cells could play an important role in plaque destabili-
zation by reducing the fibrous cap.74,75 Histopathological
findings of activated T cells at sites of rupture in culprit
lesions support this notion.76
Further support for a proatherogenic role came from
studies of compound KO mice lacking the IFN-receptor as
well as apoE. These mice had an 60% reduction in
atherosclerosis, supporting the notion that IFN-is a strongly
proatherogenic cytokine77 (Table 4). The lack of IFN-
signaling affected the lipoprotein profile (reduced apoA-IV)
as well as the vessel wall (increased collagen), implying that
both systemic and local effects could be important for the
antiatherogenic action. However, IFN-was recently shownto aggravate transplant vasculopathy by its local action on the
vessel wall.78 Even in severe combined-immunodeficient
(SCID) mice, IFN- induced vascular pathology in xeno-
grafts, indicating that its direct vascular actions are sufficient
to promote disease. Finally, recent experiments have shown
that administration of this cytokine accelerates atherosclero-
sis in apoE-KO mice.79 All these data imply that IFN- is a
proatherogenic cytokine.
Proinflammatory Cytokines: Mediators of Innate andTh1 ResponsesTNF- and IL-1 are also present in human lesions.16,80,81
Similarly to IFN-, they affect smooth muscle proliferation,but their effects are more complex and indirect. IL-1 not only
stimulates SMC replication by inducing an autocrine plate-
let-derived growth factor loop but also inhibits proliferation
by inducing the growth-inhibitory autacoid, prostaglandin
E1.82,83 The net effect on SMC growth therefore depends on
the precise conditions in experimental systems and remains
TABLE 2. Some Immune Cytokine-Regulated Genes of Importance in Atherosclerosis
Gene Product Cytokine Cytokine Producers Target Cells Effect Reference No.
VCAM-1 IL-1, TNF-, IL-4 M, Th2, SMC, EC EC, SMC Adhesion 214
ICAM-1 IL-1, TNF-, IFN- M, Th1, SMC, EC EC Adhesion 215
CD36 IL-4 Th2 M OxLDL uptake 216
SR-A IFN-, TNF-, IL-6 Th1, M, SMC M 2 OxLDL uptake 4850
NOS2 IFN-, TNF-, IL-1 Th1, M, SMC, EC M, SMC, EC 1 NO 217, 218
NOS2 IL-4 Th2 M, SMC, EC 2 NO 101
COX2 IFN-, TNF-, IL-1 M, Th1, SMC, EC M, SMC, EC 1 Eicosanoids 219
COX2 IL-4 Th2 M, SMC, EC 2 Eicosanoids 103
15-LO IL-4, IL-13 Th2 M, SMC Oxidation, leukotrienes 220, 221
IL-1, TNF- IFN- Th1 M Activ 222
IL-6 IL-1 M, EC, SMC SMC B-cell activ, PTX prod 92
MMPs TNF-, IL-1, CD40L* M M, SMC, EC Proteolysis 84, 201, 223, 224
MMPs IFN- Th1 M, SMC, EC 2 Proteolysis 84, 201
tPA, uPA TNF-, IL-1 M, EC, SMC EC 1 Fibrinolysis 225
uPA IFN- Th1 EC 2 Fibrinolysis 226
PAI-1, -2 IFN-, TNF-, IL-1 M, Th1 EC Antifibrinolysis 227
PPAR-dep genes IL-4 Th2 M 1 CD36 expression 228
ApoA-IV IFN- Th1 Hepatocytes 2 HDL 77
ABCA1 IFN- Th1 M foam cells 2 Cholesterol efflux 229
sPLA2 IFN- Th1 SMC 1 Eicosanoids, PAF, lysoPC 71
LPL IFN-, TNF-, IL-1 M, Th1 M 2 Lipolysis 86, 87
NOS indicates nitric oxide synthase; COX, cyclooxygenase; LO, lipoxygenase; MMPs, matrix metalloproteinases; tPA, tissue
plasminogen activator; uPA, urokinase-type plasminogen activator; PAI, plasminogen activator inhibitor; PPAR, peroxisome
proliferatoractivated receptor; dep, dependent; LPL, lipoprotein lipase; M, macrophage; EC, endothelial cell; activ, activation; PTX,
pentraxin; prod, products; and lysoPC, lysophosphatidylcholine. See text for explanation of other abbreviations.
*The cell surface molecule CD40L (CD154) has effects similar to those of a soluble cytokine.
TABLE 3. T-Cell Types Potentially Involved in Atherosclerosis
Cell Type
Antigen
Rec Epitope Restriction Element
Present in
Lesions
Effect Shown in
Exp Model
CD4 TCR Peptide MHC class II Yes Yes
CD8 TCR Peptide MHC class I Yes Yes
T TCR Lipid CD1 Yes No
rec indicates receptor; exp, experimental. See text for explanation of other abbreviations.
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controversial in the in vivo situation. TNF- and IL-1 are
powerful inducers of local inflammation in blood vessels and
elsewhere (Table 2). For instance, they stimulate further
activation of macrophages, induce secretion of matrix
metalloproteinase-9,84 and promote expression of leukocyte
adhesion molecules (see above). IL-1 is also an important
costimulatory factor for T-cell activation and TNF-, a
proapoptotic cytokine.
The metabolic effects of IL-1 and TNF- are even more
striking than those of IFN- (Table 2). They are powerful
inhibitors of lipoprotein lipase, which leads to increased
systemic levels of VLDL and hypertriglyceridemia.85,86 In
addition, they exert important effects on glucose and energymetabolism. High-dose stimulation with TNF- therefore
results in cachexia. It is possible that much lower TNF-
levels lead to metabolic changes of the kind observed in the
metabolic syndrome, such as hypertriglyceridemia, redistri-
bution of adipose tissue, and reduced insulin sensitivity.8789
Interestingly, this syndrome is considered an important risk
factor for atherosclerotic cardiovascular disease.
The proinflammatory cytokine pathway is a cascade that
involves activation by TNF- and IL-1 to IL-6 expression90
and also to secretion of pentraxins such as C-reactive protein
(CRP).91 This cascade is amplified in each step. For instance,
IFN- produced by Th1 cells stimulates macrophages to
secrete IL-1. The latter cytokine stimulates SMCs to make
copious amounts of IL-6,92 a mediator that is present in
atherosclerotic lesions64,93 and that may also be induced by
the terminal complement complex C5b-994 (Table 2). CRP
and other pentraxins may not only be markers of inflamma-tion but also exert direct effects on leukocyte recruitment and
apoptosis in the vessel wall.95,96
Patients with unstable coronary syndromes have elevated
levels of IL-6, CRP, and pentraxin-3,9799 which may be due
to increased inflammatory activity in their culprit lesions.
Importantly, even a modestly elevated CRP level is a risk
factor for coronary heart disease in healthy, middle-aged
men.100 This suggests that the modest inflammatory activity
of silent plaques results in a cascade leading to CRPproduction and also accelerates disease progression.
Th2, Th3, and More: Are Anti-inflammatory
Cytokines Antiatherosclerotic?Th2 cytokines such as IL-4, IL-5, and IL-10 are less abundant
than cytokines of the Th1 type in end-stage human lesions.64
In cell culture systems, IL-4 and IL-10 inhibit inflammatory
genes such as inducible nitric oxide (NO) synthase101 and
cyclooxygenase 2,102,103 but IL-4 also upregulates the scav-
enger receptor CD36 (Table 2). In apoE-KO mice, Th2
cytokines can be found in atherosclerotic lesions only in
conditions of excessive hypercholesterolemia, with serum
cholesterol levels of 40 to 50 mmol/L.104 Th1 and Th2
cytokines are cross-regulatory, IL-10 being an inhibitor of the
Th1 pathway and IL-12 a Th2 inhibitor. The low level of Th2
activity in lesions may be at least partly due to local IL-12secretion.65 There may be a corresponding IL-10 damper of
the Th1 response, because IL-10 containing areas of humanplaques exhibit reduced apoptosis and expression of inflam-
matory genes such as cytokine-inducible NO synthase.105
Interestingly, IL-10/ C57BL/6J mice exhibit increased fatty
streak development,106,107 and IL-10/ apoE/
compound-KO mice show increased plaque activation and
coronary thrombosis (G. Caligiuri, G.K. Hansson, and A.
Nicoletti, unpublished observations, 2001). However, IL-10
appears to be a cytokine secretioninhibiting cytokine with a
Figure 3. Antigen presentation of modified lipoproteins. WhenLDL is modified, eg, by oxidation, it is transformed into anautoantigen. Uptake by scavenger receptors (SR) leads to intra-cellular processing in macrophages (MPh) and presentation ofpeptide fragments on MHC class II molecules (MHC-II). T cellsthat carry the appropriate antigen receptors (TCR) are activatedby contact to the MHC-II:peptide complex in the presence ofcostimulatory factors (co-stim) such as CD4, CD40, and B7molecules. This results in T-cell activation, with proliferation andcytokine secretion.
TABLE 4. Effects of Immune Deficiency and Immunomodulation on Atherosclerosis
Experiment
Immune
Defect Immune Phenotype
Atherosclerosis
Model
Effect on
Disease
Reference
No.
Compound KO RAG-1 SCID ApoE 2 Athero 194
Compound KO RAG-2 SCID ApoEfatty diet No effect 195
Compound KO SCID/SCID SCID ApoE 2 Athero 197
Compound KO IFN- rec Defective Th1 ApoE 2 Athero 77
IvIg inj Immunosuppression ApoE 2 Athero 209
Anti-CD40 inj Immunosuppression LDLR 2 Athero 204
Compound KO CD40L Reduced immune activation ApoE 2 Athero 205
IFN- inj Increased Th1 ApoE 1 Athero 79
KO on B6 background TNF- rec Defective inflammation Fat feeding 2 Fatty streaks 230
KO on B6 background IL-10 Increased proinflammatory cytokines, 1 Th1 Fat feeding 1 Fatty streaks 106, 107
IvIg inj indicates intravenous immunoglobulin injection; rec, receptor; and athero, atherosclerosis. See text for explanation of other
abbreviations.
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broader set of targets than Th1 cells alone, and its effects may
not be equivalent to those of Th2 activity.
A third T-helper cell called Th3 was recently described.108
It produces TGF- on activation. This cytokine stimulates
collagen synthesis and is fibrogenic. Furthermore, it is
strongly anti-inflammatory, as illustrated by the fact that
TGF-KO mice die of fulminant inflammation by the age of6 weeks.109 TGF- and its receptor are present in the
atherosclerotic lesion,64,110 where it may act to stimulate
collagen synthesis and cap formation and to dampen inflam-
mation. Several different cell types, including macrophages,
SMCs, and Th3 cells, can express TGF-, which might be
important for plaque stabilization. The SMC growthpromot-ing action of T cells that release heparin-binding growth
factors might add to this effect.111
In conclusion, although Th1 cytokines are abundant in
lesions, it seems less likely that atherosclerosis will be
considered a strict Th1 disease. It might even be speculated
that different phases of this chronic disease are promoted by
different effector pathways. Clearly, the development andregulation of Th pathways in atherosclerosis require further
studies.
CD8 Cells andT Cells: Additional Players inthe Plaque Orchestra?CD8 T cells are found at varying proportions in human
lesions (Table 3). Most of the cytotoxic activity associated
with T cells is found in this subpopulation (Tc cells), which
is activated by cells that express proteasomally processed
peptide fragments of nascent proteins in the context of MHC
class I. It was recently shown that expression of a foreignantigen on vascular SMCs can lead to cytotoxic attack by
CD8 T cells.112 In an apoE-deficient mouse, this results in
significant aggravation of atherosclerosis. Thus, it is possible
that CD8 T cells cause some of the widespread apoptosis
that is associated with atherosclerosis.113 However, apoptosis
can also be induced by reactive oxygen and nitrogen species,
which are generated by macrophages and SMCs on stimula-
tion with proinflammatory cytokines.114 Therefore, activation
of CD4 as well as CD8 T cells can lead to cell death in
lesions. In addition, CD8 T cells may respond to antigens
not only by cytotoxic activity but also by secretion of
cytokines in a manner parallel to that observed for Th1 and
Th2 cells. Functional Tc1 and Tc2 subsets of CD8 T cells
seem to be important for the tissue response in mycobacterial
infections, but it is not known whether they play a role inatherosclerosis.
A third type of T cell has a CD3 4 8 phenotype and
expresses TCRs that are rather than dimers. Such T
cells are important in mucosal immunity and in the recogni-
tion of complex lipids as antigens. TCR binds such
antigens, which are presented on CD1 rather than MHC
proteins. The capacity ofT cells to recognize lipids makes
them potentially interesting in atherosclerosis. T cells and
CD1-expressing cells have been found at varying proportions
in arterial inflammatory lesions115 and atherosclerotic le-
sions,116,117 but their role remains unclear.
Other Immune Cells May Also Participate in theLocal Immune ResponseThe 2 other types of lymphocytes, B cells and natural killer
(NK) cells, are less frequent in atheroscleroticlesions than T
cells. Relatively few B and NK cells are found in advanced
human lesions, but prominent B-cell infiltrates may occur in
the adventitia and the periadventitial connective tissue.118
They can develop into pathological perivascular lymphoid
aggregates, a condition termed periaortitis.119 In lesions of
hypercholesterolemic rabbits and mice, B cells are relatively
abundant, and clones of immunoglobulin-producing cells canbe found.120,121 In humans as well as animals, IgG accumu-
lation is prominent in lesions.118,122 Some of these IgGs may
be specific for antigens present in the tissue. Although a
substantial proportion of the IgG may have entered the lesion
by filtration, there is also evidence for local synthesis.120
Plasma cells, which may secrete large amounts of IgG, are
present in lesions and are the likely source of this locally
produced IgG.
A different kind of hematopoietic cell, the mast cell, has
been identified in atherosclerotic lesions.20 Mast cells are less
frequent than macrophages and T cells but may be important
in plaque activation and acute coronary syndromes because
they produce several proteases and accumulate at sites ofplaque rupture.123125 Factors released from mast cells may
degrade the extracellular matrix126 and could also influence
the functions of surrounding cells and modify locally depos-
ited lipoproteins.127 Finally, the dendritic cell, which is a
specialized member of the macrophage lineage, has been
found in human and experimental atherosclerotic lesions.19,128
This cell performs a key role in immune activation because it
is specialized on antigen presentation and appears to be the
only cell that can activate naive T cells. It has a high
migratory capacity and maypatroltissues such as the arterywall in search of antigens, which are endocytosed and
transported to regional lymph nodes, where presentation of
the antigen to naive and memory T cells, and hence, induction
of adaptive immunity, can take place.
Immune Specificity in the Atherosclerotic Lesion
Restricted Heterogeneity Suggests LocalImmune ActivationThe antigen specificity of T cells is encoded in the sequence
of their rearranged TCR genes, which determine the confor-
mation of the antigen-binding site in the CDR3 domain of the
TCR protein.129 Because the rearrangement process is sto-
chastic, each nascent T cell carries a unique TCR gene and
protein. On activation, the stimulated T cell divides to give
rise to a clone of cells with identical specificities. Thepresence in tissue of a population of T cells with an identical
TCR is therefore indicative of clonal proliferation and hence,
of expansion of these particular T cells due to antigenic
stimulation. Such clonal expansions are found in early lesions
of apoE-KO mice.130 This finding is suggestive of local
clonal proliferation of T cells, which is compatible with
activation by local antigens. Interestingly, similar TCRs
containing the V6 variable domain are frequently expressed
by T cells that recognize oxidatively modified LDL, one of
the candidate antigens in atherosclerosis (A. Nicoletti, G.
Paulsson, and G.K. Hansson, unpublished observations,
2001).
In human lesions, the situation is more complex. A
heterogeneous population of TCRs and therefore, of T cells is
found in lesions,131 and the enormous allelic variation in
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MHC molecules, ie, HLA proteins, between individuals
makes it difficult to identify patterns that could reflect local
expansions of HLA-restricted T cells. Although this may be
partly due to technical difficulties, it seems unlikely that the
immunological situation in atherosclerosis could be as simple
as the one in type 1 diabetes, for example, where one specific
HLA-DQ allele permits an autoimmune response that leads to
-cell destruction and disease. Instead, it is likely that several
antigens and antigenic epitopes are involved and can be
presented by several different HLA alleles. Nevertheless,
autoantigens have also been identified in atherosclerosis.
OxLDL Is a Candidate AutoantigenAntibodies to oxLDL can be detected in atherosclerotic
patients and experimental animals119,132,133 and are present in
atherosclerotic lesions.134 These studies identified oxLDL as
a candidate antigen in atherosclerosis (Table 5). Further
support for this notion came with the identification of cellular
immune responses to oxLDL. T cells can be isolated from
fresh human plaques, cloned, expanded in culture, andchallenged with candidate antigens. By using this approach,
oxLDL was shown to be a major autoantigen in the cellular
immune response of atherosclerosis.135 One fourth of all
CD4 T cells cloned from human plaques recognized ox-
LDL in an HLA-DR dependent manner. OxLDL-specific Tcells are present in lymph nodes of apoE-KO mice,136,137
which have strong humoral as well as cellular immune
responses to such modified lipoproteins.138,139 In humans,
oxLDL induces activation of a subset of peripheral T cells,
suggesting that it is a quantitatively important antigen.140
The antibody specificity of IgG molecules in lesions can be
determined by isolating them and permitting them to reactwith an antigen, eg, in ELISA or Western blot analyses. With
this approach, it was demonstrated that IgGs of atheroscle-
rotic lesions contain antibodies reactive with oxLDL.134 The
antigens, ie, LDL carrying various kinds of oxidative modi-
fications, could be demonstrated in the lesions by immuno-
staining and Western blot. Therefore, oxLDL is an autoanti-
gen that is formed in the lesion, and it elicits a local cellular
as well as a humoral immune response.
The immune response to oxLDL plays a pathogenetic role
in atherosclerosis because lesion progression can be inhibited
by immunization141143 or induction of neonatal tolerance to
oxLDL.137 It seems paradoxical that both tolerization and
hyperimmunization can reduce the extent of disease; this may
be due to the different effector pathways activated by these
two kinds of treatment.
Heat Shock Proteins Are Common Autoantigens inInflammatory DiseaseHeat shock proteins have also been implicated in the patho-
genesis of atherosclerosis144 (Table 5). Such proteins are
involved in protein folding in the normal cell, are produced in
large amounts by injured cells, are released on tissue inju-
ry,145 and serve as targets for autoimmune responses in many
inflammatory diseases. Interestingly, heat shock proteins arealso released by monocytes exposed to oxLDL.146 Antibodies
to heat shock protein 60 (hsp60) and its prokaryotic homo-
logue hsp65 are frequently detected in rheumatoid arthritis
and other inflammatory conditions.145
Xu and coworkers147 immunized rabbits with hsp65/60 and
recorded induction of vascular inflammation, with endothelial
activation and mononuclear cell adhesion. The developing
lesions also contained T cells, and cell lines derived from
such infiltrates exhibited anti-hsp60 reactivity. Anti-hsp60
antibodies occurred in peripheral blood, and immunization
with hsp60 was found to increase fatty streak development in
hypercholesterolemic rabbits and mice.147,148
In humans,antibodies to hsp 65/60 are elevated in hypertension149 and
early atherosclerosis150 and may predict progression of ath-
erosclerotic disease.151 Because heat shock proteins of hu-
mans and microbes are structurally and antigenically similar,
it is possible that molecular mimicry between immune re-
sponses to microbial heat shock proteins and homologues
expressed by vascular cells could account for the association
between infections and atherosclerosis.152
A third autoantigen, 2-glycoprotein Ib (2-GPI), is pres-
ent on platelets but may also be expressed by endothelial cells
(Table 5). Autoantibodies to 2-GPI are produced in several
inflammatory disorders, including atherosclerosis.153,154 The
immune response to 2-GPI appears to be proatherogenic,because hyperimmunization with 2-GPI155 or transfer of
2-GPIreactive T cells aggravates fatty streak formation inLDLR/ mice.156 The pathogenetic mechanism by which
2-GPI acts remains unclear, but it may be related to this
proteins capacity to bind phospholipids.
A Role for Phospholipid Antibodiesin Atherosclerosis?Antibodies reacting with phospholipids such as cardiolipin
are associated with recurrent thrombosis157 and accelerated
atherosclerosis.158 Many of these antibodies recognize
phospholipid-binding plasma proteins such as -GPI,159 and
it could be speculated that 2-GPI affects atherosclerosis by
targeting immune responses to membrane lipids. Interest-
ingly, another set of phospholipid antibodies recognizes
TABLE 5. Candidate Antigens in Atherosclerosis
Antigen Type Processing Presentation Recognition Effect of Immun.
OxLDL Autoantigen Endosomal MHC-II CD4T (T?) 2 atheroma
hsp60 Autoantigen Endosomal, cytosolic MHC-II
MHC-I
CD4
CD8
1 atheroma
2-Gp1b Autoantigen Endosomal MHC-II CD4 fatty streak
C pneum Microbe Endosomal MHC-II CD4 ?
CMV Virus Cytosolic MHC-I CD8 ?
C pneum indicates Chlamydia pneumoniae; CMV, cytomegalovirus; and immun, immunization. See text for
explanation of other abbreviations.
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oxidized phospholipids in oxLDL160 and may representnat-ural antibodies that appear in early life and also bindphospholipids on apoptotic cells and certain bacteria.161
Perhaps pathogenic immune responses are due tomolecularmimicry between oxLDL and modified lipids on microbesand apoptotic cells.
Microbes as Antigens in AtherosclerosisIn 1988, Saikku et al162 discovered that patients with cardiovas-
cular diseases often have high-titer antibodies to Chlamydia
pneumoniae(Table 5). This common pathogen can cause pneu-
monia, but it has also been associated with a variety of other
chronic diseases. Further investigations revealed that C pneu-
moniaesurvives intracellularly in macrophages, can be detected
in atherosclerotic lesions, and can be isolated and grown from
such lesions.163165 This established that C pneumoniae is in-
volved in atherosclerosis. However, the extent ofC pneumoniae
infiltrates in lesions remains controversial,166 as does the impor-
tance of C pneumoniae infection as an aggravating factor in
experimental atherosclerosis.167170
It therefore remains to beclarified how important C pneumoniae is for disease develop-
ment and whether the microorganism or the immune response
against it can be harmful.
Viruses of the Herpesviridae family have also been implicated
in atherosclerosis (Table 5). Both herpes simplex type 1 and
cytomegalovirus have been detected in human lesions.171173 An
avian analogue, Mareks disease virus, aggravates cholesterol-induced atherosclerosis in chickens. Cytomegalovirus has been
linked to transplant arteriosclerosis174,175 and may also be asso-
ciated withgarden-varietyatherosclerosis and restenosis afterangioplasty.176,177 Several pathogenic mechanisms have been
proposed.178 Cell culture studies have identified a role for this
virus as a stimulus for smooth muscle migration and scavengerreceptor expression, which may be important in vascular pathol-
ogy.179 However, it appears that direct action of the virus, rather
than immune responses against it, is playing the important
pathogenic role.
Systemic Immune Responses and SerodiagnosisSystemic humoral immune responses are characteristic for
atherosclerotic disease in humans and experimental models.
Antibodies to oxidatively modified LDL are commonly found in
patients; as expected from the incidence of silent disease, they
are frequent also in healthy individuals.133,180 Immunodominant
epitopes in modified LDL include malondialdehyde-conjugated
and 4-hydroxynonenal conjugated lysine residues.139,181 Thesemodifications are generated by enzymatic or nonenzymatic
attack on fatty acid residues, which leads to release of reactive
aldehydes that can bind to the polypeptide chain of apoB-100.
Other B-cell epitopes on oxLDL include oxidized phospholipids
such as phosphorylcholine, which is also present on several
microbes and apoptotic cells and is recognized by naturalantibodies present in most individuals.161
Anti-oxLDL antibody titers are correlated with the pro-
gression of advanced atherosclerosis in some studies,133,182
whereas others have been unable to find any such correlation.
Interestingly, titers are correlated negatively with early car-
diovascular diseases, including borderline hypertension andcarotid intima/media thickening.183185 It appears that no
simple, positive correlation occurs between antibodies and
disease throughout its natural history. Instead, it may be that
bursts of plaque activity boost immune responses, possibly by
releasing antigenic material, and give rise to titer increases.
Such episodic activity might be interspersed with periods of
slow, silent growth of lesions and fading immune activity. It
is also possible that antibodies can serve to eliminate modi-
fied lipoproteins from the circulation, thus reducing the load
of atherogenic lipoproteins in arterial lesions. Antibodies maytherefore be viewed both as markers of disease activity and as
vehicles for clearance of antigen. The situation with regard to
other antigens appears to be similar to that for modified LDL.
Anti-hsp65/60 antibodies have been positively correlated
with the progression of carotid atherosclerotic disease in an
epidemiological study,151 but more data are needed before
these assays find their place in clinical diagnostics.
Evidence That Immunity Affects Atherosclerosis
Atherosclerosis in Patients With Immune DisordersIt is by now well established that atherosclerosis is accom-
panied by adaptive immune responses and that the earlyphase of the disease is dominated by immune cells, particu-
larly macrophages. These facts do not necessarily imply that
atherosclerosis can be treated or prevented by interfering with
immune mechanisms. To clarify whether that could be
possible, it has been important to determine whether the
extent of atherosclerosis is different (reduced or increased) in
individuals with immune defects.
The situation in immune-deficient patients is complicated
and difficult to interpret. Individuals with severe combined
immune deficiencies have not survived long enough to
develop cardiovascular disease, and most of the congenital
immune deficiencies affect too few patients to make epide-miological investigations into cardiovascular disease mean-
ingful. Individuals with selective, congenital defects in the
humoral immune responses are relatively frequent, and the
clinical syndrome is compatible with life into adult age.
These patients do not exhibit any reduced heart disease,
suggesting that humoral immunity does not aggravate athero-
sclerosis.186 HIV patients, who lack CD4 T cells (and
particularly Th1 activity), develop aggressive cardiovascular
disease, particularly when modern highly active antiretroviral
treatment has been used to prevent rapid development of
AIDS.187189 However, the protease inhibitor treatment may
itself cause metabolic syndromes, and it is difficult todetermine whether the increased cardiovascular morbidity is
due to the disease or its treatment.
Some of the most remarkable data in support of a link
between immunity and atherosclerosis come from epidemio-
logical studies of patients with autoimmune disorders. Pa-
tients with rheumatoid arthritis have a 2- to 5-fold increase in
cardiovascular morbidity and mortality,190 and patients with
systemic lupus erythematosus exhibit an even higher increase
in cardiovascular disease.191,192 Although some of this mor-
bidity is clearly due to small-vessel vasculitis associated with
the underlying autoimmune disease, there is also evidence for
atherosclerotic large-vessel disease in many cases. Interest-
ingly, patients with systemic lupus erythematosus share
several autoimmune phenomena with atherosclerotic pa-
tients.193 Further studies into these aspects are clearly needed.
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Mechanistic Insights From Gene-TargetedMouse ModelsTo clarify the role for adaptive immunity in atherosclerosis, it
was necessary to generate immunodeficient animal models
(Table 4). The apoE-KO mouse was crossed with the
recombinase-activating gene-1/ (RAG-1/) mouse, which
lacks functional T and B cells due to a mutation in therearrangement machinery. The offspring exhibited a 40%
reduction of atherosclerosis, indicating that adaptive immu-
nity accelerates disease.194 However, the impact of the im-
mune defect was undetectable in cases of excessive hyper-
cholesterolemia.194,195 This could be due to either an
overwhelming effect of very high cholesterol levels or a
qualitative difference in immune activity in this metabolic
condition. The finding of a Th13Th2 switch in severehypercholesterolemia104 supports the latter conclusion. Inter-
estingly, the atheroprotective effect of estrogens was recently
found to be lacking in immunodeficient mice, suggesting that
the atheroprotective effect of estrogen depends on estrogen
action via immune mechanisms.196
Whether this involvesswitches in effector functions remains to be determined.
A more recently constructed apoE/ scid/scid mouse,
which also lacks adaptive immunity, shows an even more
striking phenotype, with a 70% reduction of disease in
immunodeficient female apoE/ scid/scidmice compared
with immunocompetent apoE/ scid/ littermates197 (Table
4). Neither the RAG nor the SCID immunodeficient mice
exhibited any changes in serum cholesterol compared with
single-KO apoE/ mice; this points to important effects on
the vascular wall rather than on systemic metabolism for the
effect on atherosclerosis.
This conclusion was further supported when immune cell
populations were transferred into the apoE/ scid/scidmice.Transfer of CD4 T cells from immunocompetent apoE/
mice to immunodeficient apoE/ scid/scidmice increased
atherosclerosis dramatically in the recipient, from 27% to 79%
of the level in fully immunocompetent apoE/ mice.197 Trans-
ferred T cells migrated to lesions and induced expression of
MHC class II genes, probably through IFN-secretion. These
data show that immune activity increases atherosclerosis and
identifies CD4 T cells as the proatherogenic subset.
In another recent study, a T-cellmediated response to avascular autoantigen was found to aggravate atherosclerosis
in apoE-KO mice.112 These mice were bred with a mouse
strain that carries the -galactosidase gene under the control
of a smooth musclespecific promotor activated by atamoxifen-inducible Cre recombinase. When such mice were
immunized by injections of dendritic cells presenting
-galactosidase, CD8 T cells were activated to specifically
recognize this antigen. Subsequent induction of
-galactosidase expression in SMCs by tamoxifen treatment
led to a lytic attack of the SMCs by antigen-specific CD8 T
cells. This resulted in a dramatic increase in atherosclerosis.
Important Roles for Immunoregulatory CellSurface MoleculesImmune activation depends on interactions between proteins
displayed on the surfaces of adjacent cells as well as onsoluble cytokines. Such proteins include adhesion molecules,
such as ICAM-1, and the more narrowly expressed pairs of
costimulatory molecules. The latter include theT-cell protein
CD28, which binds 2 alternative counterreceptors, B7.1
(CD80) and B7.2 (CD86). CD28 ligation promotes T-cell
activation, whereas ligation of B7 proteins to the alternative
T-cell surface receptor, cytotoxic T-lymphocyte antigen-4
(CTLA-4, CD152), induces a negative signal for cell-
mediated immune responses. Soluble CTLA-4 proteins have
been used to inhibit immune reactions and can preventchronic rejection of organ transplants.198 However, they do
not appear to reduce experimental atherosclerosis.
Another costimulatory molecule, CD40, is expressed by B
cells and dendritic cells and can be induced on many different
cell types. It ligates the constitutively expressed T-cell
protein, CD40 ligand (CD40L, or CD154). This interaction is
necessary for T-B cell cooperation in the induction of
antibody responses. CD40 is constitutively expressed by
endothelial cells and can be induced in both vascular endo-
thelial cells and SMCs by stimulation with proinflammatory
cytokines and IFN-.199,200 Similarly, CD40L could be in-
duced on these cells by cytokine stimulation.200 Ligation of
CD40 leads to tissue factor expression by endothelial cellsand can stimulate proteinase secretion from macrophages and
SMCs.201203 Interestingly, CD40 and CD40L are present on
vascular cells and macrophages of atherosclerotic lesions, and
their activation may be involved in the progression of
atherosclerotic disease. Recent animal experiments support
this notion (Table 4). First, anti-CD40L antibody injections
reduced fatty streak development in LDLR mice.204 Second,
CD40L/ apoE/ compound-KO mice exhibited slower
induction of lesions than did the CD40L/ apoE/ con-
trols.205 These data suggest that inhibition of the CD40
pathway might be a means of treating atherosclerosis. How-
ever, the mechanism of action for inhibitors such as anti-
CD40L antibodies remains unclear and could involve not only
immunomodulation but also direct effects on vascular cells.
Can We Prevent Atherosclerosisby Immunization?
Encouraging Experimental Data for theImmune StrategyAfter having cited a wealth of studies that establish adap-
tiveand innateimmunity as proatherogenic, it may seemtotally unrealistic to ask whether immunization, ie, deliberate
activation of specific immunity, might protect against athero-
sclerosis. However, one should consider that several infec-
tions in which cellular immunity plays a pathogenic role canbe prevented by vaccination. Experimental autoimmune dis-
eases such as experimental autoimmune encephalomyelitis
can be prevented by protective immunization. It is now
evident that entirely different immune effector responses can
be induced against the same antigen, with some important
ones elicited by local antigen release in parenchymal tissue
and others by subcutaneous or oral immunization.
As discussed, several different antigens have been impli-
cated in the pathogenesis of atherosclerosis. Interestingly,
immunization with one of them, oxLDL, can reduce disease
in several animal models141143,206,207 (Table 4), whereas
immunization with hsp65/60 or 2-GPIb aggravates lesion
development147,148,155,156 (Table 4). The reason for this appar-
ent discrepancy is not known; however, there are important
differences between the antigens. Hsp60 is an intracellular
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molecule that can be expressed on the surface of stressed
cells. OxLDL, in contrast, is an extracellular particle that is
present in the interstitial space of the intima and may even
circulate in the blood.208 It could be speculated that protective
immunization against atherosclerosis works by inducing
high-titer antibodies that increase the clearance of oxLDL by
way of Fc and C3 receptors. In support of this, the protectiveeffect of oxLDL immunization can be correlated with the titer
of T-cell dependent IgG antibodies,143 and transfer of poly-clonal immunoglobulins, which contain anti-oxLDL antibod-
ies, reduces atherosclerosis in apoE/ mice.209
The detrimental effect of immunization with hsp60 may
depend on the fact that this protein can appear on the surface of
endothelial cells and/or SMCs. This could lead to antibody
binding that is followed by complement activation and lysis of
the vascular cells. In addition, peptides derived from hsp60
synthesis might bind to MHC class I molecules, which would
permit attack by cytolytic CD8 T cells. The potential impor-
tance of the latter pathway was recently demonstrated in mice in
which an autoimmune response to a transgene expressed onSMCs led to a CD8 T-cell attack on the vessel wall and
aggravation of atherosclerosis.112 It is possible that endogenous
antigens such as hsp60 could elicit a similar attack once a
cellular immune response has developed toward the protein.
Therapeutic Potential of Vaccinationand ImmunomodulationCan we use our current knowledge about immune activity in
atherosclerosis to prevent or treat the disease? Although no such
therapy is used clinically today, there is reason for optimism.
The success in protective immunization with oxLDL as an
immunogen in experimental models suggests that this could also
be a fruitful approach in humans. However, oxLDL is aheterogeneous particle that may be unsuitable for parenteral
administration in patients. It may also be extremely difficult to
standardize to the extent that is required for vaccines. For these
reasons, it will be necessary to identify the most important B-
and T-cell epitopes on oxLDL and to test whether either of them
can be used as an immunogen with the same success as the intact
particle. If this turns out to be the case, clinical trials should be
encouraged.
Immunomodulation is also attractive as a possible therapeutic
principle. However, broadly acting immunosuppressants such as
corticosteroids and cyclosporins have undesirable, direct vascu-
lar effects that make them unsuitable for this purpose. Instead,
we should try to develop more specific immunomodulators that
act on the key mechanisms in the pathogenesis of atherosclero-
sis. Potential targets are proinflammatory lipids such as PAF and
lysophosphatidylcholine, lipoprotein-derived antigens, and sig-
nal transduction pathways leading to inflammatory innate and
adaptive immune responses.
Interestingly, certain drugs targeting lipid and carbohydrate
metabolism may also act as immunomodulators. Statins act as
repressors of MHC class IImediated T-cell activation210 andcan improve the outcome of cardiac transplantation.211 Gli-
tazones, which are agonists for peroxisome-proliferator acti-
vating receptor-, can also inhibit T-cell activation and
cytokine secretion.
212
It is tempting to speculate that some ofthe beneficial effects of these types of compounds are due to
their immuomodulatory effects rather than their action on
cholesterol or glucose metabolism.
Because the proinflammatory/Th1 pathway appears to play
a key role, interference with signal transduction molecules,
receptors, or cytokines involved in this cascade could be
interesting as a potential therapeutic approach. TNF-antag-
onists are already in clinical use for rheumatoid arthritis and
have been tested clinically for heart failure. It will be
important to determine whether they also act against athero-sclerosis. Similarly, IFN antagonists and inhibitors of the
NF-B and Janus kinase/signal transducer and activator of
transcription (Jak/STAT) pathways could turn out to be
useful. Experimental studies have already shown beneficial
effects of blockers of the costimulatory molecules CD40/
CD40L; inhibition of this or similar costimulatory proteins
might also be effective against atherosclerosis (see above).
Finally, it would be theoretically attractive to apply an
immunomodulatory treatment that promotes anti-
inflammatory immunity. This might be accomplished by
enhancing the Th2 or TGF-/Th3 effector mechanisms, for
example, or by the more general inhibition of cell-mediated
immunity that can be achieved by treatment with large dosesof polyclonal immunoglobulins.209 The latter treatment, if
useful clinically, would have to be reserved for selected cases
of rapidly accelerating atherosclerosis. However, it may point
to a useful principle for immunomodulation that could be
used to develop more defined pharmaceuticals.
To summarize, several interesting drugs and immunogens
have shown effects against atherosclerosis in experimental
systems, and an additional set of molecules is attractive from
a theoretical point of view. We should have some interesting
years ahead of us.
AcknowledgmentsOur work is supported by the Swedish Heart-Lung Foundation andScience Council (project 6816) and by the Ragnar and TorstenSderberg foundation. I thank Johan Frostegrd, Zhong-qun Yan,and Xinghua Zhou for constructive criticism.
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