Arterioscler Thromb Vasc Biol 2001 Hansson 1876 90

Immune Mechanisms in Atherosclerosis
Gran K. Hansson
Arterioscler Thromb Vasc Biol. 2001;21:1876-1890
doi: 10.1161/hq1201.100220
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
Greenville Avenue, Dallas, TX 75231
Copyright 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 1079-5642. Online ISSN: 1524-4636
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://atvb.ahajournals.org/content/21/12/1876
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the
Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which
permission is being requested is located, click Request Permissions in the middle column of the Web page
under Services. Further information about this process is available in thePermissions and Rights Question and
Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular Biology is online
at:
http://atvb.ahajournals.org//subscriptions/
Downloaded from http://atvb.ahajournals.org/ by guest on October 7, 2014
Brief Reviews
Gran K. Hansson
AbstractAtherosclerosis is an inflammatory disease. Its lesions are filled with immune cells that can orchestrate and
effect inflammatory responses. In fact, the first lesions of atherosclerosis consist of macrophages and T cells. Unstable
plaques are particularly rich in activated immune cells, suggesting that they may initiate plaque activation. We have seen
a rapid increase in the understanding of the mechanisms that govern the recruitment, differentiation, and activation of
immune cells in atherosclerosis. Experimental research has identified several candidate antigens, and there are
encouraging 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
he atherosclerotic lesion contains large numbers of immune cells, particularly macrophages and T cells. Furthermore, the disease is associated with systemic immune
responses and signs of inflammation. Histopathological and
clinical investigations point to inflammatory/immune activation of plaques as a cause of acute coronary syndromes, and
seroepidemiological studies have suggested links between
atherosclerosis and microbial infections. During recent years,
experiments in gene-targeted mice have provided mechanistic
evidence in support of the hypothesis that immune mechanisms are involved in atherosclerosis. This review will
provide an update on immune mechanisms in atherosclerosis,
with particular focus on mechanistic studies.
Immune Cells in the Lesions of Atherosclerosis

Adaptive (ie, antigen-specific) immune reactions are initiated
when a macrophage (or a dendritic cell of the macrophage
lineage) displays a surface complex consisting of an antigenic
peptide bound to a major histocompatibility complex (MHC)
protein to a neighbor T cell. This can elicit T-cell activation,
cytokine secretion, cytotoxicity, antibody production, and
many other components of an immune reaction. There is now
good evidence that atherosclerosis is associated with immune
reactions and that antigen presentation occurs in atherosclerotic lesions. The cellular composition of an atheroma is
illustrated in Figure 1. It has been known for many years that
monocyte-derived macrophages are present in large numbers
in atherosclerotic lesions.17 The discovery of the scavenger
receptor pathway for uptake of modified lipoproteins8 10
provided an explanation for the finding that most foam cells
bear macrophage differentiation markers.
The other main immune cell of atherosclerotic lesions, the
T 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 cell
surface protein that is induced by the T-cell cytokine
interferon- (IFN-).11 By using T-cellspecific CD3 antibodies, it could be established that T cells are abundant in
human plaques.12 A large proportion of them are in an
activated state1316; ie, they express adhesion molecules and
other surface molecules, secrete cytokines, and may proliferate. The activation of T cells and macrophages leads to a
cascade of cytokines that induce an inflammatory state. With
the cDNA cloning and production of recombinant cytokines,
it became possible to study their effects in the context of
vascular biology. Such studies revealed that vascular endothelial cells and SMCs are important targets for inflammatory
cytokines and that they are capable of producing significant
amounts of cytokines themselves on stimulation.17,18
Studies during the last decade have identified other types of
immune cells in atherosclerotic plaques. Among them, dendritic
cells are professional antigen-presenting cells that may be
particularly important in the initiation of immune responses to
plaque antigens.19 Mast cells are immune effector cells with a
capacity to modify lipoproteins and digest matrix components;
they could be important in plaque activation and rupture.20 All
these different cells may be involved in the initiation, progression, and/or development of complications to atherosclerosis. At
present, there is evidence for pathogenic roles of monocytederived macrophages and T cells.
Recruitment of Immune Cells to the Vessel Wall

Leukocyte Adhesion to the Endothelium
During the initiation of atherosclerosis, mononuclear leukocytes, ie, monocytes and T cells, are recruited to the vessel
wall 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
Downloaded from http://atvb.ahajournals.org/

by guest on October 7, 2014
1876
Hansson
Figure 1. Immune cells in atheroma. Macrophages (MPh) and T

cells are common components of lesions, which may also contain mast cells and occasional B cells. T cells are activated by
local antigens presented by antigen-presenting macrophages
and dendritic cells. Activation leads to production of interferon-
(IFNg), which not only primes macrophages for activation but
also regulates smooth muscle and endothelial functions. Activated macrophages produce proinflammatory cytokines such as
tumor necrosis factor- (TNFa) and IL-1, which can induce procoagulant (Coag), fibrinolytic (fibr.), and adhesive properties on
endothelial cells (EC). Macrophages also make matrix metalloproteinases (MMP), and both T cells and macrophages produce
cytotoxic factors, which contribute to apoptosis. See text for
explanation of other abbreviations.
the endothelium to express leukocyte adhesion molecules.

These cell surface proteins are mainly regulated transcriptionally in a process that involves nuclear factor (NF)-B,21 a
transcription factor that is transactivated when proinflammatory cytokines ligate their receptors on the endothelial surface. Both E-selectin and 2 imunoglobulin-like adhesion
molecules, 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 macromolecules. Lipopolysaccharides of Gram-negative bacteria activate 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 increased 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
Figure 2. Hypercholesterolemia leads to recruitment of immune

cells to the vessel wall. LDL accumulates in the arterial intima.
Lipid products of LDL oxidation induce VCAM-1 in endothelial
cells. Monocytes and T cells adhere through their VLA-4 receptors. Their subsequent migration through the endothelial layer is
stimulated by chemokines such as MCP-1 and also by complement activation products (Cpt), which can be generated by oxidized cholesterol aggregates. See text for explanation of other
abbreviations.
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 cytokinedependent 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 and
hypertension, 2 major risk factors for atherosclerosis, increase 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 lateactivation
antigen-4 (VLA-4), a major counterreceptor for VCAM-1, is
expressed by monocytes and lymphocytes but not by granulocytes.31 This explains the selective recruitment of mononuclear cells to the arterial intima during early atherosclerosis.32
Immunopharmacological blockade of ICAM-1 and VCAM-1
has 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-
TABLE 1. Animal Studies Demonstrating Important Roles for Leukocyte Adhesion and Migration
in Atherosclerosis
Molecule
Function
Experiment
Atherosclerosis Model
Result
Reference No.
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
P-, E-selectin
1877
CCR-2 indicates C-C chemokine receptor-2; PMN, polymorphonuclear leukocytes; MC, monocytes; Ly, lymphocytes; rec, receptor;
Downloaded
from http://atvb.ahajournals.org/
and Tg, transgenic. See
text for explanation
of other abbreviations.
1878
Arterioscler Thromb Vasc Biol.
December 2001
velop fewer fatty streaks when bred into an atherosclerosisprone mouse strain, the apoE-knockout (KO) mouse34,35
(Table 1).
Chemotactic Transmigration
In the classic inflammatory response, adhesion is followed by
transmigration of the leukocytes through the endothelial layer
and into the intima. This is governed by chemotactic factors
produced in the subendothelial layer. Several studies of
hypercholesterolemic rabbits and human samples show that
the complement cascade is activated subendothelially during
hypercholesterolemia.36,37 This leads to release of small,
proteolytic peptide fragments of complement proteins. Such
fragments include C5a, which is strongly chemotactic for
monocytes and may be important for the recruitment of these
cells to the intima.
Several chemotactic cytokines called chemokines are produced by endothelial cells, SMCs, and intimal macrophages
during lesion formation. The best-characterized of these
chemokines is monocyte chemotactic protein-1 (MCP-1),
which can be induced by complement activation or cytokines38,39 and promotes recruitment of monocytes and T
cells.40 42 MCP-1 is expressed in significant amounts in all
stages of atherosclerosis.40,43 When atherosclerosis-prone
mice such as apoE-KO or LDL receptor (LDLR)KO mice
were bred with mice deficient in MCP-1 or its receptors,
CCR2, lesion formation was reduced drastically44 46 (Table
1). This demonstrates that chemokine-dependent migration of
mononuclear cells into the intima is an important phenomenon in atherogenesis (Figure 2).
tor (LOX-1) is controlled by TNF- and transforming growth

factor- (TGF-).52 That cytokines regulate scavenger receptors probably reflects important roles for these receptors in
the innate host defense. Additional support for this notion is
the finding that SR-A deficient mice are highly susceptible
to infections by intracellular bacteria such as Listeria monocytogenes.53 However, SR-A can also internalize antigens,
which are routed for presentation to T cells.54,55 By binding
foreign antigens and initiating their transfer to antigenprocessing as well as degradative compartments, scavenger
receptors may be important links between innate and adaptive
immunity.
Components of oxLDL may not only be degraded or
processed for antigen presentation but also may activate the
macrophage itself. This was initially demonstrated in studies
of peripheral human monocytes and macrophage cell
lines56,57 and later confirmed in other cell culture systems.
This effect may be mediated by proinflammatory lipids acting
on specific receptors. OxLDL contains platelet-activating
factor (PAF)like lipids, which are strongly proinflammatory
and activate macrophages as well as endothelial cells.58 61 In
addition, oxLDL components might bind to signaling surface
receptors such as TLRs or nuclear receptors such as lipid X
receptors (LXR). Both of these receptor families are important in the regulation of macrophage function: TLRs mediate
macrophage activation in response to bacterial toxins,62
whereas LXRs regulate the ATP binding cassette-1 (ABCA1)
transporter and other aspects of cholesterol metabolism in the
macrophage.63
T-Cell Types and Their Functions
Cellular Immunity of Atherosclerotic Lesions
Important Role for Th1 Cells and Their Cytokines

Most of the T cells in atherosclerotic lesions are CD3 CD4
T-cell receptor (TCR) cells12,15 (Table 3). This implies
that they recognize protein antigens presented to them by
Macrophages are major players in inflammation and innate
macrophages after uptake and processing through the endo(ie, antigen-independent) immune responses. These actions
somal pathway (Figure 3). Such cells represent approximately
largely depend on their capacity to produce free oxygen
two thirds of all CD3 T cells in advanced human lesions and
radicals, proteases, complement factors, and cytokines. Immost of the T cells in lesions of apoE-KO mice. Many of the
portantly, the macrophage may also initiate adaptive immune
cells exhibit surface markers indicative of a population of
responses by presenting foreign antigens to T cells. All these
memory cells in a state of chronic activation.15 They are
activities may be important in atherogenesis.
largely of the T-helper (Th1) subtype, which secretes IFN-,
The differentiation from monocyte to macrophage is govIL-2, and TNF- and -, which cause macrophage activation,
erned by macrophage colony stimulating factor (M-CSF), a
vascular activation, and inflammation.64 At least 2 important
cytokine that is produced not only by macrophages but also
stimuli for Th1 differentiation are present in the atheroscleby vascular and stromal cells. Lack of M-CSF prevents
rotic plaque. The cytokine IL-12, which is produced by many
macrophage differentiation, the consequences of which can
lesion cells, is an important stimulus for Th1 differentiation.65
be observed in many different organs. A striking phenotype
Osteopontin, also called early T-lymphocyte activation
of the M-CSF deficient op/op mouse is the lack of osteprotein-1 (Eta-1), is needed for Th1 responses and promotes
oclasts, which prevents bone remodeling and leads to the
IL-12 expression and granuloma formation.66 It is expressed
disease osteopetrosis. The op/op phenotype is also characterby macrophages, endothelial cells, and SMCs in plaques67,68
ized by a lack of macrophages in tissues. When op/op mice
and may be important for local immunity as well as for
were mated with apoE-KO mice, the offspring developed
mineralization.
very little atherosclerosis despite high cholesterol levels in
IFN- is an important immune-activating cytokine that can
the blood.47 This demonstrates that macrophage differentiaprime macrophages for activation and induce inflammatory
tion is necessary for atherosclerosis.
responses such as those observed in delayed-type hypersenMacrophage uptake of modified lipoproteins by way of
sitivity and granulomatous lesions (Table 2). It has been
scavenger receptors is tightly regulated by cytokines (Table 2
detected in human plaques, both on the mRNA and protein
and Figure 1). IFN-, tumor necrosis factor- (TNF-), and
levels.13,64 Cell culture studies have shown it to be a powerful
IL-6 downregulate scavenger receptor-A (SR-A),48 50 IL-4
51
by guest
on October
7, 2014 cells and SMCs.69,70 In
lectinlike, oxidized
LDL recepupregulates CD36, and the Downloaded
growth
inhibitor
for endothelial
Macrophages: Scavenging, Secretory, and

Antigen-Presenting Cells
Hansson
TABLE 2.
1879
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
IL-4
Th2
OxLDL uptake
216
Th1, M, SMC
2 OxLDL uptake
4850
1 NO
217, 218
2 NO
101
1 Eicosanoids
219
CD36
SR-A
IFN-, TNF-, IL-6
NOS2
IFN-, TNF-, IL-1
NOS2
IL-4
COX2
IFN-, TNF-, IL-1
Th1, M, SMC, EC M, SMC, EC

Th2
M, SMC, EC
M, Th1, SMC, EC M, SMC, EC
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
Activ
222
IL-1
M, EC, SMC
SMC
B-cell activ, PTX prod
92
MMPs
TNF-, IL-1, CD40L*
M, SMC, EC
Proteolysis
84, 201, 223, 224
MMPs
IFN-
Th1
M, SMC, EC
2 Proteolysis
84, 201
TNF-, IL-1
M, EC, SMC
EC
1 Fibrinolysis
225
IFN-
Th1
EC
2 Fibrinolysis
226
IFN-, TNF-, IL-1
M, Th1
EC
Antifibrinolysis
227
IL-4
Th2
1 CD36 expression
228
ApoA-IV
IFN-
Th1
Hepatocytes
2 HDL
77
ABCA1
IFN-
Th1
M foam cells
2 Cholesterol efflux
229
IFN-
Th1
SMC
1 Eicosanoids, PAF, lysoPC
71
IFN-, TNF-, IL-1
M, Th1
2 Lipolysis
86, 87
IL-6
tPA, uPA
uPA
PAI-1, -2
PPAR-dep genes
sPLA2
LPL
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.
addition, IFN- induces expression of secretory phospholipase 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-producing T cells could play an important role in plaque destabilization 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
TABLE 3.
antiatherogenic action. However, IFN- was recently shown

to aggravate transplant vasculopathy by its local action on the
vessel wall.78 Even in severe combined-immunodeficient
(SCID) mice, IFN- induced vascular pathology in xenografts, indicating that its direct vascular actions are sufficient
to promote disease. Finally, recent experiments have shown
that administration of this cytokine accelerates atherosclerosis in apoE-KO mice.79 All these data imply that IFN- is a
proatherogenic cytokine.
Proinflammatory Cytokines: Mediators of Innate and
Th1 Responses
TNF- 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 platelet-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
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
CD8
TCR
Peptide
MHC class II
Yes
Yes
MHC class I
Yes
TCR
Lipid
Yes
CD1
Yes
No
fromexp,
http://atvb.ahajournals.org/
by guestofon
October
7, 2014
recDownloaded
indicates receptor;
experimental. See text for explanation
other
abbreviations.
1880
December 2001
Figure 3. Antigen presentation of modified lipoproteins. When

LDL is modified, eg, by oxidation, it is transformed into an
autoantigen. Uptake by scavenger receptors (SR) leads to intracellular processing in macrophages (MPh) and presentation of
peptide fragments on MHC class II molecules (MHC-II). T cells
that carry the appropriate antigen receptors (TCR) are activated
by contact to the MHC-II:peptide complex in the presence of
costimulatory factors (co-stim) such as CD4, CD40, and B7
molecules. This results in T-cell activation, with proliferation and
cytokine secretion.
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 energy
metabolism. 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, redistribution of adipose tissue, and reduced insulin sensitivity.87 89
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
TABLE 4.
(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 inflammation 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 CRP
production 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 scavenger 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-12
secretion.65 There may be a corresponding IL-10 damper of
the Th1 response, because IL-10 containing areas of human
plaques exhibit reduced apoptosis and expression of inflammatory 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
Effects of Immune Deficiency and Immunomodulation on Atherosclerosis

Immune
Defect
Immune Phenotype
Compound KO
RAG-1
Compound KO
RAG-2
Compound KO
Compound KO
Experiment
Atherosclerosis
Model
Effect on
Disease
Reference
No.
SCID
ApoE
2 Athero
194
SCID
ApoEfatty diet
No effect
195
SCID/SCID
SCID
ApoE
2 Athero
197
IFN- rec
Defective Th1
ApoE
2 Athero
77
IvIg inj
Immunosuppression
ApoE
2 Athero
209
Anti-CD40 inj
Immunosuppression
LDLR
2 Athero
204
Reduced immune activation
ApoE
2 Athero
205
Increased Th1
ApoE
1 Athero
79
Compound KO
CD40L
IFN- inj
KO on B6 background TNF- rec
KO on B6 background
IL-10
Defective inflammation
Fat feeding
2 Fatty streaks
230
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.
Hansson
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 of
6 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 inflammation. Several different cell types, including macrophages,
SMCs, and Th3 cells, can express TGF-, which might be
important for plaque stabilization. The SMC growthpromoting 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 and
regulation of Th pathways in atherosclerosis require further
studies.
CD8 Cells and T Cells: Additional Players in

the 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 foreign
antigen 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 stimulation 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 in
atherosclerosis.
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 recognition of complex lipids as antigens. TCR binds such
antigens, which are presented on CD1 rather than MHC
proteins. The capacity of T 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 lesions,116,117 but their role remains unclear.
1881
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 can
be found.120,121 In humans as well as animals, IgG accumulation 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 of
plaque rupture.123125 Factors released from mast cells may
degrade the extracellular matrix126 and could also influence
the functions of surrounding cells and modify locally deposited 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 may patrol tissues such as the artery
wall 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 Local
Immune Activation
The antigen specificity of T cells is encoded in the sequence

of their rearranged TCR genes, which determine the conformation of the antigen-binding site in the CDR3 domain of the
TCR protein.129 Because the rearrangement process is stochastic, 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. The
presence 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).
Other Immune Cells May Also Participate in the
In human lesions, the situation is more complex. A
Local Immune Response
heterogeneous population of TCRs and therefore, of T cells is
The 2 other types of lymphocytes, B cells and natural killer
131 and7,the
Downloaded
on October
2014
enormous allelic variation in
(NK) cells, are less frequent in
atherosclerotic
lesions than T
foundbyinguest
lesions,
1882

TABLE 5.
Antigen
December 2001
Candidate Antigens in Atherosclerosis

Type
Processing
Presentation
Recognition
Effect of Immun.
OxLDL
Autoantigen
Endosomal
MHC-II
CD4 T (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
Virus
Cytosolic
MHC-I
CD8
CMV
C pneum indicates Chlamydia pneumoniae; CMV, cytomegalovirus; and immun, immunization. See text for
explanation of other abbreviations.
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 Autoantigen
Heat Shock Proteins Are Common Autoantigens in

Inflammatory Disease
Heat shock proteins have also been implicated in the pathogenesis 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 injury,145 and serve as targets for autoimmune responses in many
inflammatory diseases. Interestingly, heat shock proteins are
also released by monocytes exposed to oxLDL.146 Antibodies
to heat shock protein 60 (hsp60) and its prokaryotic homologue 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 atherosclerotic disease.151 Because heat shock proteins of humans and microbes are structurally and antigenically similar,
it is possible that molecular mimicry between immune responses 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 present 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 in
LDLR/ mice.156 The pathogenetic mechanism by which
2-GPI acts remains unclear, but it may be related to this
proteins capacity to bind phospholipids.
Antibodies 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, and
challenged 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 oxLDL in an HLA-DR dependent manner. OxLDL-specific T
cells 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 react
with an antigen, eg, in ELISA or Western blot analyses. With
this approach, it was demonstrated that IgGs of atherosclerotic lesions contain antibodies reactive with oxLDL.134 The
antigens, ie, LDL carrying various kinds of oxidative modifications, could be demonstrated in the lesions by immunostaining and Western blot. Therefore, oxLDL is an autoantigen that is formed in the lesion, and it elicits a local cellular
A Role for Phospholipid Antibodies
as well as a humoral immune response.
in Atherosclerosis?
The immune response to oxLDL plays a pathogenetic role
Antibodies reacting with phospholipids such as cardiolipin
in atherosclerosis because lesion progression can be inhibited
are associated with recurrent thrombosis157 and accelerated
by immunization141143 or induction of neonatal tolerance to
atherosclerosis.158 Many of these antibodies recognize
oxLDL.137 It seems paradoxical that both tolerization and
phospholipid-binding plasma proteins such as -GPI,159 and
hyperimmunization can reduce the extent of disease; this may
it could be speculated that 2-GPI affects atherosclerosis by
be due to the different effector pathways activated by these
targeting immune responses to membrane lipids. InterestDownloaded from http://atvb.ahajournals.org/
guest onset
October
7, 2014
ingly,byanother
of phospholipid
antibodies recognizes
two kinds of treatment.
Hansson
oxidized phospholipids in oxLDL160 and may represent natural antibodies that appear in early life and also bind
phospholipids on apoptotic cells and certain bacteria.161
Perhaps pathogenic immune responses are due to molecular
mimicry between oxLDL and modified lipids on microbes
and apoptotic cells.
Microbes as Antigens in Atherosclerosis

In 1988, Saikku et al162 discovered that patients with cardiovascular diseases often have high-titer antibodies to Chlamydia
pneumoniae (Table 5). This common pathogen can cause pneumonia, but it has also been associated with a variety of other
chronic diseases. Further investigations revealed that C pneumoniae survives 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 involved in atherosclerosis. However, the extent of C pneumoniae
infiltrates in lesions remains controversial,166 as does the importance of C pneumoniae infection as an aggravating factor in
experimental atherosclerosis.167170 It therefore remains to be
clarified how important C pneumoniae is for disease development 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 cholesterolinduced atherosclerosis in chickens. Cytomegalovirus has been
linked to transplant arteriosclerosis174,175 and may also be associated with garden-variety atherosclerosis and restenosis after
angioplasty.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 scavenger
receptor expression, which may be important in vascular pathology.179 However, it appears that direct action of the virus, rather
than immune responses against it, is playing the important
pathogenic role.
1883
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 modified lipoproteins from the circulation, thus reducing the load
of atherogenic lipoproteins in arterial lesions. Antibodies may
therefore 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 Disorders
It is by now well established that atherosclerosis is accompanied by adaptive immune responses and that the early
phase of the disease is dominated by immune cells, particularly 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 epidemiological investigations into cardiovascular disease meaningful. 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,
Systemic Immune Responses and Serodiagnosis
suggesting that humoral immunity does not aggravate atheroSystemic humoral immune responses are characteristic for
sclerosis.186 HIV patients, who lack CD4 T cells (and
atherosclerotic disease in humans and experimental models.
particularly Th1 activity), develop aggressive cardiovascular
Antibodies to oxidatively modified LDL are commonly found in
disease, particularly when modern highly active antiretroviral
patients; as expected from the incidence of silent disease, they
treatment has been used to prevent rapid development of
are frequent also in healthy individuals.133,180 Immunodominant
AIDS.187189 However, the protease inhibitor treatment may
epitopes in modified LDL include malondialdehyde-conjugated
itself cause metabolic syndromes, and it is difficult to
and 4-hydroxynonenal conjugated lysine residues.139,181 These
determine whether the increased cardiovascular morbidity is
modifications are generated by enzymatic or nonenzymatic
due to the disease or its treatment.
attack on fatty acid residues, which leads to release of reactive
Some of the most remarkable data in support of a link
aldehydes that can bind to the polypeptide chain of apoB-100.
between immunity and atherosclerosis come from epidemioOther B-cell epitopes on oxLDL include oxidized phospholipids
logical studies of patients with autoimmune disorders. Pasuch as phosphorylcholine, which is also present on several
tients with rheumatoid arthritis have a 2- to 5-fold increase in
microbes and apoptotic cells and is recognized by natural
cardiovascular morbidity and mortality,190 and patients with
161
antibodies present in most individuals.
systemic lupus erythematosus exhibit an even higher increase
Anti-oxLDL antibody titers are correlated with the proin cardiovascular disease.191,192 Although some of this mor133,182
gression of advanced atherosclerosis in some studies,
bidity is clearly due to small-vessel vasculitis associated with
whereas others have been unable to find any such correlation.
the underlying autoimmune disease, there is also evidence for
Interestingly, titers are correlated negatively with early caratherosclerotic large-vessel disease in many cases. Interestdiovascular diseases, including borderline hypertension and
ingly, patients with systemic lupus erythematosus share
carotid intima/media thickening.183185 It appears that no
several autoimmune phenomena with atherosclerotic pasimple, positive correlation occurs between antibodies and
193guest
on October
7, 2014
disease throughout its naturalDownloaded
history. Instead,
it may be that
Further
studies into
these aspects are clearly needed.
tients.by
1884
December 2001
Mechanistic Insights From Gene-Targeted

Mouse Models
To 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 the
rearrangement machinery. The offspring exhibited a 40%
reduction of atherosclerosis, indicating that adaptive immunity accelerates disease.194 However, the impact of the immune defect was undetectable in cases of excessive hypercholesterolemia.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 Th13 Th2 switch in severe
hypercholesterolemia104 supports the latter conclusion. Interestingly, 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 involves
switches 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/scid mice 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/scid mice.
Transfer of CD4 T cells from immunocompetent apoE/
mice to immunodeficient apoE/ scid/scid mice increased
atherosclerosis dramatically in the recipient, from 27% to 79%
of the level in fully immunocompetent apoE/ mice.197 Transferred 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 a
vascular 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 a
tamoxifen-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.
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 cellmediated immune responses. Soluble CTLA-4 proteins have
been used to inhibit immune reactions and can prevent
chronic 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 endothelial cells and SMCs by stimulation with proinflammatory
cytokines and IFN-.199,200 Similarly, CD40L could be induced on these cells by cytokine stimulation.200 Ligation of
CD40 leads to tissue factor expression by endothelial cells
and 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/ controls.205 These data suggest that inhibition of the CD40
pathway might be a means of treating atherosclerosis. However, the mechanism of action for inhibitors such as antiCD40L antibodies remains unclear and could involve not only
immunomodulation but also direct effects on vascular cells.
Can We Prevent Atherosclerosis

by Immunization?
Encouraging Experimental Data for the
Immune Strategy
After having cited a wealth of studies that establish adaptiveand innateimmunity as proatherogenic, it may seem
totally unrealistic to ask whether immunization, ie, deliberate
activation of specific immunity, might protect against atherosclerosis. However, one should consider that several infections in which cellular immunity plays a pathogenic role can
be prevented by vaccination. Experimental autoimmune diseases 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 implicated in the pathogenesis of atherosclerosis. Interestingly,
Important Roles for Immunoregulatory Cell
immunization with one of them, oxLDL, can reduce disease
Surface Molecules
in several animal models141143,206,207 (Table 4), whereas
Immune activation depends on interactions between proteins
immunization with hsp65/60 or 2-GPIb aggravates lesion
displayed on the surfaces of adjacent cells as well as on
development147,148,155,156 (Table 4). The reason for this apparsoluble cytokines. Such proteins include adhesion molecules,
ent discrepancy is not known; however, there are important
such as ICAM-1, and the more narrowly expressed pairs of
from
by guest
on October
2014 Hsp60 is an intracellular
costimulatory molecules. TheDownloaded
latter include
thehttp://atvb.ahajournals.org/
T-cell protein
differences
between
the 7,
antigens.
Hansson
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 protective
effect of oxLDL immunization can be correlated with the titer
of T-cell dependent IgG antibodies,143 and transfer of polyclonal immunoglobulins, which contain anti-oxLDL antibodies, 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 importance of the latter pathway was recently demonstrated in mice in
which an autoimmune response to a transgene expressed on
SMCs 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 Vaccination

and Immunomodulation
1885
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- antagonists 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 atherosclerosis. 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 antiinflammatory 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 doses
of 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.
Can 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
Acknowledgments
be a fruitful approach in humans. However, oxLDL is a
Our work is supported by the Swedish Heart-Lung Foundation and
heterogeneous particle that may be unsuitable for parenteral
Science Council (project 6816) and by the Ragnar and Torsten
administration in patients. It may also be extremely difficult to
Sderberg foundation. I thank Johan Frostegrd, Zhong-qun Yan,
and Xinghua Zhou for constructive criticism.
standardize to the extent that is required for vaccines. For these
reasons, it will be necessary to identify the most important BReferences
and T-cell epitopes on oxLDL and to test whether either of them
1. Poole JCF, Florey HW. Changes in the endothelium of the aorta and the
can be used as an immunogen with the same success as the intact
behaviour of macrophages in experimental atheroma of rabbits. J Pathol
particle. If this turns out to be the case, clinical trials should be
Bacteriol. 1958;75:245252.
encouraged.
2. Schaffner T, Taylor K, Bartucci EJ, Fischer DK, Beeson JH, Glagov S,
Wissler RW. Arterial foam cells with distinctive immunomorphologic and
Immunomodulation is also attractive as a possible therapeutic
histochemical features of macrophages. Am J Pathol. 1980;100:5780.
principle. However, broadly acting immunosuppressants such as
3. Fowler S, Shio H, Haley NJ. Characterization of lipid-laden aortic cells from
corticosteroids and cyclosporins have undesirable, direct vascucholesterol-fed rabbits, IV: investigation of macrophage-like properties of
lar effects that make them unsuitable for this purpose. Instead,
aortic cell populations. Lab Invest. 1979;41:372378.
4. Gerrity RG. The role of the monocyte in atherogenesis, I: transition of
we should try to develop more specific immunomodulators that
blood-borne monocytes into foam cells in fatty lesions. Am J Pathol.
act on the key mechanisms in the pathogenesis of atherosclero1981;103:181190.
sis. Potential targets are proinflammatory lipids such as PAF and
5. Gerrity RG. The role of the monocyte in atherogenesis, II: migration of
lysophosphatidylcholine, lipoprotein-derived antigens, and sigfoam cells from atherosclerotic lesions. Am J Pathol. 1981;103:191200.
6. Faggiotto A, Ross R. Studies of hypercholesterolemia in the nonhuman
nal transduction pathways leading to inflammatory innate and
primate, I: changes that lead to fatty streak formation. Arteriosclerosis.
adaptive immune responses.
1984;4:323340.
Interestingly, certain drugs targeting lipid and carbohydrate
7. Faggiotto A, Ross R. Studies of hypercholesterolemia in the nonhuman
metabolism may also act as immunomodulators. Statins act as
primate, II: fatty streak conversion to fibrous plaque. Arteriosclerosis. 1984;
4:341356.
repressors of MHC class IImediated T-cell activation210 and
8. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol
can improve the outcome of cardiac transplantation.211 Glihomeostasis. Science. 1986;232:3447.
tazones, which are agonists for peroxisome-proliferator acti9. Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA.
vating receptor-, can also inhibit T-cell activation and
Malondialdehyde alteration of low density lipoproteins leads to cholesteryl
ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci
cytokine secretion.212 It is tempting to speculate that some of
U S A. 1980;77:22142218.
the beneficial effects of these types of compounds are due to
10. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond
their immuomodulatory effects rather than their action on
cholesterol: modifications of low-density lipoprotein that increase its atheroDownloaded from http://atvb.ahajournals.org/genicity.
by guest
on October
7, 2014
N Engl
J Med. 1989;320:915924.
cholesterol or glucose metabolism.
1886
December 2001
11. Jonasson L, Holm J, Skalli O, Gabbiani G, Hansson GK. Expression of class

34. Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD.
II transplantation antigen on vascular smooth muscle cells in human athThe combined role of P- and E-selectins in atherosclerosis. J Clin Invest.
erosclerosis. J Clin Invest. 1985;76:125131.
1998;102:145152.
12. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accu35. Dong ZM, Brown AA, Wagner DD. Prominent role of P-selectin in the
mulations of T cells, macrophages, and smooth muscle cells in the human
development of advanced atherosclerosis in ApoE-deficient mice. Circuatherosclerotic plaque. Arteriosclerosis. 1986;6:131138.
lation. 2000;101:22902295.
13. Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in
36. Seifert PS, Hugo F, Hansson GK, Bhakdi S. Prelesional complement actithe human atherosclerotic plaque. Am J Pathol. 1989;135:169175.
vation in experimental atherosclerosis: terminal C5b-9 complement depo14. van der Wal AC, Das PK, van de Berg DB, van der Loos CM, Becker AE.
sition coincides with cholesterol accumulation in the aortic intima of hyperAtherosclerotic lesions in humans: in situ immunophenotypic analysis sugcholesterolemic rabbits. Lab Invest. 1989;60:747754.
gesting an immune mediated response. Lab Invest. 1989;61:166170.
37. Seifert PS, Hugo F, Tranum-Jensen J, Zahringer U, Muhly M, Bhakdi S.
15. Stemme S, Holm J, Hansson GK. T lymphocytes in human atherosclerotic
Isolation and characterization of a complement-activating lipid extracted
plaques are memory cells expressing CD45RO and the integrin VLA-1.
from human atherosclerotic lesions. J Exp Med. 1990;172:547557.
Arterioscler Thromb. 1992;12:206211.
38. Wang JM, Sica A, Peri G, Walter S, Padura IM, Libby P, Ceska M, Lindley
16. Kishikawa H, Shimokama T, Watanabe T. Localization of T lymphocytes
I, Colotta F, Mantovani A. Expression of monocyte chemotactic protein and
and macrophages expressing IL-1, IL-2 receptor, IL-6 and TNF in human
interleukin-8 by cytokine-activated human vascular smooth muscle cells.
aortic intima: role of cell-mediated immunity in human atherogenesis.
Arterioscler Thromb. 1991;11:11661174.
Virchows Arch A Pathol Anat Histopathol. 1993;423:433 442.
39. Torzewski J, Oldroyd R, Lachmann P, Fitzsimmons C, Proudfoot D,
17. Pober JS, Collins T, Gimbrone MA Jr, Cotran RS, Gitlin JD, Fiers W,
Bowyer D. Complement-induced release of monocyte chemotactic
Clayberger C, Krensky AM, Burakoff SJ, Reiss CS. Lymphocytes recprotein-1 from human smooth muscle cells: a possible initiating event in
ognize human vascular endothelial and dermal fibroblast Ia antigens
atherosclerotic lesion formation. Arterioscler Thromb Vasc Biol. 1996;16:
induced by recombinant immune interferon. Nature. 1983;305:726729.
673677.
18. Warner S, Auger KR, Libby P. Interleukin-1 induces interleukin-1, II:
40. Mackay CR. Chemokine receptors and T cell chemotaxis. J Exp Med.
recombinant human interleukin-1 induces interleukin-1 production by adult
1994;184:799802.
human vascular endothelial cells. J Immunol. 1987;139:19111917.
41. Terkeltaub R, Boisvert WA, Curtiss LK. Chemokines and atherosclerosis.
19. Bobryshev YV, Lord RSA. S-100 positive cells in human arterial intima and
Curr Opin Lipidol. 1998;9:397405.
in atherosclerotic lesions. Cardiovasc Res. 1995;29:689 696.
42. Weber KS, Draude G, Erl W, de Martin R, Weber C. Monocyte arrest and
20. Kaartinen M, Penttil A, Kovanen PT. Accumulation of activated mast cells
transmigration on inflamed endothelium in shear flow is inhibited by
in the shoulder region of human coronary atheroma, the predilection site of
adenovirus-mediated gene transfer of IB-. Blood. 1999;93:36853693.
43. Yl-Herttuala S, Lipton BA, Rosenfeld ME, Sarkioja T, Yoshimura T,
atheromatous rupture. Circulation. 1994;90:1669 1678.
Leonard EJ, Witztum JL, Steinberg D. Expression of monocyte chemoat21. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T.
tractant protein 1 in macrophage-rich areas of human and rabbit atheroTranscriptional regulation of endothelial cell adhesion molecules: NF-B
and cytokine-inducible enhancers. FASEB J. 1995;9:899909.
sclerotic lesions. Proc Natl Acad Sci U S A. 1991;88:52525256.
22. Kume N, Cybulsky MI, Gimbrone MA. Lysophosphatidylcholine, a com44. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ.
ponent of atherogenic lipoproteins, induces mononuclear leukocyte
Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in
adhesion molecules in cultured human and rabbit arterial endothelial cells.
low density lipoprotein receptor-deficient mice. Mol Cell. 1998;2:275281.
J Clin Invest. 1992;90:11381144.
45. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in
23. Watson AD, Leitinger N, Navab M, Faull KF, Hrkk S, Witztum JL,
CCR2-/- mice reveals a role for chemokines in the initiation of atherosclePalinski W, Schwenke D, Salomon RG, Sha W, Subbanagounder G,
rosis. Nature. 1998;394:894897.
Fogelman AM, Berliner JA. Structural identification by mass spectrometry
46. Gosling J, Slaymaker S, Gu L, Tseng S, Zlot CH, Young SG, Rollins BJ,
of oxidized phospholipids in minimally oxidized low density lipoprotein
Charo IF. MCP-1 deficiency reduces susceptibility to atherosclerosis in
that induce monocyte/endothelial interactions and evidence for their
mice that overexpress human apolipoprotein B. J Clin Invest. 1999;103:
presence in vivo. J Biol Chem. 1997;272:1359713607.
773778.
24. Frostegrd J, Haegerstrand A, Gidlund M, Nilsson J. Biologically modified
47. Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M. Decreased
LDL increases the adhesive properties of endothelial cells. Atherosclerosis.
atherosclerosis in mice deficient in both macrophage colony-stimulating
1991;90:119126.
factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A. 1995;92:
25. Cybulsky MI, Gimbrone MA. Endothelial expression of a mononuclear
82648268.
leukocyte adhesion molecule during atherosclerosis. Science. 1991;251:
48. Geng YJ, Hansson GK. Interferon- inhibits scavenger receptor expression
and foam cell formation in human monocyte-derived macrophages. J Clin
788 791.
Invest. 1992;89:13221330.
26. Li H, Cybulsky MI, Gimbrone MA, Libby P. An atherogenic diet rapidly
49. Van Lenten BJ, Fogelman AM. Lipopolysaccharide-induced inhibition of
induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion
scavenger receptor expression in human monocyte-macrophages is
molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993;13:
mediated through tumor necrosis factor-. J Immunol. 1992;148:112116.
197204.
50. Liao HS, Matsumoto A, Itakura H, Doi T, Honda M, Kodama T, Geng YJ.
27. Walpola PL, Gotlieb AI, Cybulsky MI, Langille BL. Expression of ICAM-1
Transcriptional inhibition by interleukin-6 of the class A macrophage
and VCAM-1 and monocyte adherence in arteries exposed to altered shear
scavenger receptor in macrophages derived from human peripheral
stress. Arterioscler Thromb Vasc Biol. 1995;15:210.
monocytes and the THP-1 monocytic cell line. Arterioscler Thromb Vasc
28. Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of
Biol. 1999;19:18721880.
VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in
51. Silverstein RL, Febbraio M. CD36 and atherosclerosis. Curr Opin Lipidol.
the apoE-deficient mouse. Arterioscler Thromb Vasc Biol. 1998;18:
2000;11:483491.
842851.
52. Nagase M, Abe J, Takahashi K, Ando J, Hirose S, Fujita T. Genomic
29. Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial
organization and regulation of expression of the lectin-like oxidized lowcells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol.
density lipoprotein receptor (LOX-1) gene. J Biol Chem. 1998;273:
1998;18:677 685.
3370233707.
30. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte
53. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M, Jishage K, Ueda
emigration: the multistep paradigm. Cell. 1994;76:301314.
O, Sakaguchi H, Higashi T, Suzuki T, Takashima Y, Kawabe Y, Cynshi O,
31. Hemler ME. VLA proteins in the integrin family: structures, functions, and
Wada Y, Honda M, Kurihara H, Aburatani H, Doi T, Matsumoto A, Azuma
their role on leukocytes. Annu Rev Immunol. 1990;8:365400.
S, Noda T, Toyoda Y, Itakura H, Yazaki Y, Kodama T, et al. A role for
32. Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ, Ley K.
macrophage scavenger receptors in atherosclerosis and susceptibility to
Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear
infection. Nature. 1997;386:292296.
cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient
54. Abraham R, Choudhury A, Basu SK, Bal V, Rath S. Disruption of T cell
mice. Circ Res. 1999;84:12371244.
tolerance by directing a self antigen to macrophage-specific scavenger
33. Nie Q, Fan J, Haraoka S, Shimokama T, Watanabe T. Inhibition of monoreceptors. J Immunol. 1997;158:40294035.
nuclear cell recruitment in aortic intima by treatment with anti-ICAM-1 and
55. Nicoletti A, Caligiuri G, Trnberg I, Kodama T, Stemme S, Hansson GK.
anti-LFA-1 monoclonal antibodies in hypercholesterolemic rats: impliThe macrophage scavenger receptor type A directs modified proteins to
cations of the ICAM-1 and LFA-1 pathway in atherogenesis. Lab Invest.
Downloaded from http://atvb.ahajournals.org/antigen
by guest
on October
2014 1999;29:512521.
presentation.
Eur J 7,
Immunol.
1997;77:469482.
Hansson
1887
78. Tellides G, Tereb DA, Kirkiles-Smith NC, Kim RW, Wilson JH, Schechner
56. Frostegrd J, Nilsson J, Haegerstrand A, Hamsten A, Wigzell H, Gidlund
JS, Lorber MI, Pober JS. Interferon- elicits arteriosclerosis in the absence
M. Oxidized low density lipoprotein induces differentiation and adhesion of
of leukocytes. Nature. 2000;403:207211.
human monocytes and the monocytic cell line U937. Proc Natl Acad Sci
79. Whitman SC, Ravisankar P, Elam H, Daugherty A. Exogenous interferon-
U S A. 1990;87:904908.
enhances atherosclerosis in apolipoprotein E-/- mice. Am J Pathol. 2000;
57. Jovinge S, Ares MPS, Kallin B, Nilsson J. Human monocytes/macrophages
157:18191824.
release TNF- in response to ox-LDL. Arterioscler Thromb Vasc Biol.
80. Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS.
1996;16:15731579.
Detection and localization of tumor necrosis factor in human atheroma.
58. Lehr HA, Seemuller J, Hubner C, Menger MD, Messmer K. Oxidized
Am J Cardiol. 1990;65:297302.
LDL-induced leukocyte/endothelium interaction in vivo involves the
81. Moyer CF, Sajuthi D, Tulli H, Williams JK. Synthesis of IL-1 and IL-1
receptor for platelet-activating factor. Arterioscler Thromb. 1993;13:
by arterial cells in atherosclerosis. Am J Pathol. 1992;138:951960.
10131018.
82. Libby P, Warner S, Friedman GB. Interleukin-1: a mitogen for human
59. Watson AD, Navab M, Hama SY, Sevanian A, Prescott SM, Stafforini DM,
vascular smooth muscle cells that induces the release of growth-inhibitory
McIntyre TM, Du BN, Fogelman AM, Berliner JA. Effect of platelet
prostanoids. J Clin Invest. 1988;81:487498.
activating factor-acetylhydrolase on the formation and action of minimally
83. Tingstrm A, Reuterdahl C, Lindahl P, Heldin CH, Rubin K. Expression of
oxidized low density lipoprotein. J Clin Invest. 1995;95:774782.
platelet-derived growth factor- receptors on human fibroblasts: regulation
60. Frostegrd J, Huang YH, Ro nnelid J, Scha fer-Elinder L. Platelet-activating
by recombinant platelet-derived growth factor-BB, IL-1, and tumor necrosis
factor and oxidized LDL induce immune activation by a common
factor-. J Immunol. 1992;148:546554.
mechanism. Arterioscler Thromb Vasc Biol. 1997;17:963968.
84. Sarn P, Welgus HG, Kovanen PT. TNF- and IL-1 selectively induce
61. Huang YH, Scha fer-Elinder L, Wu R, Claesson HE, Frostegrd J. Lysoexpression of 92-kDa gelatinase by human macrophages. J Immunol. 1996;
phosphatidylcholine (LPC) induces proinflammatory cytokines by a plate157:41594165.
let-activating factor (PAF) receptor-dependent mechanism. Clin Exp
85. Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A. Purification of
Immunol. 1999;116:326331.
cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin62. Wright SD. Toll, a new piece in the puzzle of innate immunity. J Exp Med.
induced RAW 264.7 cells. J Exp Med. 1985;161:984995.
1999;189:605 609.
86. Beutler BA, Cerami A. Recombinant interleukin 1 suppresses lipoprotein
63. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the
lipase activity in 3T3-L1 cells. J Immunol. 1985;135:39693971.
ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem.
87. Tracey KJ, Cerami A. Metabolic responses to cachectin/TNF: a brief
2000;275:2824028245.
review. Ann N Y Acad Sci. 1990;587:325331.
64. Frostegrd J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U,
88.
Nilsson J, Jovinge S, Niemann A, Reneland R, Lithell H. Relation between
Hansson GK. Cytokine expression in advanced human atherosclerotic
plasma tumor necrosis factor- and insulin sensitivity in elderly men with
plaques: dominance of pro-inflammatory (Th1) and macrophagenoninsulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol.
stimulating cytokines. Atherosclerosis. 1999;145:33 43.
1998;18:11991202.
65. Uyemura K, Demer LL, Castle SC, Jullien D, Berliner JA, Gately MK,
89. Jovinge S, Hamsten A, Tornvall P, Proudler A, Bvenholm P, Ericsson CG,
Warrier RR, Pham N, Fogelman AM, Modlin RL. Cross-regulatory roles of
Godsland I, de Faire U, Nilsson J. Evidence for a role of tumor necrosis
interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest. 1996;97:
factor- in disturbances of triglyceride and glucose metabolism predis21302138.
posing to coronary heart disease. Metabolism. 1998;47:113118.
66. Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M,
90. Introna M, Mantovani A. Early activation signals in endothelial cells:
Zawaideh S, Rittling SR, Denhardt DT, Glimcher MJ, Cantor H. Eta-1
stimulation by cytokines. Arterioscler Thromb Vasc Biol. 1997;17:
(osteopontin): an early component of type-1 (cell-mediated) immunity.
423428.
Science. 2000;287:860 864.
91. Gewurz H, Zhang XH, Lint TF. Structure and function of the pentraxins.
67. Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM.
Curr Opin Immunol. 1995;7:5464.
Osteopontin is elevated during neointima formation in rat arteries and is a
92. Loppnow H, Libby P. Proliferating or interleukin 1-activated human
novel component of human atherosclerotic plaques. J Clin Invest. 1993;92:
vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest.
16861696.
1990;85:731738.
68. OBrien ER, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Schwartz
93. Ikeda U, Ikeda M, Seino Y, Takahashi M, Kano S, Shimada K. Interleukin
SM, Giachelli CM. Osteopontin is synthesized by macrophage, smooth
6 gene transcripts are expressed in atherosclerotic lesions of genetically
muscle, and endothelial cells in primary and restenotic human coronary
hyperlipidemic rabbits. Atherosclerosis. 1992;92:213218.
atherosclerotic plaques. Arterioscler Thromb. 1994;14:16481656.
94. Viedt C, Hansch GM, Brandes RP, Kubler W, Kreuzer J. The terminal
69. Friesel R, Komoriya A, Maciag T. Inhibition of endothelial cell proliferation
complement complex C5b-9 stimulates interleukin-6 production in human
by -interferon. J Cell Biol. 1987;104:689696.
smooth muscle cells through activation of transcription factors NF-B and
70. Hansson GK, Hellstrand M, Rymo L, Rubbia L, Gabbiani G. Interferon-
AP-1. FASEB J. 2000;14:23702372.
inhibits both proliferation and expression of differentiation-specific
95. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of
-smooth muscle actin in arterial smooth muscle cells. J Exp Med. 1989;
C-reactive protein on human endothelial cells. Circulation. 2000;102:
170:15951608.
21652168.
71. Peilot H, Rosengren B, Bondjers G, Hurt-Camejo E. Interferon- induces
96. Rovere P, Peri G, Fazzini F, Bottazzi B, Doni A, Bondanza A, Zimmermann
secretory group IIA phospholipase A2 in human arterial smooth muscle
VS, Garlanda C, Fascio U, Sabbadini MG, Rugarli C, Mantovani A,
cells: involvement of cell differentiation, STAT-3 activation, and moduManfredi AA. The long pentraxin PTX3 binds to apoptotic cells and reglation by other cytokines. J Biol Chem. 2000;275:2289522904.
ulates their clearance by antigen-presenting dendritic cells. Blood. 2000;96:
72. Hansson GK, Holm J. Interferon- inhibits arterial stenosis after injury.
43004306.
Circulation. 1991;84:12661272.
97. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB,
73. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and growth factors
Maseri A. The prognostic value of C-reactive protein and serum amyloid A
positively and negatively regulate interstitial collagen gene expression in
protein in severe unstable angina. N Engl J Med. 1994;331:417424.
human vascular smooth muscle cells. Arterioscler Thromb. 1991;11:
98. Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C,
12231230.
Rebuzzi AG, Ciliberto G, Maseri A. Elevated levels of interleukin-6 in
74. Hansson GK, Libby P. The role of the lymphocyte. In: Fuster V, Ross R,
unstable angina. Circulation. 1996;94:874877.
Topol EJ, eds. Atherosclerosis and Coronary Artery Disease. Philadel99. Peri G, Introna M, Corradi D, Iacuitti G, Signorini S, Avanzini F, Pizzetti F,
phia/New York: Lippincott-Raven Publishers; 1995;1:557568.
Maggioni AP, Moccetti T, Metra M, Cas LD, Ghezzi P, Sipe JD, Re G,
75. Libby P. Molecular bases of the acute coronary syndromes. Circulation.
Olivetti G, Mantovani A, Latini R. PTX3, a prototypical long pentraxin, is
1995;91:2844 2850.
an early indicator of acute myocardial infarction in humans. Circulation.
76. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal
2000;102:636641.
rupture or erosion of thrombosed coronary atherosclerotic plaques is char100. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of
acterized by an inflammatory process irrespective of the dominant plaque
interleukin-6 and the risk of future myocardial infarction among apparently
morphology. Circulation. 1994;89:3644.
healthy men. Circulation. 2000;101:17671772.
77. Gupta S, Pablo AM, Jiang X-c, Wang N, Tall AR, Schindler C. IFN-
101. Bogdan C, Vodovotz Y, Paik J, Xie Q-w, Nathan C. Mechanism of suppotentiates atherosclerosis in apoE knock-out mice. J Clin Invest. 1997;99:
pression of nitric oxide synthase expression by interleukin-4 in primary
Downloaded from http://atvb.ahajournals.org/mouse
by guest
on October
7, 2014
27522761.
macrophages.
J Leukoc
Biol. 1994;55:227233.
1888
December 2001
123. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at

102. Niiro H, Otsuka T, Kuga S, Nemoto Y, Abe M, Hara N, Nakano T, Ogo T,
Niho Y. IL-10 inhibits prostaglandin E2 production by lipopolysaccharidethe site of coronary atheromatous erosion or rupture in myocardial
stimulated monocytes. Int Immunol. 1994;6:661 664.
infarction. Circulation. 1995;92:10841088.
103. Mehindate K, al-Daccak R, Aoudjit F, Damdoumi F, Fortier M, Borgeat P,
124. Kaartinen M, Penttila A, Kovanen PT. Mast cells in rupture-prone areas of
Mourad W. Interleukin-4, transforming growth factor 1, and dexamethahuman coronary atheromas produce and store TNF-. Circulation. 1996;
sone inhibit superantigen-induced prostaglandin E2-dependent collagenase
11:27872792.
gene expression through their action on cyclooxygenase-2 and cytosolic
125. Kaartinen M, van der Wal AC, van der Loos CM, Piek JJ, Koch KT, Becker
phospholipase A2. Lab Invest. 1996;75:529538.
AE, Kovanen PT. Mast cell infiltration in acute coronary syndromes: impli104. Zhou X, Paulsson G, Stemme S, Hansson GK. Hypercholesterolemia is
cations for plaque rupture. J Am Coll Cardiol. 1998;32:606612.
associated with a Th1/Th2 switch of the autoimmune response in athero126. Saarinen J, Kalkkinen N, Welgus HG, Kovanen PT. Activation of human
sclerotic apo E-knockout mice. J Clin Invest. 1998;101:17171725.
interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond
105. Mallat Z, Heymes C, Ohan J, Faggin E, Leseche G, Tedgui A. Expression
by mast cell chymase. J Biol Chem. 1994;269:1813418140.
of interleukin-10 in advanced human atherosclerotic plaques: relation to
127. Lindstedt KA, Kokkonen JO, Kovanen PT. Soluble heparin proteoglycans
inducible nitric oxide synthase expression and cell death. Arterioscler
released from stimulated mast cells induce uptake of low density
Thromb Vasc Biol. 1999;19:611616.
lipoproteins by macrophages via scavenger receptor-mediated phagocytosis.
106. Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF,
J Lipid Res. 1992;33:6575.
Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman
128. Bobryshev YV, Lord RSA. Ultrastructural recognition of cells with denD, Tedgui A. Protective role of interleukin-10 in atherosclerosis. Circ Res.
dritic cell morphology in human aortic intima: contacting interactions of
1999;85:e17 e24.
vascular dendritic cells in athero-resistant and athero-prone areas of the
107. Pinderski-Oslund LJ, Hedrick CC, Olvera T, Hagenbaugh A, Territo M,
normal aorta. Arch Histol Cytol. 1995;58:307322.
Berliner JA, Fyfe AI. Interleukin-10 blocks atherosclerotic events in vitro
129. Bentley GA, Mariuzza RA. The structure of the T cell antigen receptor.
and in vivo. Arterioscler Thromb Vasc Biol. 1999;19:28472853.
Annu Rev Immunol. 1996;14:563590.
108. Shi FD, Li H, Wang H, Bai X, van der Meide PH, Link H, Ljunggren HG.
130. Paulsson G, Zhou X, Trnquist E, Hansson GK. Oligoclonal T cell
Mechanisms of nasal tolerance induction in experimental autoimmune
expansions in atherosclerotic lesions of apoE-deficient mice. Arterioscler
myasthenia gravis: identification of regulatory cells. J Immunol. 1999;162:
57575763.
131. Stemme S, Rymo L, Hansson GK. Polyclonal origin of T lymphocytes in
109. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts
human atherosclerotic plaques. Lab Invest. 1991;65:654660.
AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor 1 null
132. Palinski W, Rosenfeld ME, Yl-Herttuala S, Gurtner GC, Socher SS, Butler
mutation in mice causes excessive inflammatory response and early death.
SW, Parthasarathy S, Carew TE, Steinberg D, Witztum JL. Low density
Proc Natl Acad Sci U S A. 1993;90:770774.
lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci
110. McCaffrey TA, Du B, Consigli S, Szabo P, Bray PJ, Hartner L, Weksler
U S A. 1989;86:13721376.
BB, Sanborn TA, Bergman G, Bush HL. Genomic instability in the type II
133. Salonen JT, Yl-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R,
TGF-1 receptor gene in atherosclerotic and restenotic vascular cells. J Clin
Nyyssnen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL
Invest. 1997;100:21822188.
and progression of carotid atherosclerosis. Lancet. 1992;339:883887.
111. Peoples GE, Blotnick S, Takahashi K, Freeman MR, Klagsbrun M, Eberlein
134. Yl-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL.
TJ. T lymphocytes that infiltrate tumors and atherosclerotic plaques produce
Rabbit and human atherosclerotic lesions contain IgG that recognizes
heparin-binding epidermal growth factor-like growth factor and basic
epitopes of oxidized LDL. Arterioscler Thromb. 1994;14:3240.
fibroblast growth factor: a potential pathologic role. Proc Natl Acad Sci
135. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T
U S A. 1995;92:6547 6551.
lymphocytes from human atherosclerotic plaques recognize oxidized LDL.
112. Ludewig B, Freigang S, Jaggi M, Kurrer MO, Pei YC, Vlk L, Odermatt B,
Proc Natl Acad Sci U S A. 1995;92:38933897.
Zinkernagel RM, Hengartner H. Linking immune-mediated arterial inflam136. Caligiuri G, Nicoletti A, Trnberg I, Zhou X, Hansson GK. Effects of sex
mation and cholesterol-induced atherosclerosis in a transgenic mouse
and age on atherosclerosis and autoimmunity in apoE-deficient mice. Athmodel. Proc Natl Acad Sci U S A. 2000;97:1275212757.
erosclerosis. 1999;145:301308.
113. Geng YJ, Henderson LE, Levesque EB, Muszynski M, Libby P. Fas is
137. Nicoletti A, Paulsson G, Caligiuri G, Zhou X, Hansson GK. Induction of
expressed in human atherosclerotic intima and promotes apoptosis of cytoneonatal tolerance to oxidized lipoprotein reduces atherosclerosis in apoE
kine-primed human vascular smooth muscle cells. Arterioscler Thromb
knockout mice. Mol Med. 2000;6:283290.
Vasc Biol. 1997;17:2200 2208.
138. Palinski W, Ord V, Plump AS, Breslow JL, Steinberg D, Witztum JL.
114. Geng Y-J, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of
ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis:
vascular smooth muscle cells induced by in vitro stimulation with
demonstration of oxidation-specific epitopes in lesions and high titers of
interferon-, tumor necrosis factor-, and interleukin-1. Arterioscler
autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb.
1994;14:605616.
115. Seitz CS, Kleindienst R, Xu QB, Wick G. Coexpression of heat-shock
139. Palinski W, Hrkk S, Miller E, Steinbrecher UP, Powell HC, Curtiss LK,
protein 60 and intercellular-adhesion molecule-1 is related to increased
Witztum JL. Cloning of monoclonal autoantibodies to epitopes of oxidized
adhesion of monocytes and T cells to aortic endothelium of rats in response
lipoproteins from apolipoprotein E-deficient mice: demonstration of
to endotoxin. Lab Invest. 1996;74:241252.
epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest.
116. Kleindienst R, Xu Q, Willeit J, Waldenberger FR, Weimann S, Wick G.
1996;98:800814.
Immunology of atherosclerosis: demonstration of heat shock protein 60
140. Frostegrd J, Wu R, Giscombe R, Holm G, Lefvert AK, Nilsson J. Induction
expression and T lymphocytes bearing / or / receptor in human athof T-cell activation by oxidized low density lipoprotein. Arterioscler
erosclerotic lesions. Am J Pathol. 1993;142:19271937.
Thromb. 1992;12:461467.
117. Melian A, Geng YJ, Sukhova GK, Libby P, Porcelli SA. CD1 expression in
141. Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein
human atherosclerosis: a potential mechanism for T cell activation by foam
(LDL) receptor-deficient rabbits with homologous malondialdehydecells. Am J Pathol. 1999;155:775786.
modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A. 1995;92:
118. Parums DV, Chadwick DR, Mitchinson MJ. The localization of immuno821825.
globulin in chronic periaortitis. Atherosclerosis. 1986;61:117123.
142. Ameli S, Hultgrdh-Nilsson A, Regnstrm J, Calara F, Yano J, Cercek B,
119. Parums DV, Brown DL, Mitchinson MJ. Serum antibodies to oxidized
Shah PK, Nilsson J. Effect of immunization with homologous LDL and
low-density lipoprotein and ceroid in chronic periaortitis. Arch Pathol Lab
oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits.
Med. 1990;114:383387.
Arterioscler Thromb Vasc Biol. 1996;16:10741079.
120. Sohma Y, Sasano H, Shiga R, Saeki S, Suzuki T, Nagura H, Nose M,
143. Zhou X, Caligiuri G, Hamsten A, Lefvert AK, Hansson GK. Protection
Yamamoto T. Accumulation of plasma cells in atherosclerotic lesions of
against atherosclerosis by LDL immunization is associated with T celldeWatanabe heritable hyperlipidemic rabbits. Proc Natl Acad Sci U S A. 1995;
pendent IgG antibodies in apoE-deficient mice. Arterioscler Thromb Vasc
92:4937 4941.
Biol. 2001;21:108114.
121. Zhou X, Hansson GK. Detection of B cells and proinflammatory cytokines
144. Wick G, Schett G, Amberger A, Kleindienst R, Xu Q. Is atherosclerosis an
in atherosclerotic plaques of hypercholesterolemic apoE knockout mice.
immunologically mediated disease? Immunol Today. 1995;16:2733.
Scand J Immunol. 1999;50:2530.
145. Kiessling R, Gro nberg A, Ivanyi J, So derstrom K, Ferm M, Kleinau S,
122. Hansson GK, Holm J, Kral JG. Accumulation of IgG and complement
Nilsson E, Klareskog L. Role of hsp60 during autoimmune and bacterial
factor C3 in human arterial endothelium and atherosclerotic lesions. Acta
from http://atvb.ahajournals.org/inflammation.
by guest onImmunol
October
2014
Pathol Microbiol Immunol ScandDownloaded
A. 1984;92:429435.
Rev.7,1991;121:91111.
Hansson
1889
146. Frostega rd J, Kjellman B, Gidlund M, Andersson B, Jondahl M, Kiessling

168. Hu H, Pierce GN, Zhong G. The atherogenic effects of Chlamydia are
dependent on serum cholesterol and specific to Chlamydia pneumoniae.
R. Induction of heat shock protein in monocytic cells by oxidized low
J Clin Invest. 1999;103:747753.
density lipoprotein. Atherosclerosis. 1996;121:93103.
169. Caligiuri G, Rottenberg M, Nicoletti A, Wigzell H, Hansson GK.
147. Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann
Chlamydia pneumoniae infection does not induce or modify atherosclerosis
S, Wick G. Induction of arteriosclerosis in normocholesterolemic rabbits by
in mice. Circulation. 2001;103:28342838.
immunization with heat shock protein 65. Arterioscler Thromb. 1992;12:
170. Aalto-Setala K, Laitinen K, Erkkila L, Leinonen M, Jauhiainen M, Ehnholm
789799.
C, Tamminen M, Puolakkainen M, Penttila I, Saikku P. Chlamydia pneu148. George J, Shoenfeld Y, Afek A, Gilburd B, Keren P, Shaish A, Kopolovic
moniae does not increase atherosclerosis in the aortic root of apolipoprotein
J, Wick G, Harats D. Enhanced fatty streak formation in C57BL/6J mice by
Edeficient mice. Arterioscler Thromb Vasc Biol. 2001;21:578584.
immunization with heat shock protein-65. Arterioscler Thromb Vasc Biol.
171. Hendrix MGR, Salimans MMM, Boven CPA, van Bruggeman CA. High
1999;19:505510.
prevalence of latently present cytomegalovirus in arterial walls of patients
149. Frostega rd J, Lemne C, Andersson B, van der Zee R, Kiessling R, de Faire
suffering from grade III atherosclerosis. Am J Pathol. 1990;136:2328.
U. Association of serum antibodies to heat-shock protein 65 with borderline
172. Nicholson AC, Hajjar DP. Herpesviruses in atherosclerosis and thrombosis:
hypertension. Hypertension. 1997;29:4044.
etiologic agents or ubiquitous bystanders? Arterioscler Thromb Vasc Biol.
150. Pockley AG, Wu R, Lemne C, Kiessling R, de Faire U, Frostega rd J.
1998;18:339348.
Circulating heat shock protein 60 is associated with early cardiovascular
173. Hunter GC, Henderson AM, Westerband A, Kobayashi H, Suzuki F, Yan
disease. Hypertension. 2000;36:303307.
ZQ, Sirsj A, Putnam CW, Hansson GK. The contribution of inducible
151. Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F, Kiechl S,
nitric oxide and cytomegalovirus to the stability of carotid plaque. J Vasc
Stulnig T, Luef G, Wick G. Association of serum antibodies to heat-shock
Surg. 1999;30:36 49.
protein 65 with carotid atherosclerosis. Lancet. 1993;341:255259.
174. McDonald K, Rector TS, Braunlin EA, Kubo SH, Olivari MT. Association
152. Mayr M, Metzler B, Kiechl S, Willeit J, Schett G, Xu Q, Wick G. Endoof coronary artery disease in cardiac transplant recipients with cytomegathelial cytotoxicity mediated by serum antibodies to heat shock proteins of
lovirus infection. Am J Cardiol. 1989;64:359362.
Escherichia coli and Chlamydia pneumoniae: immune reactions to heat
175. Melnick JL, Adam E, DeBakey ME. Possible role of cytomegalovirus in
shock proteins as a possible link between infection and atherosclerosis.
atherogenesis. JAMA. 1990;263:22042207.
Circulation. 1999;99:15601566.
176. Nieto FJ, Adam E, Sorlie P, Farzadegan H, Melnick JL, Comstock GW,
153. Frostega rd J, Wu R, Gillis-Haegerstrand C, Lemne C, de Faire U. AntiSzklo M. Cohort study of cytomegalovirus infection as a risk factor for
bodies to endothelial cells in borderline hypertension. Circulation. 1998;98:
carotid intimal-medial thickening, a measure of subclinical atherosclerosis.
10921098.
Circulation. 1996;94:922927.
154. Shoenfeld Y, Harats D, George J. Atherosclerosis and the antiphospholipid
177. Zhou YF, Leon MB, Waclawiw MA, Popma JJ, Yu ZX, Finkel T, Epstein
syndrome: a link unravelled? Lupus. 1998;7:S140 S143.
SE. Association between prior cytomegalovirus infection and the risk of
155. George J, Afek A, Gilburd B, Blank M, Levy Y, Aron-Maor A, Levkovitz
restenosis after coronary atherectomy. N Engl J Med. 1996;335:624630.
H, Shaish A, Goldberg I, Kopolovic J, Harats D, Shoenfeld Y. Induction of
178. Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis: emerging mechearly atherosclerosis in LDL-receptor-deficient mice immunized with
anistic paradigms. Circulation. 1999;100:e20e28.
2-glycoprotein I. Circulation. 1998;98:11081115.
179. Streblow DN, So derberg-Naucle r C, Vietra J, Smith P, Wakabayashi E,
156. George J, Harats D, Gilburd B, Afek A, Shaish A, Kopolovic J, Shoenfeld
Ruchti F, Mattison K, Altschuler Y, Nelson JA. The human cytomegaY. Adoptive transfer of (2)-glycoprotein I-reactive lymphocytes enhances
lovirus chemokine receptor US28 mediates vascular smooth muscle cell
early atherosclerosis in LDL receptor-deficient mice. Circulation. 2000;102:
migration. Cell. 1999;99:511520.
18221827.
180. Witztum JL, Palinski W. Are immunological mechanisms relevant for the
157. Hughes GR. The antiphospholipid syndrome: ten years on. Lancet. 1993;
development of atherosclerosis? Clin Immunol. 1999;90:153156.
342:341344.
181. Palinski W, Yl-Herttuala S, Rosenfeld ME, Butler SW, Socher SA,
158. Lecerf V, Alhenc-Gelas M, Laurian C, Bruneval P, Aiach M, Cormier JM,
Parthasarathy S, Curtiss LK, Witztum JL. Antisera and monoclonal antiFiessinger JN. Antiphospholipid antibodies and atherosclerosis. Am J Med.
bodies specific for epitopes generated during oxidative modification of low
1992;92:575576.
density lipoprotein. Arterioscler Thromb. 1990;10:325335.
159. Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a
182. Bergmark C, Wu R, de Faire U, Lefvert AK, Swedenborg J. Patients with
new view of lupus anticoagulants and other antiphospholipid autoantiearly-onset peripheral vascular disease have increased levels of autoantibodies. Blood. 1994;84:28542867.
bodies against oxidized LDL. Arterioscler Thromb Vasc Biol. 1995;15:
160. Hrkk S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ, Terkeltaub
441445.
R, Pierangeli SS, Branch DW, Palinski W, Witztum JL. Antiphospholipid
183. Hulthe J, Wikstrand J, Lidell A, Wendelhag I, Hansson GK, Wiklund O.
antibodies are directed against epitopes of oxidized phospholipids: recogAntibody titers against oxidized LDL are not elevated in patients with
nition of cardiolipin by monoclonal antibodies to epitopes of oxidized low
familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1998;18:
density lipoprotein. J Clin Invest. 1996;98:815825.
12031211.
161. Shaw PX, Ho rkko S, Chang MK, Curtiss LK, Palinski W, Silverman GJ,
184. Wu R, de Faire U, Lemne C, Witztum JL, Frostegard J. Autoantibodies to
Witztum JL. Natural antibodies with the T15 idiotype may act in atheroOxLDL are decreased in individuals with borderline hypertension. Hypersclerosis, apoptotic clearance, and protective immunity. J Clin Invest. 2000;
tension. 1999;33:5359.
105:17311740.
185. Hulthe J, Wiklund O, Hurt-Camejo E, Bondjers G. Antibodies to oxidized
162. Saikku P, Leinonen M, Mattila K, Ekman MR, Nieminen MS, Mkel PH,
LDL in relation to carotid atherosclerosis, cell adhesion molecules, and
Huttunen JK, Valtonen V. Serological evidence of an association of a novel
phospholipase A(2). Arterioscler Thromb Vasc Biol. 2001;21:269274.
Chlamydia, TWAR, with chronic coronary heart disease and acute myo186. Hammar N, Linnersjo A, Hansson GK, Bjorkander J, Hammarstrom L.
cardial infarction. Lancet. 1988;2:983986.
Ischaemic heart disease in primary immunodeficiency. Lancet. 1998;
163. Kuo CC, Gown AM, Benditt EP, Grayston JT. Detection of Chlamydia
352:1786.
pneumoniae in aortic lesions of atherosclerosis by immunocytochemical
187. Paton P, Tabib A, Loire R, Tete R. Coronary artery lesions and human
stain. Arterioscler Thromb. 1993;13:15011504.
immunodeficiency virus infection. Res Virol. 1993;144:225231.
164. Muhlestein JB, Hammond EH, Carlquist JF, Radicke E, Thomson MJ,
188. Lewis W, Grupp IL, Grupp G, Hoit B, Morris R, Samarel AM, Bruggeman
Karagounis LA, Woods ML, Anderson JL. Increased incidence of
L, Klotman P. Cardiac dysfunction occurs in the HIV-1 transgenic mouse
Chlamydia species within the coronary arteries of patients with symptomatic
treated with zidovudine. Lab Invest. 2000;80:187197.
atherosclerotic versus other forms of cardiovascular disease. J Am Coll
189. Lewis W. Atherosclerosis in AIDS: potential pathogenetic roles of antiretCardiol. 1996;27:15551561.
roviral therapy and HIV. J Mol Cell Cardiol. 2000;32:21152129.
165. Saikku P. Chlamydia pneumoniae and atherosclerosis: an update. Scand
190. Wallberg-Jonsson S, hman ML, Dahlqvist SR. Cardiovascular morbidity
J Infect Dis Suppl. 1997;104:5356.
and mortality in patients with seropositive rheumatoid arthritis.
166. Weiss SM, Roblin PM, Gaydos CA, Cummings P, Patton DL, Schulhoff N,
J Rheumatol. 1997;24:445451.
Shani J, Frankel R, Penney K, Quinn TC, Hammerschlag MR, Schachter J.
191. Sturfelt G, Eskilsson J, Nived O, Truedsson L, Valind S. Cardiovascular
Failure to detect Chlamydia pneumoniae in coronary atheromas of patients
disease in systemic lupus erythematosus. a study of 75 patients form a
undergoing atherectomy. J Infect Dis. 1996;173:957962.
defined population. Medicine (Baltimore). 1992;71:216223.
167. Moazed TC, Campbell LA, Rosenfeld ME, Grayston JT, Kuo CC.
192. Ward MM, Pyun E, Studenski S. Causes of death in systemic lupus eryChlamydia pneumoniae infection accelerates the progression of atherosclethematosus: long-term follow-up of an inception cohort. Arthritis Rheum.
Downloaded
http://atvb.ahajournals.org/1995;38:14921499.
rosis in apolipoprotein E-deficient
mice. J Infect from
Dis. 1999;180:238241.
1890
December 2001
193. Wu R, Svenungsson E, Gunnarsson I, Andersson B, Lundberg I, Schafer

Elinder L, Frostegard J. Antibodies against lysophosphatidylcholine and
oxidized LDL in patients with SLE. Lupus. 1999;8:142150.
194. Dansky HM, Charlton SA, Harper MM, Smith JD. T and B lymphocytes
play a minor role in atherosclerotic plaque formation in the apolipoprotein
E-deficient mouse. Proc Natl Acad Sci U S A. 1997;94:46424646.
195. Daugherty A, Pur E, Delfel-Butteiger D, Leferovich J, Roselaar SE. The
effects of total lymphocyte deficiency on the extent of atherosclerosis in
apolipoprotein E-/- mice. J Clin Invest. 1997;100:15751580.
196. Elhage R, Clamens S, Reardon-Alulis C, Getz GS, Fievet C, Maret A, Arnal
JF, Bayard F. Loss of atheroprotective effect of estradiol in immunodeficient
mice. Endocrinology. 2000;141:462 465.
197. Zhou X, Nicoletti A, Elhage R, Hansson GK. Transfer of CD4 T cells
aggravates atherosclerosis in immunodeficient apoE knockout mice. Circulation. 2000;102:29192922.
198. Sun H, Subbotin V, Chen C, Aitouche A, Valdivia LA, Sayegh MH, Linsley
PS, Fung JJ, Starzl TE, Rao AS. Prevention of chronic rejection in mouse
aortic allografts by combined treatment with CTLA-4Ig and anti-CD40
ligand monoclonal antibody. Transplantation. 1997;64:1838 1843.
199. Karmann K, Hughes CC, Schechner J, Fanslow WC, Pober JS. CD40 on
human endothelial cells: inducibility by cytokines and functional regulation
of adhesion molecule expression. Proc Natl Acad Sci U S A. 1995;92:
4342 4346.
200. Mach F, Schnbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS,
Libby P. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for
CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A.
1997;94:19311936.
201. Schnbeck U, Mach F, Sukhova GK, Murphy C, Bonnefoy JY, Fabunmi
RP, Libby P. Regulation of matrix metalloproteinase expression in human
vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling
in plaque rupture? Circ Res. 1997;81:448 454.
202. Mach F, Schnbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of
monocyte/macrophage functions related to acute atheroma complication by
ligation of CD40: induction of collagenase, stromelysin, and tissue factor.
Circulation. 1997;96:396399.
203. Schnbeck U, Mach F, Sukhova GK, Atkinson E, Levesque E, Herman M,
Graber P, Basset P, Libby P. Expression of stromelysin-3 in atherosclerotic
lesions: regulation via CD40-CD40 ligand signaling in vitro and in vivo. J
Exp Med. 1999;189:843 853.
204. Mach F, Schnbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of
atherosclerosis in mice by inhibition of CD40 signalling. Nature. 1998;394:
200203.
205. Lutgens E, Gorelik L, Daemen MJ, de Muinck ED, Grewal IS, Koteliansky
VE, Flavell RA. Requirement for CD154 in the progression of atherosclerosis. Nat Med. 1999;5:13131316.
206. Freigang S, Hrkk S, Miller E, Witztum JL, Palinski W. Immunization of
LDL receptordeficient mice with homologous malondialdehyde-modified
and native LDL reduces progression of atherosclerosis by mechanisms other
than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vasc Biol. 1998;18:19721982.
207. George J, Afek A, Gilburd B, Levkovitz H, Shaish A, Goldberg I,
Kopolovic Y, Wick G, Shoenfeld Y, Harats D. Hyperimmunization of
apo-E-deficient mice with homologous malondialdehyde low-density
lipoprotein suppresses early atherogenesis. Atherosclerosis. 1998;138:
147152.
208. Holvoet P, Perez G, Zhao Z, Brouwers E, Bernar H, Collen D.
Malondialdehyde-modified low density lipoprotein in patients with atherosclerotic disease. J Clin Invest. 1995;95:26112619.
209. Nicoletti A, Kaveri S, Caligiuri G, Barity J, Hansson GK. Immunoglobulin
treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest.
1998;102:910 918.
210. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type
of immunomodulator. Nat Med. 2000;6:1399 1402.
211. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang

XM, Chia D, Terasaki PI, Sabad A, Cogert GA, et al. Effect of pravastatin
on outcomes after cardiac transplantation. N Engl J Med. 1995;333:
621627.
212. Marx N, Mach F, Sauty A, Leung JH, Sarafi MN, Ransohoff RM, Libby P,
Plutzky J, Luster AD. Peroxisome proliferator-activated receptor- activators inhibit IFN--induced expression of the T cell-active CXC chemokines
IP-10, Mig, and I-TAC in human endothelial cells. J Immunol. 2000;164:
65036508.
213. Kling D, Fingerle J, Harlan JM, Lobb RR, Lang F. Mononuclear leukocytes invade rabbit arterial intima during thickening formation via
CD18- and VLA-4-dependent mechanisms and stimulate smooth muscle
migration. Circ Res. 1995;77:11211128.
214. Bevilacqua MP, Pober JS, Mendrick DL, Cotran RS, Gimbrone MA. Identification of an inducible endothelial-leukocyte adhesion molecule. Proc
Natl Acad Sci U S A. 1987;84:92389242.
215. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA. Induction by
IL-1 and interferon-: tissue distribution, biochemistry, and function of a
natural adherence molecule (ICAM-1). J Immunol. 1986;137:245254.
216. Yesner LM, Huh HY, Pearce SF, Silverstein RL. Regulation of monocyte
CD36 and thrombospondin-1 expression by soluble mediators. Arterioscler
217. Geng YJ, Hansson GK, Holme E. Interferon- and tumor necrosis factor
synergize to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth muscle cells. Circ Res. 1992;71:12681276.
218. de Vera ME, Shapiro RA, Nussler AK, Mudgett JS, Simmons RL, Morris
SM Jr, Billiar TR, Geller DA. Transcriptional regulation of human inducible
nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the
human NOS2 promoter. Proc Natl Acad Sci U S A. 1996;93:10541059.
219. Crofford LJ. COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol. 1997;24(suppl 49):1519.
220. Conrad DJ, Kuhn H, Mulkins M, Highland E, Sigal E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc Natl Acad Sci U S A. 1992;89:217221.
221. Nassar GM, Morrow JD, Roberts LD, Lakkis FG, Badr KF. Induction of
15-lipoxygenase by interleukin-13 in human blood monocytes. J Biol Chem.
1994;269:2763127634.
222. Gordon S. Macrophages and the immune response. In: Paul WE, ed. Fundamental Immunology. 4th ed. Philadelphia, Pa: Lippincott-Raven; 1999:
533545.
223. Lee E, Vaughan DE, Parikh SH, Grodzinsky AJ, Libby P, Lark MW, Lee
RT. Regulation of matrix metalloproteinases and plasminogen activator
inhibitor-1 synthesis by plasminogen in cultured human vascular smooth
muscle cells. Circ Res. 1996;78:4449.
224. Goetzl EJ, Banda MJ, Leppert D. Matrix metalloproteinases in immunity.
J Immunol. 1996;156:14.
225. Niedbala MJ, Stein Picarella M. Tumor necrosis factor induction of endothelial cell urokinase-type plasminogen activator mediated proteolysis of
extracellular matrix and its antagonism by -interferon. Blood. 1992;79:
678687.
226. Gallicchio M, Hufnagl P, Wojta J, Tipping P. IFN- inhibits thrombin- and
endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells. J Immunol. 1996;157:26102617.
227. Arnman V, Stemme S, Rymo L, Risberg B. Interferon- modulates the
fibrinolytic response in cultured human endothelial cells. Thromb Res.
1995;77:431440.
228. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum
JL, Funk CD, Conrad D, Glass CK. Interleukin-4-dependent production of
PPAR- ligands in macrophages by 12/15-lipoxygenase. Nature. 1999;400:
378382.
229. Panousis CG, Zuckerman SH. Interferon- induces downregulation of
Tangier disease gene (ATP-binding-cassette transporter 1) in macrophagederived foam cells. Arterioscler Thromb Vasc Biol. 2000;20:15651571.
230. Schreyer SA, Peschon JJ, LeBoeuf RC. Accelerated atherosclerosis in mice
lacking tumor necrosis factor receptor p55. J Biol Chem. 1996;271:
2617426178.

Arterioscler Thromb Vasc Biol 2001 Hansson 1876 90

Загружено:

Сведения о документе

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Arterioscler Thromb Vasc Biol 2001 Hansson 1876 90

Загружено:

Авторское право:

Доступные форматы

Immune Mechanisms in Atherosclerosis

Downloaded from http://atvb.ahajournals.org/ by guest on October 7, 2014

Immune Cells in the Lesions of Atherosclerosis

that many vascular smooth muscle cells (SMCs) in human

Recruitment of Immune Cells to the Vessel Wall

Received May 21, 2001; revision accepted October 2, 2001.

Downloaded from http://atvb.ahajournals.org/

Figure 1. Immune cells in atheroma. Macrophages (MPh) and T

the endothelium to express leukocyte adhesion molecules.

Immune Mechanisms in Atherosclerosis

Figure 2. Hypercholesterolemia leads to recruitment of immune

lipoprotein deposition and oxidation in the intima but also to

Rolling (PMN, MC, Ly)

Rolling (PMN, MC, Ly)

Firm adhesion (MC, Ly)

Chemoattractant (MC, Ly)

LDLR-KO, apoE-KO, apoB-Tg

MCP-1 rec (MC, Ly)