Download Review Immune Mechanisms in Atherosclerosis

Review
Immune Mechanisms in Atherosclerosis
Goran K. Hansson, Lena Jonasson, Paul S. Seifert, and Sten Stemme
T
Monocytes and Macrophages
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he atherosclerotic plaque bears many similarities to
chronic inflammatory conditions, perhaps the most
striking one being the accumulation of macrophages in
both situations. This has been pointed out repeatedly
over the years, and Rudolf Virchow1 described atherosclerosis as a chronic irritation of the vessel wall. Poole
and Florey,2 in their classic papers on the effects of
mechanical injury to the aorta, pointed out the involvement of leukocytes in the response to injury process. A
few years later, Roberts3 found that serum sickness significantly aggravates cholesterol-induced atherosclerosis. Minick and Murphy4 subsequently elucidated the
role of immune complexes, and it is clear today that
circulating immune complexes are potent pro-atherogenic
factors in experimental animal models.
One of the major functions of macrophages is to
participate in the immune response by presenting foreign
antigen to T lymphocytes. The macrophage internalizes
foreign antigens by endocytosis, partially degrades them
in its lysosomes, and then transfers antigen fragments, to
the cell surface. The fragments associate with polymorphic cell-surface MHC proteins, and the antigen receptor
of the T lymphocyte binds to this macromolecular complex
on the macrophage surface.1011
Studies involving cholesterol-fed animals in the latter
part of the 1970s re-emphasized the importance of monocytes in atherosclerosis. Fowler et al. 12 demonstrated that
many foam cells in the lesions of cholesterol-fed rabbits
express Fc and C3b receptors characteristic for monocytes and macrophages. A provocative series of electron
micrographic studies on monocytes in early lesions of fat-fed
swine by Gerrity and his colleagues1314 showed that monocytes enter very early lesions and pre-atherosclerotic areas,
penetrate the endothelium, and take up cholesterol in the
intjma Other monocytes, now filled with lipid, seemed to
emigrate from the forming lesion. Similar electron microscopic findings were reported by Faggiotto et al. 1 5 1 6 The
hypothesis was formulated that monocytes mobilize cholesterol from the lipid-laden intima and therefore constitute an
important defense mechanism in cholesterol-induced
atherosclerosis.12-15
The relevance of immune mechanisms to human atherosclerosis has been less clear. It has been difficult to
assess the contribution of immunocompetent cells to
plaque, and very few studies have examined the prevalence of immune responses to microorganisms or specific
major histocompatibilrty complex (MHC) alleles in atherosclerotic patients. Progress in the field of immunology
during recent years has, however, made it possible to
characterize the inflammatory cell populations that form
the atherosclerotic plaque and to evaluate the effects of
immune cytokines on the cells of the vasculature.
Our own work showed that monocytes preferentially
bind to injured endothelium.1718 This is at least in part due
to an interaction between the Fc receptor of the monocyte
and IgG that has been absorbed onto cytoskeletal intermediate filaments.1920-21 The binding of IgG to the cytoskeleton also activates the complement cascade.21-22 This, in
turn, generates the anaphylatoxin C5a, which is an important chemoattractant for monocytes and granulocytes.21 A
hypothetical scheme for the relationship between endothelial injury and monocyte recruitment is shown in Figure 1.
Another potentially significant mechanism for recruitment
of monocytes to the vessel wall is via endothelial expression of specific leukocyte adhesive proteins (see below).
Immune Components In Human Plaques
The three major cellular components of the human
atherosclerotic plaque are the smooth muscle cell, which
dominates the fibrous cap; the macrophage, which is the
most abundant cell type in the lipid-rich core region; and
the lymphocyte, which is mainly found in the fibrous
cap. 6 - 8 Whereas smooth muscle cells and macrophages
were identified by light and electron microscopy several
years ago, 86 the degree of lymphocytic infiltration was not
apparent until monoclonal antibodies were used for immunohistochemical analysis of the plaque. 78
From the Department of Clinical Chemistry, Gothenburg University, Gothenburg, Sweden.
This work was supported by grants from the Swedish Medical
Research Council (project 6816) and the Swedish National
Association against Heart and Chest Diseases. Paul S. Serfert
was the recipient of a Fogarty International Postdoctoral Research
Fellowship.
Address for correspondence: Dr. G6ran Hansson, Department
of Clinical Chemistry, Gothenburg University, Sahlgren's Hospital, S-413 45 Gothenburg, Sweden.
Received December 27,1988; revision accepted May 3,1989.
(Arteriosclerosis 9:567-578, September/October 1989)
The role of monocytes in human atherosclerosis has
been more difficult to determine. Early electron microscopic studies had suggested that macrophages derived
from monocytes are present in the human lesion. 2324 - 28 It
was, however, evident from all light microscopic, cytochemical, and uttrastructural analyses of human plaques that
many of the cells could not be identified as either smooth
muscle cells or monocytes.
Monoclonal antibody technology has made it possible
to address the question of cellular composition of the
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ARTERIOSCLEROSIS
VOL 9, No 5, SEPTEMBER/OCTOBER 1989
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Figure 1. Postulated mechanism of complement activation and leukocyte recruitment in endothellal cell injury. When the
plasma membrane is damaged (A), macromolecules of the extracellular fluid enter the cytosol. These macromolecules
include IgG and complement factor, Ckj, which may bind to high-affinity binding sites on cytoskeletal intermediate filaments
and mitochondria (B). The formation of like IgG-CI complexes on intracellular structures (C) activates the complement
cascade, leading to opsonization of these structures by complement components (C3b) as well as to release of chemotactic
anaphylatoxlns (C5a). Chemotactically recruited monocytes and granulocytes may then phagocytize and eliminate the
remnants of the injured cell (D). (Reprinted from Hansson et al. 21 with kind permission of Experimental Cell Research and
Academic Press, Incorporated.)
plaque with sensitive and specific reagents. Monocytes
share a set of specific cell-surface proteins that do not
appear on other cells. Some of the first markers that were
supposedly monocyte specific, like the Fc receptor and
the MHC class II proteins, have turned out to be more
broadly distributed. 2627 Other monoclonal antibodies, however, appear to react exclusively with monocyte-specific
surface proteins. Such leukocyte differentiation antigens
have recently been evaluated in a series of international
workshops, and antigenic clusters of differentiation have
been identified. For identification of monocytes and macrophages, the most widely used antibodies are those that
recognize the CD14 antigen cluster. (CD numbers of
antigens refer to clusters of differentiation defined by the
International Workshops on Leukocyte Differentiation
Antigens.28) This family of antibodies includes AntiLeu-M3, My4, Mo2, and others. Another monocytespecific antibody is HAM35.8
The identification of monocytes in atherosclerotic
plaques by monoclonal antibody cytochemistry was made
simultaneously by Vedeler et al., 29 Aqel et al., 30 and
ourselves.31 We performed a detailed quantitative analysis of cell types in complicated human plaques7 and found
that 60% of the cells in the lipid core express the CD14
antigen (Figure 2). In the fibrous cap, on the other hand,
smooth muscle cells dominate, and only 20% of the cells
were identified as monocyte derived by immunocytochemistry. Subsequent studies of plaques have confirmed that monocyte-derived macrophages are present
both in the early fibrofatty lesion and in the complicated
plaque. 73233
Immunohistochemical analyses of the human fatty streak
lesion 3438 showed that it is dominated by monocytederived macrophages. The evolution of the fatty streak to
the advanced lesion has been controversial, but recent
studies of hypercholesterolemic rabbits and monkeys1519'36
show that at least some fatty streaks are converted into
fibrous plaques during the progression of the disease.
T Lymphocytes In Atherosclerosis
The close functional relationship between macrophages
and T lymphocytes suggested to us that T cells could be
present in the atherosclerotic plaque. In fact, lymphocytes
had been observed in human plaques and experimental
lesions in several microscopic studies,23-242837-38-39 but
their quantitative significance or functional state could not
be estimated.
We included the CD3 antibody, which recognizes all
T lymphocytes, as well as the subtype markers CD4 and
CD8, in our panel for immunocytochemical analysis of
carotid plaques. Substantial amounts of CD3-positive
T lymphocytes could be detected in the plaque with these
reagents (Figure 2). Approximately one fifth of the cells in
the fibrous cap were T cells.7 In contrast, almost no B or
natural killer (NK) cells were found. Other immunohistochemical studies have shown that lymphocytes are
present in fatty streaks, fibrous plaques, and advanced
plaques.8-33-35-40
IMMUNE MECHANISMS IN ATHEROSCLEROSIS
At
60%
7
9%
Hansson et al.
569
M 2*%
T
rty.
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Rgure 2. Monocyte-derlved macrophages (M) and T lymphocytes (T) in the carotid atherosclerotic
plaque. Values are expressed as percentages of total cells in different regions of the plaque and are
based on Immunohlstochemlcal analyses of endarterectomy samples (data from reference 7).
CD4-type T lymphocytes induce antibody production
and regulate cell-mediated immune responses. They were
found to quantitatively dominate in all regions of the
complicated carotid plaque,7 as they do in peripheral
blood. In contrast, CD8 cells are more frequent in early
plaques40 and also in the fatty streak,35 and they dominate
over CD4 cells in the intimal thickening surrounding the
complicated plaque.7 The CD8 subtype contains most of
the cytoxic T cell activity. One possibility is that CD8 cells
are involved in the initiation of the lesion, but that a switch
toward a CD4-dominated situation occurs during progression of the individual lesion.
The finding of T lymphocytes in the plaque does not
necessarily imply that these cells are immunologically
active. It is possible that they could represent a dormant
population of blood cells trapped during plaque formation.
This can be clarified by immunocytochemical analyses,
since activated T lymphocytes express cell-surface proteins that are absent from resting T cells. Approximately
one third of the T lymphocytes in the plaque were found to
express the activation markers, HLA-DR and VLA-1 (very
late activation antigen-1), with fewer T cells expressing
the receptor for interieukin-2.41 This pattern is similar to
that observed in the synovium of patients with rheumatoid
arthritis.42 It has been suggested that a phenotype with a
high VLA-1 frequency and a low interieukin-2 receptor
frequency represents a long-standing form of T cell
activation.43 It is, however, unknown what role T lymphocytes play in atherosclerosis. Do they, for example, represent an immune response to a specific component of
the plaque? This issue needs to be clarified and requires
an immunologic characterization of T lymphocytes derived
from plaque tissue.
Aberrant Class IIMHC Antigen Expression
T lymphocytes are not activated by foreign antigens in
solution but by peptide fragments of antigens bound to
MHC proteins on the cell surface of antigen-presenting
cells. 1011 The class I family of MHC proteins comprises
HLA-A, -B, and -C; participates in the activation of CD8type T lymphocytes; and is expressed on most cell
types. 1011 MHC class II proteins, in contrast, are normally
expressed mainly by cells of the immune system. 1011
They include HLA-DR, -DQ, and -DP antigens and are
restriction elements in the activation of CD4 type T lymphocytes.10'11 The limited tissue distribution of class II
antigens may be important in the control of the immune
response, since CD4 cells have important "helper" functions in the induction of immune responses.
Although normally restricted to cells of the immune
system, class II MHC antigens are expressed by parenchymal and stromal cells in many inflammatory and autoimmune conditions. For instance, class II antigens appear
on synovial cells in rheumatoid arthritis,44 on thyrocytes in
Graves' disease,45 and on enterocytes in celiac disease.48
They can also be induced during infections, for example,
in the urinary tract47 and gut.48 In experimental immune
responses, injection of a foreign antigen results in the
appearance of antigen-presenting, class II M H C expressing cells together with T cells. 48 - 67 These findings
suggest that "aberrantly" class ll-expressing cells can
play a central role in the immune response of autoimmune
diseases.
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Capillary endothelial cells appear to express class II
MHC antigens constitutively,9809 whereas large-vessel
endothelium is normally class ll-negative. Pober and
Gimbrone60 have shown that cultured endothelial cells
express the class II antigen, HLA-DR, when treated with
interferon-y (IFN-y). Such HLA-DR-positive endothelial
cells can serve as antigen-presenting cells and thus
substitute for macrophages during the initiation of the
immune response.61 It appears likely that endothelial
antigen presentation, for example, in the microvasculature, may be physiologically and pathophysiologically
important for the initiation and propagation of local immune
responses.
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Vascular smooth muscle cells do not normally express
class II antigens but may do so in atherosclerosis.26-27 In
fact, the majority of all plaque cells express HLA-DR. Many
of these are macrophages, but approximately one third of
the smooth muscle cells express HLA-DR and -DQ.27
Vascular HLA-DR expression is also observed in vasculitides. Moyer and Reinish62 have shown that smooth
muscle cells can express class II antigens in the autoimmune MRL/lpr mouse during vasculitis. This appears to
result in an attack by specific T lymphocytes recognizing
smooth muscle autoantigens. Similarly, in vitro immunization of lymphocytes with smooth muscle cells results in
vasculitis when these lymphocytes are injected into a
recipient.83 HLA-DR expression is also frequent in giant
cell arteritis of the human temporal artery in humans.64 In
this case, however, expression is restricted to the macrophages present in the arterrtic lesion.
The observations of class II expressing smooth muscle
cells and macrophages in the vicinity of T lymphocytes
suggested that a lymphokine induced the expression of
class II antigens. This was supported by the observation
that the addition of recombinant IFN-y to cultured rat
aortic smooth muscle cells induces class II antigen
expression. 6668 Both HLA-DR and HLA-DQ were further
enhanced by treatment with tumor necrosis factor, emphasizing the importance of lymphocyte-macrophage interactions (S. Stemme, unpubl. obs.).
It is now of central importance to find out whether
class II expression by smooth muscle cells has a functional significance. At present, data are conflicting. Murine
microvascular smooth muscle cells can present ovalbumin to ovalbumin-specific T cell clones in an MHCrestricted manner.87 In contrast, human vascular smooth
muscle cells did not induce proliferation of allogeneic
T lymphocytes.68 The discrepancy could be due to species differences; alternatively, smooth muscle cells may
be able to present foreign antigens to T cell lines and
partially activated T cells, but not to native T cells.
Humoral Components of the Immune System
Localization of Immunoglobullns
and Complement
Atherosclerotic plaques contain deposits of immunoglobulins that are not found in nonatherosclerotic arterial
tissue.6970 Similar deposits are found in the lesions of
cholesterol-fed rabbits and consist of IgG associated with
collagen fibrils, cytoskeletal filaments, and cell surfaces of
mononuclear cells. 7172 It is not known whether any of this
IgG represents specific antibodies to arterial components.
It is, however, interesting that complement factors are
found with a similar tissue distribution, 697073 suggesting
that tissue-deposited IgG may induce a local complement
activation in the plaque.
Support for this hypothesis was recently obtained by
demonstration of the C5b-9 complex in atherosclerotic
plaques.7475 This macromolecular complex is formed as
the end product of the complement cascade and serves
as a device for perforating cell membranes. The assembly
of the C5b-9 complex from the C5b, C6, C7, C8, and C9
proteins creates conformational neoantigens that are not
present on any of the native components.78 Antibodies to
the neoantigens are specific for the C5b-9 macromolecular complex, and the presence of C5b-9 complexes in a
tissue, therefore, indicates that complement activation
has taken place. The finding of C5b-9 on fibrillar structures in the fibrous cap and in an amorphous pattern in the
lipid core strongly suggests that complement activation is
occurring in the plaque. Recent studies of cholesterol-fed
rabbits show that local complement activation occurs at a
very early stage of cholesterol deposition in arterial tissue,
before any fatty streak-like lesions are observed.77 This
supports the idea that cholesterol deposits can activate
complement and that products released during activation
serve as chemotactic stimuli for monocytes to enter the
forming lesion.77
Further support for the hypothesis that complement
activation may play an important role in atherosclerosis
was obtained by recent studies of C3-binding proteins in
plaques.78 It was observed that the smooth muscle cells of
atherosclerotic plaques (but not of normal arteries) express
decay-accelerating factor, which protects the cells from
complement-mediated lysis by inhibiting C3/C5 convertase formation. This shows that the phenotypic changes of
smooth muscle cells during atherogenesis involve the
induction of complement regulatory molecules. A more
thorough review of complement activation in atherosclerosis has recently been published.79
Circulating Autoantlbodles and
Immune Complexes
Serum sickness has been repeatedly correlated with
development or aggravation of the atherosclerotic process.3
Minick and Murphy4 showed that injection of foreign
serum proteins synergize with a cholesterol-rich diet to
produce rapidly developing atherosclerotic lesions. This
may be initiated by immune complex-mediated complement activation, resulting in endothelial injury and followed by the deposition of immune complexes and complement activation in deeper layers of the arterial wall. 80
The work of Cerilli et al. 81 shows that autoimmune
responses to endothelial antigens correlate strongly to
peripheral vascular disease and suggests that antiendothelial autoantibodies are involved in the pathogenesis of
atherosclerosis (see Table 1).
Clarkson and Alexander82 proposed that vasectomy
may lead to accelerated atherosclerosis due to the presence of circulating immune complexes consisting of sperm
proteins and autoantibodies. Subsequent studies, how-
IMMUNE MECHANISMS IN ATHEROSCLEROSIS
Table 1. Antigens Proposed or Shown to Elicit Arrtibody Responses Related to Atherosclerosis
Antigen
Clinical
condition
Endothelial surface
antigen
Reference
Table 2.
Hansson et al.
Cytoklnes of Immune System
Cytokine
Cellular source
lnterleukln-1
Monocyte-macrophage
Endothelial cell
Smooth muscle cell
Other cell types
T lymphocytes
81
Sperm components
Vasectomy
82,83
lnterleukln-2
Herpes viruses
Viral
infections
84,85,86
lnterieukln-3
lnterieukin-4
lnterleukin-5
lnterleukin-6/
interferon-02
Interferon-a
Interferon-y
Tumor necrosis factor
(TNF-a)
Lymphotoxin
LJpoproteins
Qlycosylated
lipoprotelns
Cardiotipin
Oxidized lipid
Structural vessel
wall antigens
Milk proteins
Diabetes
88-92
93,94
96
97-100
Malignant
hypertension
101, 102
103, 104
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ever, have not confirmed any proatherogenic effect of
vasectomy.83
Several microorganisms, particularly herpes viruses,
have been implicated in the pathogenesis of atherosclerosis. 848586 Trie local response to such pathogens is
likely to involve both cell-mediated and antibody-based
immune reactions. Autoantibodies to an endogenous virus
can induce complement-mediated lysis of vascular smooth
muscle cells leading to arteritis in SL/Ni mice.87 The
relevance of these findings to human atherosclerosis is,
however, still unclear.
Autoantibodies to lipoproteins have been observed in
patients with atherosclerosis.88-82 The frequency of such
autoantibodies in the population at large is, however, still
unclear.
Lipoproteins that are extracellularty modified may be
recognized as neoantigens by the immune system. One
example is glycosylated low density lipoproteins (LDL),
which give rise to autoantibodies in patients with diabetes93
and in cholesterol-fed rabbits. Such autoantibodies form
immune complexes with glycosylated LDL, and these
complexes are rapidly cleared from the circulation via
macrophage Fc receptors.94 Delivery of LDL as part of
immune complexes could, therefore, serve as a mechanism for cholesterol accumulation in macrophage-derived
foam cells.95
The lipid components of the plaque may elicit immune
responses as well as the proteins, and antibodies to
phospholipids have been observed in sera from patients
with myocardial infarction and other atherosclerotic diseases. It has, therefore, been suggested that patients with
cardiolipin antibodies are at risk for recurrent cardiovascular disease.96
PeriadventitJal infiltrates consisting of T and B lymphocytes and plasma cells are frequent around atherosclerotic plaques,97-100 and may perhaps represent a specific
immune response to plaque components such as oxidized
lipid.97
Antibodies, as well as T cell responses to antigens
present in extracts of the arterial wall, have been described
both in atherosclerosis101 and in malignant hypertension.102
571
(TNF-0)
Platelet-derived growth
factor
T lymphocytes
T lymphocytes
T lymphocytes
Many cell types
Leukocytes
T lymphocytes
Monocyte-macrophage
Smooth muscle cell
T lymphocytes
Monocyte-macrophage
Endothelial cell
Smooth muscle cell
Megakaryocyte/platelet
It has been suggested that they aggravate vascular
damage.
In conclusion, it seems clear that autoantibodies to
lipoproteins, lipids, or other components of the arterial wall
can be formed during the course of an atherosclerotic
disease. The development of an antibody response to
arterial structural proteins may be analogous, for example, to the formation of antibodies to thyroglobulin in
thyroiditis. Molecules released after tissue damage could
be presented to T lymphocytes by local antigenpresenting cells. A delicately balanced immunologic tolerance to this autoantigen breaks down, and the immune
system responds by antibody production.49 Currently available data suggest that several types of autoantibodies can
form in atherosclerosis. It is not clear, however, whether
they appear frequently enough to be useful as markers of
disease or of a specific state of the disease. We know
even less about the pathogenetic significance of such
autoantibodies in atherosclerosis.
Interleukln Secretion
The activation and propagation of the immune response
depends not only on interactions between cell surface
molecules, but also on humoral factors. In fact, the cells of
the immune system can be viewed as endocrine cells,
which, in their activated state, produce high amounts of
hormone-like substances called interieukins or cytokines
(Table 2). Several of these molecules have been shown to
affect growth and gene expression in vascular cells, and,
although the interieukin-vessel wall field merits a review of
its own, we will briefly describe some aspects of interieukinvascular interactions.
lnterleukln-1 and Growth Stimulation
Monocytes and macrophages, when activated, produce
several factors that are important for immune and inflammatory responses. They also secrete growth-promoting
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ARTERIOSCLEROSIS
VOL 9, No 5, SEPTEMBER/OCTOBER 1989
Table 3. Vascular Effects of lrrterleukin-1
Cells
Endothelial cells
Induces reorganization of endothelial
monolayers
Induces procoagulant activity
Stimulates adhesion of granulocytes,
monocytes, and lymphocytes by
inducing expression of specific
adhesive proteins
Induces IL-1 release by positive
feedback
Stimulates proliferation
Increases vascular permeability
Smooth muscle cells
Induces IL-1 release by positive
feedback
Stimulates proliferation
Table 4. Vascular Effects of Tumor Necrosis Factor
Reference
106
107
108,109
110
Cells
Endothelial cells
Induces reorganization of monolayers
Induces procoagulant activity
Stimulates leukocyte adhesion by inducing
expression of adhesive surface proteins
Inhibits proliferation in vitro
Induces angiogenesis
Superinduces MHC gene expression
Reference
124
107
125,126
128
128
129,130
Smooth muscle cells
111
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112
Superinduces class I MHC genes
Modulates IFN-y-induced class II MHC
genes
113
MHC=major histocompatbillty complex, IFN-y=interferon-y.
114
that TNF-a can be produced by vascular smooth muscle
cells. 130 TNF-a induces vascular and inflammatory
responses similar to those of IL-1 (Table 4), but may, in
addition, cause tumor cytotoxicity and the cachexia seen
in malignant diseases. 117119 ' 132133 TNF, therefore, interferes with metabolic processes at many steps. One of
them is the control of lipotytic activity.
Upoprotein lipase (LPL) is synthesized by parenchymal
cells of several tissues including skeletal and cardiac
muscle, adipose tissue, and also the arterial wall. 1 3 4 1 3 5 1 3 6
TNF and also IL-1 suppress LPL activity in adipocytes,
and this may be an important part of the catabolic activity
of these cytokines. 132137138139
LPL is secreted by macrophages in culture, and it has
been proposed that macrophages induce local lipolysis in
the atherosclerotic plaque by LPL secretion. 140141 We
have recently found that immunoreactive LPL cannot be
detected in macrophages of atherosclerotic lesions.142
Instead, the smooth muscle cell is the major source of
immunodetectable LPL in both the atherosclerotic and the
normal artery.142 HLA-DR-expressing muscle cells are,
however, frequently LPL-negative. This may imply that
inflammatory stimuli such as IFN-yand TNF-a may inhibit
local LPL production in the plaque.
Induces synthesis of growth-inhibitory
prostaglandlns
114
Induces PDGF secretion
115
PDGF=platelet-dertved growth factor, IL-1=interieukin-1.
substances, the best-known of which is platelet-derived
growth factor.108
lnterleukin-1 (IL-1) is probably the best characterized
monocyte-derived irrterleukin (Table 3). It was originally
identified as a lymphocyte-activating factor in conditioned
media from activated monocytes.116-119 It has subsequently been purified, cloned, and characterized. There are
two forms of IL-1, a and 0, with similar effects including
induction of tissue catabolism and acute inflammatory
responses.116-119 When added to cultured endothelia) cells,
IL-1 induces a variety of responses, resulting in expression
of adhesive surface proteins, metabolic changes, and
structural reorganization (Table 3).106-109,120,121 /\ common
denominator for these responses may be an induction of a
pro-inflammatory endothelial phenotype.
LJbby and co-workers122 have shown that IL-1 may
participate in autocrine and paracrine growth regulation in
the vessel wall. They first observed that endothelial cells
produce IL-1 when stimulated, for example, by endotoxin.
They then found that smooth muscle cells, when appropriately stimulated, also synthesize and secrete large
amounts of IL-1. 1 2 3 IL-1 production by both endothelial
and smooth muscle cells is stimulated in the presence of
IL-1, forming a positive-feedback loop. 110113 It has recently
been shown 115 that IL-1 induces secretion of plateletderived growth factor (PDGF) by smooth muscle cells,
and this may account for the growth-promoting effect of
IL-1. However, IL-1 also induces production of growthinhibitory prostaglandins,114 and the in vivo effect of a
local IL-1 release in the arterial wall is therefore unclear.
Tumor Necrosis Factor-a and Upolysls
The activated macrophage produces a 17-kD protein
called tumor necrosis factor (TNF). It is also known as
cachectin, and since the lymphocyte makes a structurally
related substance, lymphotoxin, the macrophage product
is often identified as TNF-a. It has recently been shown
131
131
Interferon-y and Growth Control
The resting T lymphocyte does not secrete any hormonelike substances, but the activated cell is a rich source of
biologically active proteins. The best studied of these is
IFN-y. (See Table 5.)
IFN-ywas initially recognized as an antiviral factor, but
it has subsequently become clear that it is a major
activating factor of the immune system. 148147 IFN-y has
three major effects: it induces expression of MHC genes,
inhibits cell proliferation, and induces antiviral activity. In
addition, it affects expression of a variety of genes in
many different cell types including macrophages and
vascular cells.148
Poberetal.80'81 demonstrated that IFN-y induces expression of class II genes of the MHC by a variety of target
cells including endothelial cells. Such class ll-expressing
endothelial cells become capable of presenting antigens
IMMUNE MECHANISMS IN ATHEROSCLEROSIS
Table 5.
Vascular Effects of Interferon-y
Cells
Endothelial cells
Induces reorganization of
monolayers
Inhibits proliferation
Superinduces class 1 MHC
genes
Induces class II MHC genes
Induces "new" surface proteins
associated with autoimmune
response (Kawasaki
disease)
Increases vascular
permeability
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Inhibits PDGF and IL-1
expression
Smooth muscle cells
Inhibits proliferation
Superinduces class I MHC
genes
Induces class II MHC genes
Reference
124
143
144
60,61
145
112
158
66,131
131
65,66
MHC=major histocompatibility complex, PDGF=plateletderfved growth factor, IL-1 =interleukin 1.
to T cells, thus substituting for macrophages in the initiation of the immune response.
A number of other genes are also regulated by IFN-y.
Among these are the collagens, the synthesis of which are
inhibited on the RNA level by IFN-y. 148160 IFN-y may also
reduce the elastin content of connective tissues by increasing elastase activity.151
IFN-y is a very potent growth inhibitor. As little as
10 U/ml of IFN-y, corresponding to approximately 2 ng/ml,
significantly inhibits the proliferation of rat aortic smooth
muscle cells.86 Similar observations have been made on
human arterial smooth muscle cells131 and on human
endothelial cells.143 Since IFN-y induces expression of
class II antigens on vascular and other cell types, the
expression of such antigens by cells that do not normally
express these proteins may be looked upon as markers of
IFN-y effects on the cells. We applied this reasoning in a
response-to-injury model of atherosclerosis. A proliferative intimal lesion was produced in rat carotid arteries by
balloon catheterization. This was stained for the rat class II
antigen, I-A, and analyzed for cell proliferation by 3 Hthymidine autoradiography.88 Smooth muscle cells that
expressed I-A did not proliferate, indicating that IFN-y
secreted by T cells present in the lesion acts as a
paracrine growth inhibitor during the arterial response to
injury.66
It has recently been shown that IFN-y up-regulates high
density lipoprotein (HDL) receptors on cultured
fibroblasts.152 It appears likely that this effect is secondary
to the growth-inhibitory effect of IFN-y, which would lead to
a reduced demand for cholesterol.162
Another interferon-like protein, interferon-/32 (IFN-02),
may serve as an autocrine growth regulator. Its expression
is induced by other cytokines such as TNF and PDGF, and
IFN-02 effectively inhibits cell proliferation. 1531 " IFN-02 is
Hansson et al.
573
identical to IL-6, and has also been called hybridoma
growth factor and B cell differentiation factor.
Monoklnes, Lymphoklnes, and Regulation of
Vascular Cell Growth and Differentiation
A multitude of different growth-promoting and growthinhibiting factors may be made by the inflammatory cells
present in the atherosclerotic plaque. What may be the
net effect of this? Our studies on the effects of IFN-y in the
vessel w a l l 2 6 2 7 6 6 6 6 1 3 1 show that: 1) IFN-y is locally
released by activated T lymphocytes in the atherosclerotic
plaque and during the response to injury in experimental
models, 2) IFN-y induces class II MHC antigen expression in neighboring smooth muscle cells and macrophages by paracrine stimulation, and 3) IFN-y probably
functions as a growth inhibitor in the plaque, since IFN-ystimulated, class ll-expressing smooth muscle cells do
not proliferate. (See Figure 3.)
IFN-y and other T cell products are, however, activators
of macrophages,146147 and this may lead to other effects.
The activated macrophage secretes IL-1 and PDGF,
which are growth promoters for smooth muscle cells, 114115
and also TNF-a, which has important metabolic effects.132
Endothelial cells also produce growth factors such as
PDGF, 155 ' 156157 which may promote growth of smooth
muscle cells. It has recently been shown that IFN-y
inhibits endothelial expression of PDGF and IL-1, demonstrating another level for T cell regulation of vascular
growth.158
Induction of cell proliferation depends not only on the
presence of growth factors, but also on the responsiveness of the cells to these growth factors. Although smooth
muscle cells and fibroblasts in culture express receptors
for PDGF and respond vividly to the addition of PDGF to
the culture medium, 188186 recent immunohistochemicaJ
studies show that PDGF (B type) receptors are not normally expressed on vascular cells in situ. 168 Thus, the
normal arterial media is largely devoid of such receptors.
Receptors are, however, expressed on smooth muscle
cells of the atherosclerotic intima and also on intimal
smooth muscle cells in inflammatory diseases such as
rheumatoid arthritis and transplant rejection.199 A common denominator for all these conditions, including atherosclerosis, is that macrophages and T lymphocytes infiltrate the intima, and we have, therefore, proposed that
inflammatory cell interactions lead to release of an unknown
factor that induces PDGF receptors on intimal smooth
muscle cells. This, in turn, would lead to induction of cell
proliferation in a PDGF-rich environment.159
Summary
To summarize, it is possible that T cell activation in the
plaque has four different effects: a direct inhibition of
smooth muscle proliferation mediated by IFN-y, an indirect
stimulation of smooth muscle proliferation via IFN-induced
macrophage activation, an induction of responsiveness to
PDGF by induction of PDGF receptor expression, and
finally, an up-regulation of HDL receptors.
The net effect of T cell activation during the vascular
response to injury may, therefore, depend on the balance
574
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6KH88
Figure 3. Possible cell-cell Interactions between vascular and Inflammatory cells In the atherosclerotic plaque. Cytokines known to exert effects on vascular cells are included, and synthesizing as well
as target cells are Indicated. Tumor necrosis factor (TNF) produced by macrophages (M<£) may affect
endothelial organization and regulate endothelial expression of adhesive proteins and T cell function,
expression of major histocompatibillty complex (MHC) genes, and perhaps aiso lipolytic activity in
smooth muscle cells (SMC), lnterteukin-1 (IL-1) may also affect endothelial morphology and expression
of adhesive proteins. It is a co-factor for T cell growth, and may promote growth of SMC. IL-1 could
induce secretion of platelet-derived growth factor (PDGF), a smooth musde growth factor. PDGF could
also be released by both endothelial cells, macrophages, and platelets. Interferon-y (y-IFN) and
lymphotoxin (LT), both of which are T cell lymphoklnes, could regulate growth and expression of
several genes, including HLA-DR in both endothelial and smooth muscle cells. Together, these
cytokines may have profound effects on growth and differentiation in the vessel wail.
between these mechanisms in any given situation during
lesion development. T cell activation may itself be regulated by apclipoprotein E-containing LDL, which thus
could form a direct link between lipoprotein accumulation
and immune activation.160
We have recently tried to assess the effect of T cell
activation during the response to experimental arterial
injury with the use of a drug model. Cyclosporin A is a
drug that specifically inhibits T cell activation. Rats treated
with cyclosporin A for a short period had significantly
smaller intimal lesions than did controls after balloon
injury.161 This could be due to an inhibition of T cell
activation, resulting in an inhibition of monocytemacrophage activation and thereby loss of an important
stimulus for intimai cell proliferation. When interpreting
these results, one must, however, bear in mind that
cyclosporin A could exert as yet unknown nonimmune
vascular effects.
It is also worth stressing that cell proliferation in the
human atherosclerotic plaque may not be as high as in
experimental animal lesions. In fact, cell replication may
be a very rare event in the average advanced atherosclerotic plaque. 162163 Cell proliferation may, however, be
associated with an episodic growth of lesions, and growth
factor-mediated responses could, therefore, be important
for the eventual clinical outcome in the individual patient.
In conclusion, cytokines produced during the immune
response affect growth and differentiation of vascular cells
and could modulate both the response to injury and the
local lipid metabolism in an atherosclerotic plaque (Figure 3). There is indirect support for paracrine secretion of
several of these factors in the atherosclerotic plaque, and
activated T lymphocytes and macrophages are abundant
in the plaque. This points to the possibility that specific
immune responses are associated with the development
of atherosclerosis. It is unknown, however, to what extent
such immune responses occur or which antigens may
elicit these responses.
Acknowledgments
We thank Andrzej Tarkowski for critical reading and
Anne-Marie Fredholm for manuscript preparation.
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Index Terms: atherosclerosis • immunology • inflammation • artery • monocyte • endothelium
smooth muscle, vascular • lymphokines • monokines • interleukins • irrterferons
Immune mechanisms in atherosclerosis.
G K Hansson, L Jonasson, P S Seifert and S Stemme
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Arterioscler Thromb Vasc Biol. 1989;9:567-578
doi: 10.1161/01.ATV.9.5.567
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