Inflammation, Atherosclerosis, and Coronary Artery Disease
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《新英格兰医药杂志》
Recent research has shown that inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions, and activation of inflammation can elicit acute coronary syndromes. This review highlights the role of inflammation in the pathogenesis of atherosclerotic CAD. It will recount the evidence that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree.
A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world.1 Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.
Main Features of Atherosclerotic Lesions
Atherosclerotic lesions (atheromata) are asymmetric focal thickenings of the innermost layer of the artery, the intima (Figure 1). They consist of cells, connective-tissue elements, lipids, and debris.2 Blood-borne inflammatory and immune cells constitute an important part of an atheroma, the remainder being vascular endothelial and smooth-muscle cells. The atheroma is preceded by a fatty streak, an accumulation of lipid-laden cells beneath the endothelium.3 Most of these cells in the fatty streak are macrophages, together with some T cells. Fatty streaks are prevalent in young people, never cause symptoms, and may progress to atheromata or eventually disappear.
Figure 1. Atherosclerotic Lesion in a Human Artery.
Panel A shows a cross-sectioned coronary artery from a patient who died of a massive myocardial infarction. It contains an occlusive thrombus superimposed on a lipid-rich atherosclerotic plaque. The fibrous cap covering the lipid-rich core has ruptured (area between the arrows), exposing the thrombogenic core to the blood. Trichrome stain was used, rendering luminal thrombus and intraplaque hemorrhage red and collagen blue. Panel B is a high-power micrograph of the area in Panel A indicated by the asterisk and shows that the contents of the atheromatous plaque have seeped through the gap in the cap into the lumen, suggesting that plaque rupture preceded thrombosis (the asterisk indicates cholesterol crystals). (Panels A and B courtesy of Dr. Erling Falk, University of Aarhus, Aarhus, Denmark.) Panel C illustrates the consequences of the activation of immune cells in a coronary plaque. Microbes, autoantigens, and various inflammatory molecules can activate T cells, macrophages, and mast cells, leading to the secretion of inflammatory cytokines (e.g., interferon- and tumor necrosis factor) that reduce the stability of plaque. The activation of macrophages and mast cells also causes the release of metalloproteinases and cysteine proteases, which directly attack collagen and other components of the tissue matrix. These cells may also produce prothrombotic and procoagulant factors that directly precipitate the formation of thrombus at the site of plaque rupture.
In the center of an atheroma, foam cells and extracellular lipid droplets form a core region, which is surrounded by a cap of smooth-muscle cells and a collagen-rich matrix. T cells, macrophages, and mast cells infiltrate the lesion and are particularly abundant in the shoulder region where the atheroma grows.2,4,5 Many of the immune cells exhibit signs of activation and produce inflammatory cytokines.5,6,7,8
Myocardial infarction occurs when the atheromatous process prevents blood flow through the coronary artery. It was previously thought that progressive luminal narrowing from continued growth of smooth-muscle cells in the plaque was the main cause of infarction. Angiographic studies have, however, identified culprit lesions that do not cause marked stenosis,9 and it is now evident that the activation of plaque rather than stenosis precipitates ischemia and infarction (Figure 1). Coronary spasm may be involved to some extent, but most cases of infarction are due to the formation of an occluding thrombus on the surface of the plaque.10
There are two major causes of coronary thrombosis: plaque rupture and endothelial erosion. Plaque rupture, which is detectable in 60 to 70 percent of cases,11 is dangerous because it exposes prothrombotic material from the core of the plaque — phospholipids, tissue factor, and platelet-adhesive matrix molecules — to the blood (Figure 1). Ruptures preferentially occur where the fibrous cap is thin and partly destroyed. At these sites, activated immune cells are abundant.7 They produce numerous inflammatory molecules and proteolytic enzymes that can weaken the cap and activate cells in the core, transforming the stable plaque into a vulnerable, unstable structure that can rupture, induce a thrombus, and elicit an acute coronary syndrome (Figure 1). To understand how this can happen, we need to identify the key steps leading from a normal artery wall to a rupture-prone atherosclerotic plaque.
Evolution of the Rupture-Prone Atherosclerotic Plaque
Gene-Targeted Mouse Models
Clinical investigations, population studies, and cell-culture experiments have provided important clues to the pathogenesis of atherosclerosis. However, experiments in animals are needed to dissect the pathogenetic steps and determine causality.12 Atherosclerosis does not develop in laboratory mice under normal conditions. However, targeted deletion of the gene for apolipoprotein E (apoE-knockout mice) leads to severe hypercholesterolemia and spontaneous atherosclerosis. Atherosclerosis also develops in mice lacking low-density lipoprotein (LDL) receptors, especially when the mice are fed a fatty diet. One can use these knockout mice to study the relationship between hypercholesterolemia and atherosclerosis and to assess the effects of other genes and gene products on these conditions. By mating these mice with knockout mice lacking immunoregulatory genes, it is possible to clarify the role of immunologic and inflammatory mechanisms in atherosclerosis. Obviously, the findings in such models must be corroborated, as much as possible, by studies of human cells and tissues. Our current understanding of atherosclerosis therefore rests on a combination of research in animals and cell cultures, analysis of human lesions, clinical investigations of patients with acute coronary syndromes, and epidemiologic studies of CAD.
Lipoprotein Retention and Activation of Immune Cells
Role of Endothelial Activation, Adhesion Molecules, and Chemokines
Studies in animals and humans have shown that hypercholesterolemia causes focal activation of endothelium in large and medium-sized arteries. The infiltration and retention of LDL in the arterial intima initiate an inflammatory response in the artery wall13,14 (Figure 2). Modification of LDL, through oxidation or enzymatic attack in the intima, leads to the release of phospholipids that can activate endothelial cells,14 preferentially at sites of hemodynamic strain.15 Patterns of hemodynamic flow typical for atherosclerosis-prone segments (low average shear but high oscillatory shear stress) cause increased expression of adhesion molecules and inflammatory genes by endothelial cells.16 Therefore, hemodynamic strain and the accumulation of lipids may initiate an inflammatory process in the artery.
Figure 2. Activating Effect of LDL Infiltration on Inflammation in the Artery.
In patients with hypercholesterolemia, excess LDL infiltrates the artery and is retained in the intima, particularly at sites of hemodynamic strain. Oxidative and enzymatic modifications lead to the release of inflammatory lipids that induce endothelial cells to express leukocyte adhesion molecules. The modified LDL particles are taken up by scavenger receptors of macrophages, which evolve into foam cells.
The platelet is the first blood cell to arrive at the scene of endothelial activation.17 Its glycoproteins Ib and IIb/IIIa engage surface molecules on the endothelial cell, which may contribute to endothelial activation. Inhibition of platelet adhesion reduces leukocyte infiltration and atherosclerosis in hypercholesterolemic mice.17
Activated endothelial cells express several types of leukocyte adhesion molecules, which cause blood cells rolling along the vascular surface to adhere at the site of activation.18 Since vascular-cell adhesion molecule 1 (VCAM-1) is typically up-regulated in response to hypercholesterolemia, cells carrying counterreceptors for VCAM-1 (i.e., monocytes and lymphocytes) preferentially adhere to these sites (Figure 2, Figure 3, and Figure 4).19 Once the blood cells have attached, chemokines produced in the underlying intima stimulate them to migrate through the interendothelial junctions and into the subendothelial space (Figure 2, Figure 3, and Figure 4). Genetic abrogation or pharmacologic blockade of certain chemokines and adhesion molecules for mononuclear cells inhibits atherosclerosis in mice.20,21,22,23,24
Figure 3. Role of Macrophage Inflammation of the Artery.
Monocytes recruited through the activated endothelium differentiate into macrophages. Several endogenous and microbial molecules can ligate pattern-recognition receptors (toll-like receptors) on these cells, inducing activation and leading to the release of inflammatory cytokines, chemokines, oxygen and nitrogen radicals, and other inflammatory molecules and, ultimately, to inflammation and tissue damage.
Figure 4. Effects of T-Cell Activation on Plaque Inflammation.
Antigens presented by macrophages and dendritic cells (antigen-presenting cells) trigger the activation of antigen-specific T cells in the artery. Most of the activated T cells produce Th1 cytokines (e.g., interferon-), which activate macrophages and vascular cells, leading to inflammation. Regulatory T cells modulate the process by secreting antiinflammatory cytokines (such as interleukin-10 and transforming growth factor ).
Macrophages in the Developing Plaque
A cytokine or growth factor produced in the inflamed intima, macrophage colony-stimulating factor, induces monocytes entering the plaque to differentiate into macrophages (Figure 3). This step is critical for the development of atherosclerosis25 and is associated with up-regulation of pattern-recognition receptors for innate immunity, including scavenger receptors and toll-like receptors.26,27
Scavenger receptors internalize a broad range of molecules and particles bearing molecules with pathogen-like molecular patterns.26 Bacterial endotoxins, apoptotic cell fragments, and oxidized LDL particles are all taken up and destroyed through this pathway. If cholesterol derived from the uptake of oxidized LDL particles cannot be mobilized from the cell to a sufficient extent, it accumulates as cytosolic droplets. Ultimately, the cell is transformed into a foam cell, the prototypical cell in atherosclerosis.
Toll-like receptors also bind molecules with pathogen-like molecular patterns, but in contrast to scavenger receptors, they can initiate a signal cascade that leads to cell activation.27 The activated macrophage produces inflammatory cytokines, proteases, and cytotoxic oxygen and nitrogen radical molecules. Similar effects are observed in dendritic cells, mast cells, and endothelial cells, which also express toll-like receptors. Bacterial toxins, stress proteins, and DNA motifs are all recognized by various toll-like receptors.27 In addition, human heat-shock protein 60 and oxidized LDL particles may activate these receptors.28,29 Cells in human atherosclerotic lesions display a spectrum of toll-like receptors,30 and plaque inflammation may partly depend on this pathway. In support of this notion, genetic removal of a molecule in the toll-like receptor signaling pathway inhibits atherosclerosis in apoE-knockout mice.31
T-Cell Activation and Vascular Inflammation
Immune cells, including T cells, antigen-presenting dendritic cells, monocytes, macrophages, and mast cells, patrol various tissues, including atherosclerotic arteries, in search of antigen.32,33 A T-cell infiltrate is always present in atherosclerotic lesions (Figure 4). Such infiltrates are predominantly CD4+ T cells, which recognize protein antigens presented to them as fragments bound to major-histocompatibility-complex (MHC) class II molecules (Figure 4). CD4+ T cells reactive to the disease-related antigens oxidized LDL, heat-shock protein 60, and chlamydia proteins have been cloned from human lesions.28,34,35
A minor T-cell subpopulation, natural killer T cells, is prevalent in early lesions. Natural killer T cells recognize lipid antigens, and their activation increases atherosclerosis in apoE-knockout mice.36 CD8+ T cells restricted by MHC class I antigens are also present in atherosclerotic lesions.33 These cells typically recognize viral antigens, which may be present in the lesions (see below). Activation of CD8+ T cells in apoE-knockout mice can cause the death of arterial cells and accelerate atherosclerosis.37
When the antigen receptor of the T cell is ligated by antigen, an activation cascade results in the expression of a set of cytokines, cell-surface molecules, and enzymes. In inbred mice, two stereotypical responses can be elicited.38 The type 1 helper T (Th1) response activates macrophages, initiates an inflammatory response similar to delayed hypersensitivity, and characteristically functions in the defense against intracellular pathogens. The type 2 helper T (Th2) response elicits an allergic inflammation. Although the Th1–Th2 system is more plastic in humans, the general pattern is similar.
The atherosclerotic lesion contains cytokines that promote a Th1 response (rather than a Th2 response).8,39 Activated T cells therefore differentiate into Th1 effector cells and begin producing the macrophage-activating cytokine interferon- (Figure 4). Interferon- improves the efficiency of antigen presentation and augments synthesis of the inflammatory cytokines tumor necrosis factor and interleukin-1.38 Acting synergistically, these cytokines instigate the production of many inflammatory and cytotoxic molecules in macrophages and vascular cells.33 All these actions tend to promote atherosclerosis. Indeed, in apoE-knockout mice lacking interferon- or its receptor, the development of atherosclerosis is inhibited.40,41 Similarly, the extent of the disease is reduced when the Th1 pathway is inhibited pharmacologically42 or genetically43,44,45 in animals.
Cytokines of the Th2 pathway can promote antiatherosclerotic immune reactions.46 However, they may also contribute to the formation of aneurysms by inducing elastolytic enzymes.47 Therefore, switching the immune response of atherosclerosis from Th1 to Th2 may not necessarily lead to reduced vascular disease.
T-cell cytokines cause the production of large amounts of molecules downstream in the cytokine cascade (Figure 5). As a result, elevated levels of interleukin-6 and C-reactive protein may be detected in the peripheral circulation. In this way, the activation of a limited number of immune cells can initiate a potent inflammatory cascade, both in the forming lesion and systemically.
Figure 5. The Cytokine Cascade.
Activated immune cells in the plaque produce inflammatory cytokines (interferon-, interleukin-1, and tumor necrosis factor ), which induce the production of substantial amounts of interleukin-6. These cytokines are also produced in various tissues in response to infection and in the adipose tissue of patients with the metabolic syndrome. Interleukin-6, in turn, stimulates the production of large amounts of acute-phase reactants, including C-reactive protein (CRP), serum amyloid A, and fibrinogen, especially in the liver. Although cytokines at all steps have important biologic effects, their amplification at each step of the cascade makes the measurement of downstream mediators such as CRP particularly useful for clinical diagnosis.
Antiinflammatory Factors and Disease Activity
Powerful regulators built into the immune network act as protective factors in at
A decade ago, the treatment of hypercholesterolemia and hypertension was expected to eliminate CAD by the end of the 20th century. Lately, however, that optimistic prediction has needed revision. Cardiovascular diseases are expected to be the main cause of death globally within the next 15 years owing to a rapidly increasing prevalence in developing countries and eastern Europe and the rising incidence of obesity and diabetes in the Western world.1 Cardiovascular diseases cause 38 percent of all deaths in North America and are the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts force us to revisit cardiovascular disease and consider new strategies for prediction, prevention, and treatment.
Main Features of Atherosclerotic Lesions
Atherosclerotic lesions (atheromata) are asymmetric focal thickenings of the innermost layer of the artery, the intima (Figure 1). They consist of cells, connective-tissue elements, lipids, and debris.2 Blood-borne inflammatory and immune cells constitute an important part of an atheroma, the remainder being vascular endothelial and smooth-muscle cells. The atheroma is preceded by a fatty streak, an accumulation of lipid-laden cells beneath the endothelium.3 Most of these cells in the fatty streak are macrophages, together with some T cells. Fatty streaks are prevalent in young people, never cause symptoms, and may progress to atheromata or eventually disappear.
Figure 1. Atherosclerotic Lesion in a Human Artery.
Panel A shows a cross-sectioned coronary artery from a patient who died of a massive myocardial infarction. It contains an occlusive thrombus superimposed on a lipid-rich atherosclerotic plaque. The fibrous cap covering the lipid-rich core has ruptured (area between the arrows), exposing the thrombogenic core to the blood. Trichrome stain was used, rendering luminal thrombus and intraplaque hemorrhage red and collagen blue. Panel B is a high-power micrograph of the area in Panel A indicated by the asterisk and shows that the contents of the atheromatous plaque have seeped through the gap in the cap into the lumen, suggesting that plaque rupture preceded thrombosis (the asterisk indicates cholesterol crystals). (Panels A and B courtesy of Dr. Erling Falk, University of Aarhus, Aarhus, Denmark.) Panel C illustrates the consequences of the activation of immune cells in a coronary plaque. Microbes, autoantigens, and various inflammatory molecules can activate T cells, macrophages, and mast cells, leading to the secretion of inflammatory cytokines (e.g., interferon- and tumor necrosis factor) that reduce the stability of plaque. The activation of macrophages and mast cells also causes the release of metalloproteinases and cysteine proteases, which directly attack collagen and other components of the tissue matrix. These cells may also produce prothrombotic and procoagulant factors that directly precipitate the formation of thrombus at the site of plaque rupture.
In the center of an atheroma, foam cells and extracellular lipid droplets form a core region, which is surrounded by a cap of smooth-muscle cells and a collagen-rich matrix. T cells, macrophages, and mast cells infiltrate the lesion and are particularly abundant in the shoulder region where the atheroma grows.2,4,5 Many of the immune cells exhibit signs of activation and produce inflammatory cytokines.5,6,7,8
Myocardial infarction occurs when the atheromatous process prevents blood flow through the coronary artery. It was previously thought that progressive luminal narrowing from continued growth of smooth-muscle cells in the plaque was the main cause of infarction. Angiographic studies have, however, identified culprit lesions that do not cause marked stenosis,9 and it is now evident that the activation of plaque rather than stenosis precipitates ischemia and infarction (Figure 1). Coronary spasm may be involved to some extent, but most cases of infarction are due to the formation of an occluding thrombus on the surface of the plaque.10
There are two major causes of coronary thrombosis: plaque rupture and endothelial erosion. Plaque rupture, which is detectable in 60 to 70 percent of cases,11 is dangerous because it exposes prothrombotic material from the core of the plaque — phospholipids, tissue factor, and platelet-adhesive matrix molecules — to the blood (Figure 1). Ruptures preferentially occur where the fibrous cap is thin and partly destroyed. At these sites, activated immune cells are abundant.7 They produce numerous inflammatory molecules and proteolytic enzymes that can weaken the cap and activate cells in the core, transforming the stable plaque into a vulnerable, unstable structure that can rupture, induce a thrombus, and elicit an acute coronary syndrome (Figure 1). To understand how this can happen, we need to identify the key steps leading from a normal artery wall to a rupture-prone atherosclerotic plaque.
Evolution of the Rupture-Prone Atherosclerotic Plaque
Gene-Targeted Mouse Models
Clinical investigations, population studies, and cell-culture experiments have provided important clues to the pathogenesis of atherosclerosis. However, experiments in animals are needed to dissect the pathogenetic steps and determine causality.12 Atherosclerosis does not develop in laboratory mice under normal conditions. However, targeted deletion of the gene for apolipoprotein E (apoE-knockout mice) leads to severe hypercholesterolemia and spontaneous atherosclerosis. Atherosclerosis also develops in mice lacking low-density lipoprotein (LDL) receptors, especially when the mice are fed a fatty diet. One can use these knockout mice to study the relationship between hypercholesterolemia and atherosclerosis and to assess the effects of other genes and gene products on these conditions. By mating these mice with knockout mice lacking immunoregulatory genes, it is possible to clarify the role of immunologic and inflammatory mechanisms in atherosclerosis. Obviously, the findings in such models must be corroborated, as much as possible, by studies of human cells and tissues. Our current understanding of atherosclerosis therefore rests on a combination of research in animals and cell cultures, analysis of human lesions, clinical investigations of patients with acute coronary syndromes, and epidemiologic studies of CAD.
Lipoprotein Retention and Activation of Immune Cells
Role of Endothelial Activation, Adhesion Molecules, and Chemokines
Studies in animals and humans have shown that hypercholesterolemia causes focal activation of endothelium in large and medium-sized arteries. The infiltration and retention of LDL in the arterial intima initiate an inflammatory response in the artery wall13,14 (Figure 2). Modification of LDL, through oxidation or enzymatic attack in the intima, leads to the release of phospholipids that can activate endothelial cells,14 preferentially at sites of hemodynamic strain.15 Patterns of hemodynamic flow typical for atherosclerosis-prone segments (low average shear but high oscillatory shear stress) cause increased expression of adhesion molecules and inflammatory genes by endothelial cells.16 Therefore, hemodynamic strain and the accumulation of lipids may initiate an inflammatory process in the artery.
Figure 2. Activating Effect of LDL Infiltration on Inflammation in the Artery.
In patients with hypercholesterolemia, excess LDL infiltrates the artery and is retained in the intima, particularly at sites of hemodynamic strain. Oxidative and enzymatic modifications lead to the release of inflammatory lipids that induce endothelial cells to express leukocyte adhesion molecules. The modified LDL particles are taken up by scavenger receptors of macrophages, which evolve into foam cells.
The platelet is the first blood cell to arrive at the scene of endothelial activation.17 Its glycoproteins Ib and IIb/IIIa engage surface molecules on the endothelial cell, which may contribute to endothelial activation. Inhibition of platelet adhesion reduces leukocyte infiltration and atherosclerosis in hypercholesterolemic mice.17
Activated endothelial cells express several types of leukocyte adhesion molecules, which cause blood cells rolling along the vascular surface to adhere at the site of activation.18 Since vascular-cell adhesion molecule 1 (VCAM-1) is typically up-regulated in response to hypercholesterolemia, cells carrying counterreceptors for VCAM-1 (i.e., monocytes and lymphocytes) preferentially adhere to these sites (Figure 2, Figure 3, and Figure 4).19 Once the blood cells have attached, chemokines produced in the underlying intima stimulate them to migrate through the interendothelial junctions and into the subendothelial space (Figure 2, Figure 3, and Figure 4). Genetic abrogation or pharmacologic blockade of certain chemokines and adhesion molecules for mononuclear cells inhibits atherosclerosis in mice.20,21,22,23,24
Figure 3. Role of Macrophage Inflammation of the Artery.
Monocytes recruited through the activated endothelium differentiate into macrophages. Several endogenous and microbial molecules can ligate pattern-recognition receptors (toll-like receptors) on these cells, inducing activation and leading to the release of inflammatory cytokines, chemokines, oxygen and nitrogen radicals, and other inflammatory molecules and, ultimately, to inflammation and tissue damage.
Figure 4. Effects of T-Cell Activation on Plaque Inflammation.
Antigens presented by macrophages and dendritic cells (antigen-presenting cells) trigger the activation of antigen-specific T cells in the artery. Most of the activated T cells produce Th1 cytokines (e.g., interferon-), which activate macrophages and vascular cells, leading to inflammation. Regulatory T cells modulate the process by secreting antiinflammatory cytokines (such as interleukin-10 and transforming growth factor ).
Macrophages in the Developing Plaque
A cytokine or growth factor produced in the inflamed intima, macrophage colony-stimulating factor, induces monocytes entering the plaque to differentiate into macrophages (Figure 3). This step is critical for the development of atherosclerosis25 and is associated with up-regulation of pattern-recognition receptors for innate immunity, including scavenger receptors and toll-like receptors.26,27
Scavenger receptors internalize a broad range of molecules and particles bearing molecules with pathogen-like molecular patterns.26 Bacterial endotoxins, apoptotic cell fragments, and oxidized LDL particles are all taken up and destroyed through this pathway. If cholesterol derived from the uptake of oxidized LDL particles cannot be mobilized from the cell to a sufficient extent, it accumulates as cytosolic droplets. Ultimately, the cell is transformed into a foam cell, the prototypical cell in atherosclerosis.
Toll-like receptors also bind molecules with pathogen-like molecular patterns, but in contrast to scavenger receptors, they can initiate a signal cascade that leads to cell activation.27 The activated macrophage produces inflammatory cytokines, proteases, and cytotoxic oxygen and nitrogen radical molecules. Similar effects are observed in dendritic cells, mast cells, and endothelial cells, which also express toll-like receptors. Bacterial toxins, stress proteins, and DNA motifs are all recognized by various toll-like receptors.27 In addition, human heat-shock protein 60 and oxidized LDL particles may activate these receptors.28,29 Cells in human atherosclerotic lesions display a spectrum of toll-like receptors,30 and plaque inflammation may partly depend on this pathway. In support of this notion, genetic removal of a molecule in the toll-like receptor signaling pathway inhibits atherosclerosis in apoE-knockout mice.31
T-Cell Activation and Vascular Inflammation
Immune cells, including T cells, antigen-presenting dendritic cells, monocytes, macrophages, and mast cells, patrol various tissues, including atherosclerotic arteries, in search of antigen.32,33 A T-cell infiltrate is always present in atherosclerotic lesions (Figure 4). Such infiltrates are predominantly CD4+ T cells, which recognize protein antigens presented to them as fragments bound to major-histocompatibility-complex (MHC) class II molecules (Figure 4). CD4+ T cells reactive to the disease-related antigens oxidized LDL, heat-shock protein 60, and chlamydia proteins have been cloned from human lesions.28,34,35
A minor T-cell subpopulation, natural killer T cells, is prevalent in early lesions. Natural killer T cells recognize lipid antigens, and their activation increases atherosclerosis in apoE-knockout mice.36 CD8+ T cells restricted by MHC class I antigens are also present in atherosclerotic lesions.33 These cells typically recognize viral antigens, which may be present in the lesions (see below). Activation of CD8+ T cells in apoE-knockout mice can cause the death of arterial cells and accelerate atherosclerosis.37
When the antigen receptor of the T cell is ligated by antigen, an activation cascade results in the expression of a set of cytokines, cell-surface molecules, and enzymes. In inbred mice, two stereotypical responses can be elicited.38 The type 1 helper T (Th1) response activates macrophages, initiates an inflammatory response similar to delayed hypersensitivity, and characteristically functions in the defense against intracellular pathogens. The type 2 helper T (Th2) response elicits an allergic inflammation. Although the Th1–Th2 system is more plastic in humans, the general pattern is similar.
The atherosclerotic lesion contains cytokines that promote a Th1 response (rather than a Th2 response).8,39 Activated T cells therefore differentiate into Th1 effector cells and begin producing the macrophage-activating cytokine interferon- (Figure 4). Interferon- improves the efficiency of antigen presentation and augments synthesis of the inflammatory cytokines tumor necrosis factor and interleukin-1.38 Acting synergistically, these cytokines instigate the production of many inflammatory and cytotoxic molecules in macrophages and vascular cells.33 All these actions tend to promote atherosclerosis. Indeed, in apoE-knockout mice lacking interferon- or its receptor, the development of atherosclerosis is inhibited.40,41 Similarly, the extent of the disease is reduced when the Th1 pathway is inhibited pharmacologically42 or genetically43,44,45 in animals.
Cytokines of the Th2 pathway can promote antiatherosclerotic immune reactions.46 However, they may also contribute to the formation of aneurysms by inducing elastolytic enzymes.47 Therefore, switching the immune response of atherosclerosis from Th1 to Th2 may not necessarily lead to reduced vascular disease.
T-cell cytokines cause the production of large amounts of molecules downstream in the cytokine cascade (Figure 5). As a result, elevated levels of interleukin-6 and C-reactive protein may be detected in the peripheral circulation. In this way, the activation of a limited number of immune cells can initiate a potent inflammatory cascade, both in the forming lesion and systemically.
Figure 5. The Cytokine Cascade.
Activated immune cells in the plaque produce inflammatory cytokines (interferon-, interleukin-1, and tumor necrosis factor ), which induce the production of substantial amounts of interleukin-6. These cytokines are also produced in various tissues in response to infection and in the adipose tissue of patients with the metabolic syndrome. Interleukin-6, in turn, stimulates the production of large amounts of acute-phase reactants, including C-reactive protein (CRP), serum amyloid A, and fibrinogen, especially in the liver. Although cytokines at all steps have important biologic effects, their amplification at each step of the cascade makes the measurement of downstream mediators such as CRP particularly useful for clinical diagnosis.
Antiinflammatory Factors and Disease Activity
Powerful regulators built into the immune network act as protective factors in at