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Thematic Review |
Department of Pathology, Biochemistry, and Molecular Biology, University of Chicago, Chicago, IL
Published, JLR Papers in Press, November 16, 2004. DOI 10.1194/jlr.R400013-JLR200
1 To whom correspondence should be addressed. e-mail: g-getz{at}uchicago.edu
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ABSTRACT |
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The overview is concluded with some caveats that should be considered in the analysis of atherosclerosis in experimental animals.
Abbreviations: apoE, apolipoprotein E; CD40L, CD40 ligand; CRP, C-reactive protein; dn, dominant negative; IL, interleukin; MHC, major histocompatibility complex; NF-
B, nuclear factor B; NK, natural killer; NK-T, natural killer T; OxLDL, oxidized low density lipoprotein; RAG, recombination-activating gene; SAA, serum amyloid A; TCR, T-cell receptor; TGF, transforming growth factor; Th cell, T-helper cell; TNF, tumor necrosis factor
Supplementary key words innate immunity • adaptive immunity • cytokines
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INTRODUCTION |
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A modern approach to the molecular pathogenesis of atherosclerosis has been well reviewed (2). The role of innate and adaptive immunity in its pathogenesis has been comprehensively dealt with in two recent reviews (3, 4). Readers are encouraged to consult each of these reviews alongside of this overview.
Because the following series deals in depth with important aspects of immune function in relation to atherosclerosis, in this overview I will briefly summarize the state of the subject, mostly as reflected in these aforementioned three reviews. Here, the focus will be on the lesion outcome, without dealing with the detailed cellular mechanisms. I will then update the information based upon studies published in the last 2–3 years. This will provide the backdrop for an introduction to this Thematic Series. The overview will conclude with a set of additional comments that might be helpful in the consideration of immune system participation in the modulation of atherosclerosis.
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ATHEROSCLEROSIS AS CHRONIC INFLAMMATION |
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 TOPABSTRACTINTRODUCTION ATHEROSCLEROSIS AS CHRONIC... BRIEF SUMMARY OF THE...IMMUNE MODULATION OF...INNATE IMMUNITYADAPTIVE IMMUNITYCYTOKINESTHIS SERIESADDITIONAL COMMENTSCONCLUSIONREFERENCES |
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In both human and experimental atherosclerosis, hypercholesterolemia is the major exciting factor for the development of vascular lesions. The increased cholesterol is carried either by LDL or VLDL remnants. It is now thought that increased plasma levels of LDL result in enhanced oxidation or perhaps other modifications of LDL within the vascular wall, representing a major initiating agent for the formation of the atherosclerotic response. Lipoproteins retained in the vessel wall by matrix components, the most prominent of which are the proteoglycans, are probably especially susceptible to oxidation. Oxidation of retained lipoproteins may be a function of the production of reactive oxygen species generated by the cells of inflammatory infiltrates or by enzymes such as lipoxygenases produced by infiltrating macrophages. Macrophages import oxidized LDL (OxLDL) into the endosomal system via a variety of scavenger-type receptors. The cholesterol so imported ultimately ends up in the cytoplasm, where it is esterified, generating cholesteryl ester droplets and forming foam cells that are the hallmark of early and growing atherosclerotic plaques. The accumulation of such foam cells constitutes the bulk of the early vascular lesion, designated by some as a fatty xanthoma (6). Oxidized phospholipid moieties of oxidized lipoproteins signal to many of the cells in the evolving plaque, especially to the endothelium overlying the accumulating OxLDL and to foam cells. Among other responses, this signaling increases the expression of adhesion molecules that facilitate the homing of monocytes and lymphocytes to this localized activated endothelium. The foam cells and activated endothelium may also produce proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, IFN-
, and tumor necrosis factor-
(TNF-) (7), which promote the further development of the inflammatory response. Also, the elaboration of chemotactic factors such as MCP-1 attracts the further influx of monocytes. The macrophage foam cell is a very versatile multifunctional cell, capable of elaborating reactive oxygen species, prostaglandins, nitric oxide, and growth factors. Foam cell homeostasis is the result of new recruitment and lipid loading on the one hand and efflux of lipid on the other. The latter is promoted by apolipoprotein E (apoE), apoA-I, HDL, and the ATP binding cassette proteins ABCA1, ABCG1, and ABCG4.
The progression of the lesion from the fatty xanthoma to a more complex lesion is characterized by the migration of smooth muscle cells from the media into the subendothelial intima and their subsequent proliferation. This is mediated, in part, by the growth factors secreted from macrophage foam cells. These smooth muscle cells may themselves become foam cells, but more importantly they are responsible for the synthesis of matrix proteins and proteoglycans. The foam cells may ultimately die either by necrosis or apoptosis, liberating their contained lipid and producing a necrotic core with extracellular lipid. The death of foam cells is probably related to the dysregulation of intracellular lipid metabolism and the formation of cytotoxic oxidized sterols and other lipids. Late atherosclerotic plaques may also undergo cartilaginous dysplasia with calcium deposition. The increase in the size of the evolving atherosclerotic plaque arises from the continued recruitment of monocytes and lymphocytes, the continued migration and proliferation of smooth muscle cells, the evolution of a necrotic core, and matrix protein synthesis. Activation of the macrophages in the lesions, particularly on the lesion shoulders, may lead to the release of proteases, with disruption of the plaque surface giving rise to the unstable plaque lesion becoming the nidus for thrombosis and consequent clinical complications.
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BRIEF SUMMARY OF THE IMMUNE SYSTEM |
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. NK cells when activated are particularly efficient producers of IFN-, which activates macrophages (8). NK cell activity is influenced by other cytokines, such as IL-2, IL-15, and IL-12. Dendritic cells play a key role in antigen presentation, expressing high levels of scavenger receptors and class II major histocompatibility complexes (MHCs), which present antigens to cells of the adaptive immune system. They also express costimulatory molecules, B7-1 and B7-2. Mast cells on activation release histamine, leukotrienes, platelet-activating factor, proteases, and cytokines. In a sense, all of the cells included in the initial atherosclerotic response can be regarded as part of the innate immune response, because endothelial cells and smooth muscle cells can be induced, for example by IFN-, to express class I and class II MHC proteins. The MHCs on these cells are capable of presenting antigens, although not nearly with the efficiency of the more traditional antigen-presenting cells, macrophages, and dendritic cells. B1 cells bridge the innate and adaptive immune systems. They are responsible for the production of IgM antibodies, many of which react with oxidized phospholipids. These antibodies have been shown to block the uptake of OxLDL by macrophage scavenger receptors. The activation of the inflammatory response induces the synthesis and release of IL-1, TNF-, and IL-6, which are responsible for inducing in the liver the transcription of the acute-phase plasma proteins, including C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, and ferritin, as well as proteins of the complement system. An outline of the innate immune system is shown in Fig. 1
.
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and ß chains. A small proportion of T-cells express a TCR consisting of and 
subunits. The latter T-cells recognize antigens without the necessity that they be presented on MHC molecules. Although these cells are capable of generating a large variety of antigen receptors, most of them recognize a limited number of antigens (9). Some of these cells respond to heat shock proteins (10).
T-cells may be divided into CD4+ and CD8+ subclasses. The majority of T-cells in atherosclerotic plaques are CD4+ cells, although smaller numbers of CD8+ cells have been detected. CD4+ cells recognize antigen loaded on MHC class II molecules of the antigen-presenting cell, whereas CD8+ cells recognize antigens presented in the context of MHC class I molecules. Among the CD4+ cells are several subgroups, three of which have been investigated in murine atherosclerosis. These subgroups are distinguished by the complement of cytokines they produce. Th1 cells mainly secrete proinflammatory cytokines such as IFN-, which activates macrophages and facilitates the production of antibodies of the IgG2a class by B-cells. T-helper 1 (Th1) cells do not secrete IL-4 or IL-5. Th2 cells, on the other hand, secrete IL-4 and IL-5 but not IFN-. These cells provide help for the synthesis of other antibody classes. The Th2 cytokines may be anti-inflammatory. There is cross-regulation among these two subsets of T-cells, so that each tends to inhibit the other. IFN- inhibits Th2 cells and IL-4 inhibits Th1 cell cytokine secretion. Also, IL-10 inhibits the Th1 pathway, whereas IL-12 reduces the Th2 responses (4). A third special subset of T-cells are the natural killer T cells (NK-T cells), which bear some of the same markers as NK cells, but unlike the latter they express rearranged cell surface TCRs of limited diversity. They mainly recognize lipid antigen in the context of the MHC-like compound CD1. There are other T-cell subsets that have been less studied in atherosclerosis (e.g., T-regulatory cells, Th3 cells, etc.).
B-cells are the other major group of circulating lymphocytes. They recognize antigen via the B-cell antigen receptor, in which cell surface IgM plays a central role. Like T-cells, B-cells, through these receptors, express unique specificity derived from the rearrangement of immunoglobulin genes, a process that is also RAG dependent. Mature B-cells, designated as plasma cells, secrete specific antibodies. The production of antibodies to protein antigen requires T-cell help. The interaction between T-cells and B-cells is facilitated by CD40 ligand (CD40L) expressed on T-cells and CD40 on B-cells.
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IMMUNE MODULATION OF ATHEROSCLEROSIS |
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Several lines of evidence have been adduced to implicate the immune system in the process of atherosclerosis. First, the presence of immune cells and immune cell products in the human and/or experimental atherosclerotic lesion is taken to indicate their likely participation in the lesion biology. Millonig, Malcom, and Wick (12) have described a "vascular associated lymphoid tissue" in vascular regions susceptible to atherosclerosis. Macrophages and T-cells are detectable in this tissue even before the plaque develops. Among the immune cells and molecules detected in human atherosclerotic plaques are macrophages, dendritic cells (13), CD4+ T-cells, CD8+ T-cells, MHC class II, CD40, and CD40L, the cytokines IL-1, IL-2, IFN-, IL-7, IL-10, IL-12, IL-18, TNF-, transforming growth factor-ß (TGFß), as well as immunoglobulin (4, 12). The cytokines of Th2 cells are present at much lower levels (7). The presence of both proinflammatory and anti-inflammatory cytokines speaks to the possibility of the coexistence of proatherogenic and antiatherogenic influences in lesions. B-cells are relatively rare among the cells of the human atherosclerotic plaque, although they may be found in the neighboring adventitia.
Second, more compelling evidence for the role of the immune system in atherogenesis derives from specific gene deletion or overexpression in mice. The knockout of scavenger receptors (SR-A, CD36), mediators of monocyte chemotaxis (MCP-1, CCR2), IFN- or its receptor, costimulatory molecules, CD40L, and the RAG genes, resulting in global immunodeficiency, all lead to a reduction in atherosclerosis in mouse models (3, 4). On the other hand, the knockout of the Th1 inhibitory cytokine, IL-10, results in an increase in lesions. The pattern of cell and cytokine involvement suggests a Th1 dominance in atherosclerotic lesions. This dominance has been reported to reverse in the face of marked hypercholesterolemia, at least in the apoE-deficient mouse (14). The Th2 cytokine IL-4 was thought to afford protection, but its influence may be more complex, because IL-4 deficiency in the background of either apoE deficiency or LDL receptor deficiency leads to a reduction in lesion size (15, 16). This argues that cytokine effects might not be simply explained by resorting to the Th1/Th2 paradigm. Non-T-cell-dependent effects of IL-4 may be at work (16). Recently, IL-5 has been reported to play a protective role (17). Cytokine effects on atherogenesis indeed seem to be quite complex. The knockout of immunoglobin µ results in a B-cell deficiency. Transplantation of bone marrow cells from B-cell-deficient mice into LDL-deficient mice results in an increase in atherosclerosis (18). This indicates that B-cells may have a protective effect on atherosclerosis, despite their relatively rare appearance within the plaque. This suggests that their effects may be mediated by the antibodies they secrete, or perhaps by some other immunoregulatory role.
A third basis for implicating the immune system in atherogenesis is provided by the direct transfer of immunological mediators. IFN-, IL-12, or IL-18 injection all increase atherosclerosis (3). The administration of antibodies to CD40L reduces lesion formation in LDL receptor-deficient mice, whereas the use of antibodies to TGFß in the apoE-deficient mouse increases atherosclerosis, emphasizing the atheroprotective influence of this cytokine.
The fourth type of evidence directing attention to the role of the immune system involves immune cell transfer or vaccination. When CD4+ cells from apoE-deficient mice in which the Th1 cell subtype is dominant are transferred to immunodeficient apoE-deficient mice, an increase in atherosclerosis is noted (19). On the other hand, the transfer of B-cells from apoE-deficient mice with or without T-cells reduces atherosclerosis (20). The two major antigens to which autoantibodies are detected are OxLDL and heat shock proteins. Vaccination with the former decreases lesion formation, whereas in the case of the latter, atherosclerosis is increased (3).
In the last 18–24 months (i.e., since the publication of the two reviews briefly summarized above), many additional studies have been published that bear on the topic of this overview.
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INNATE IMMUNITY |
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Most of the emphasis in atherogenesis has been on the recruitment of monocytes into the lesion-prone areas, where they become macrophage foam cells. The fact that lesions regress, leaving fewer macrophages, implies that these cells must have the capacity to migrate out of the lesion. In an elegant transplant model, Llodra and colleagues (27) have demonstrated the outward migration of macrophages and dendritic cells from the lesion-filled aortic arch of an apoE-deficient mouse when the arch was transplanted into a wild-type mouse. The migration appears to be limited by lipids, such as platelet-activating factor and lysophosphatidic acid, which are likely to be enriched in progressing lesions.
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ADAPTIVE IMMUNITY |
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-to-IL-10 ratio (29). The role of costimulatory molecules has been emphasized recently (30). It has been known for some time that the CD40-CD40L interaction is implicated in atherosclerosis (31). These molecules are members of the TNF superfamily. An alternative name for CD40 is TNF receptor superfamily 5 (TNFRSF 5), and the CD40 is designated TNFSF 5 (31, 32). Although the expression of this pair was thought to be restricted to B-cells, dendritic cells, and activated T-cells, it is now clear that they are more widely expressed in the cells present in atherosclerotic plaques. Interdiction of their interaction results in a reduction in lesion development, while also modifying the composition of the lesion toward a less inflammatory and more fibrogenic lesion phenotype (31). Another pair of costimulatory molecules that belong to the TNF superfamily is LIGHT (TNFSF 14) (32) and its receptor, either HVEM (TNFRSF 14) expressed on lymphocytes and NK cells or lymphotoxin ß expressed on stromal cells and monocytes (33). These molecules have been noted in human atherosclerotic plaques clustered in macrophage-rich regions, and their properties suggest that their interaction is proinflammatory (34, 35). The other costimulatory pair is B7-1 (CD80) and B7-2 (CD86). They are members of the immunoglobulin superfamily, are expressed in antigen-presenting cells, and bind to CD28 on resting T-cells. B7-1 and B7-2 overlap in function. When their coupled absence is combined with LDL receptor deficiency, atherosclerosis is reduced and the lesions have fewer T-cells, smooth muscle cells, and less collagen (36). Thus, like the other pairs of costimulatory molecules, they are proinflammatory.
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CYTOKINES |
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also functions as a proinflammatory cytokine in murine atherosclerosis (37). Either the absence of IL-1 or a reduced gene dosage of IL-1 receptor antagonist in the apoE-deficient background suggests an influence of IL-1 in promoting atherogenic cell signaling (38, 39). The larger lesions of the IL-1 receptor antagonist-deficient mice are enriched in macrophages relative to smooth muscle cells.
Information on the role of the proinflammatory cytokine IFN- produced mainly by Th1 and NK cells has been extended in several experiments. The knockout of IFN- in the LDL receptor-deficient background substantially reduced lesion size in several regions of the aorta, with a relative loss of macrophages and smooth muscle cells in the early lesions (40). IFN-, which has previously been reported to downregulate the SRA and CD36 scavenger receptors, is thought to be important for the uptake of modified lipoproteins and foam cell formation. IFN- has now been shown to upregulate another scavenger receptor, SR-PSOX, which recognizes phosphatidylserine and OxLDL. SR-PSOX is identical to the transmembrane protein CXCL16, a chemokine receptor involved in T-cell migration. SR-PSOX and its receptor are present in atherosclerotic lesions (41). The dominance of Th1 and their secreted products within the plaque is balanced by counterinflammatory influences, mediated in part by IL-10, expressed in macrophages and Th2 lymphocytes in the plaque. When LDL receptor-deficient mice are transplanted with bone marrow overexpressing IL-10 in T-cells, atherosclerosis is reduced (42). In contrast, the transplantation of IL-10-deficient bone marrow into LDL receptor-deficient mice led to a marked increase in lesion development at several sites, and these lesions were rich in macrophages and lymphocytes (43). Nuclear factor B (NF-B) mediates many proinflammatory effects. The recent observation that selective attenuation of NF-B signaling in macrophages results in an increase in atherosclerosis in the LDL receptor-deficient background is somewhat surprising (44). This could be attributed to the substantial reduction in IL-10 production. A most interesting recent finding hypothesizes that IL-5 influences the stimulation of the production of anti-oxidized phosphatidylcholine antibodies after immunization with malondialdehyde LDL (17). The immunization caused a preferential expansion of cognate Th2 cells that secrete IL-5, which then stimulates B1 cells. This provides a link between natural and adaptive immunity and will be fully discussed in the thematic review by Binder, Witztum, and colleagues on natural antibodies.
The atheroprotective cytokine TGFß has also received considerable attention. It functions as an anti-inflammatory cytokine, limiting the recruitment of leukocytes and promoting the synthesis of collagen and extracellular matrix (45, 46). TGFß-deficient mice die early, so alternative strategies are used to attenuate its function. Most have used either a soluble TGFß receptor that inhibits signaling (47) or a dominant negative (dn) mutant receptor driven by a T-cell-specific promoter (CD2 or CD4) expressed as a transgene (48, 49). These studies noted some similarities and some discrepancies. In the Robertson study (48), T-cell dn receptor-expressing mice were crossed with apoE-deficient mice, whereas in the Gojova study (49), bone marrow was transplanted from dn TGF receptor-expressing mice into LDL receptor-deficient mice. Both groups of investigators noted lesions that exhibited increased T-cells, macrophages, and reduced collagen, an inflammatory phenotype. The Robertson study noted increased lesion size, whereas a modest reduction in aortic root lesions was noted in the Gojova study. These experimented models are significantly distinct, so that further investigation is required to resolve the discrepancy.
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THIS SERIES |
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I will then comment on the bridge between innate and adaptive immunity in an extended editorial. This will be followed by a review of the natural antibodies recognizing modified lipoproteins and apoptotic cells as well as molecules that mimic these antigens. This is an exciting field with continuing surprises pointing in new directions of substantial potential clinical significance. The recent observations in this area will be reviewed by Peter Shaw, Christoph Binder, and Joseph Witztum and colleagues, who have contributed greatly to this field.
As mentioned above, a number of lymphocyte subclasses have come into sharp focus as influencing atherogenesis. This includes B1 cells, NK cells, and NK-T cells. These unusual suspects as well as dendritic cells and their contribution to atherogenesis will be reviewed by Catherine Reardon and Paul VanderLaan.
It is clear from the above overview that the atherosclerotic plaque is a "soup" of cytokines, produced by many cell types within the inflammatory plaque and acting upon many of their neighbors. Knockout experiments and other manipulation of expression levels of these molecules clearly demonstrate their influence on the atherogenic process. We have asked Elaine Raines and Alan Daugherty to focus our attention on the role of these cytokines on target cells within the plaque. Elaine Raines will do this for endothelial cells and smooth muscle cells. Alan Daugherty will inform us about the macrophage and leukocytes as targets.
We will conclude the series by a return to the central role of the monocyte, which must be recruited into the evolving lesion to fulfill its critical participation. Thus, Oswald Quehenberger will review monocyte chemotaxis and atherogenesis.
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ADDITIONAL COMMENTS |
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, a situation stimulated by IL-12 and IL-18. However, it seems clear that developing atherosclerotic plaques represent a balance between proinflammatory and anti-inflammatory influences, with the former being dominant during early plaque evolution. That there are anti-inflammatory influences at work is indicated by the experimental manipulation of IL-4, IL-10, and TGFß as discussed above. Also, B-cells and their secreted antibodies recognizing relevant antigens may contribute to some degree of atheroprotection. However, the adaptive immune system is not required for the development of atherosclerosis. Quite substantial lesions develop in the absence of mature T- and B-cells in mouse models in which the function of the RAG gene(s) is eliminated. Our current conception of experimental atherosclerosis derives predominantly from a limited examination of atherosclerosis either by the measurement of aortic root lesions, not a characteristic site for human atherosclerosis, or en face measurement of the extent of aortic lipid lesions. Sometimes both methods are used. This examination may be undertaken early in atherosclerosis, when the predominant lesion is a fatty streak (xanthoma), or later, when more complex lesions are seen. It should not be a surprise that influences on early lesions and more complex lesions may differ. In the early lesion, composed mostly of foam cells, the cellular composition is reasonably homogeneous. On the other hand, as the lesion increases in complexity, the potential for cellular interactions may be very different. The microarchitecture of the lesion, with the stromal separation of clusters of cells of different function, could influence the measured outcome of an intervention. Seldom does a single investigator examine lesions at two different times, and this can be misleading, because the selection of a particular time point as readout may bias the results in a lesion that evolves over time. For example, in apoE/IL-12-deficient mice, lesion area is reduced at 30 weeks of age but not at 45 weeks of age (16). Also, the major atherosclerosis parameter may rest solely or largely on the size of the lesions, often with little attention to the lesion phenotype or detailed morphology. In modeling lesions of clinical relevance, the quality and composition of the lesion is probably of more importance. In accepting the general view of the mechanisms of atherogenesis, one should bear in mind the potential limitations in the evidence that supports this view.
Some interventions have modest effects on the size of the lesion but do influence the lesion phenotype. This is exemplified in recent murine atherosclerosis studies on IFN- deficiency in atherosclerosis in the LDL receptor-deficient mouse (40). Lesion phenotype is dramatically changed with modulation of IL-10 signaling and attenuation or alteration of TGFß signaling (42, 43, 47, 49).
We have previously drawn attention to the differential responses of various vascular regions to immune modulation (52). We suggest that this is attributable to the way regional differences in hemodynamic profiles prime the endothelial phenotype to respond to such modulations. An alternative explanation could be that differences in the microenvironment in the subintimal space in which lesions develop condition the atherosclerotic response. We have seen this in comparing the response of the aortic root and the innominate artery to immune deficiency in the LDL receptor-deficient model (53). Other examples of the differential response of aortic regions to immune modulators include IL-4 deficiency combined with LDL receptor deficiency, in which there was no impact on the aortic root lesion size but substantially reduced lesion size in the aortic arch and thoracic aorta (15). A second example involves immunization of LDL receptor-deficient mice with OxLDL, which reduced aortic root lesion size but had no influence on lesions in the remainder of the aorta (54). The majority of studies of atherosclerosis in the mouse have examined lesions in the aortic root or in the whole aorta by en face analysis. Given the hitherto reported differences in response according to the vascular region examined, it seems that our understanding of the interplay of the immune system on murine atherosclerosis would be greatly enhanced by measuring the atherosclerosis response at more than one vascular site. A dramatic example of such a difference is shown by the surprising increase in abdominal aortic atherosclerosis seen in female apoE-deficient mice also lacking CD4+ cells (55).
It is well known that mouse strains differ in their susceptibility to atherosclerosis, with the C57BL/6 strain being the most sensitive. Many of the earlier experiments used mouse strains that were not fully backcrossed into this genetic background. Often, strain 129 was originally used for the generation of the knockout mice. This was the case for the knockout of the RAG genes. The initial work on the apoE-deficient strains lacking the RAG genes used animals of modestly mixed background (56–58). We have shown that the effect of immune deficiency on innominate artery atherosclerosis in LDL receptor-deficient mice is quite sensitive to the genetic background (53). An interesting illustration of this complexity is shown in studies of peroxiredoxin 6 knockouts fed atherogenic diets. Strains were either 129 or C57BL/6 or a mixed strain, 129:BL/6. 129 animals were equally resistant whether or not the peroxiredoxin function was present. Similarly, the BL/6 strain was equally sensitive with this gene functioning or not. A difference between knockout and control mice was seen with the mixed strain. The caveat is that all lesions were very early and were quite small (59).
Hypercholesterolemia is a requisite for the development of atherosclerosis in the mouse. The effects of immune modulators could operate on the level of hypercholesterolemia or upon the responding blood vessel wall or perhaps at both levels. There are clearly some immune modulators that affect atherosclerosis without influencing the level of plasma lipoproteins. On the other hand, some immune modulators (e.g., IFN- signaling) do influence lipoprotein metabolism (60). The role of cytokines on lipoprotein metabolism has mostly focused on the response to the cytokines of the acute phase response to infection (i.e., TNF-, IL-1, and IL-6) (61). However, global deficiency of the adaptive immune system generally results in a reduction in plasma cholesterol and triglyceride, especially in the VLDL fraction in both LDL receptor-deficient and apoE-deficient mice (53, 58). It has been reported that in the face of marked hypercholesterolemia in the apoE-deficient mouse, global immunodeficiency has no effect on atherosclerosis (57). We have recently shown that when apoE-deficient mice backcrossed to BL/6 mice for 10 generations are used and the plasma cholesterol levels are matched with chow as the diet, there is no obvious effect of global immunodeficiency on atherosclerosis at the aortic root up to 7 months of age (C. Reardon and G. S. Getz, unpublished data). We take this to imply that in this model the proinflammatory and anti-inflammatory influences on atherogenesis are similarly balanced in the presence or absence of an adaptive immune system. When the whole population of apoE-deficient mice that are immune competent or incompetent is considered, the plasma lipids are notably reduced in the incompetent mice. This is also the case for the LDL receptor-deficient model. The mechanisms that account for the influence of the immune system on plasma lipoprotein metabolism are largely unknown and little explored.
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CONCLUSION |
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ACKNOWLEDGMENTS |
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Manuscript received November 2, 2004
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