© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
LDL Immunization Induces T-Cell–Dependent Antibody Formation and Protection Against Atherosclerosis
From the Centre for Molecular Medicine and King Gustaf V Research Institute (A.H.), Karolinska Institutet, Stockholm, Sweden.
Correspondence to Dr Göran K. Hansson, Centre for Molecular Medicine L8:03, Karolinska Hospital, S-17176 Stockholm, Sweden. E-mail Goran.Hansson{at}cmm.ki.se
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Abstract |
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Abstract—Atherosclerosis is an inflammatory disease, and the involvement of immune mechanisms in disease progression is increasingly recognized. Immunization with oxidized low density lipoprotein (LDL) decreases atherosclerosis in several animal models. To explore humoral and cellular immune reactions involved in this protection, we immunized apolipoprotein E knockout mice with either homologous plaque homogenates or homologous malondialdehyde (MDA)-LDL. Immunization with both these antigen preparations reduced lesion development. The plaques contained immunogen(s) sharing epitopes on MDA-LDL, MDA–very low density lipoprotein, and oxidized cardiolipin. This shows that a T-cell–dependent antibody response was associated with protection against atherosclerosis. The protection was associated with specific T-cell–dependent elevation of IgG antibodies against MDA-LDL and oxidized phospholipids, and the increased titers of IgG antibodies were correlated with decreased lesion formation and lower serum cholesterol levels.
Key Words: atherosclerosis • immunization • low density lipoproteins • antibodies • T cells
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Introduction |
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Histopathologic analysis of atherosclerotic plaques suggests that lesion formation represents an inflammatory-proliferative response to lipid metabolic disturbances in regions of the vasculature exposed to hemodynamic strain.1 2 The involvement of immune mechanisms in this process is increasingly recognized.1 3 4 5 6 7 Thus, atherosclerotic plaques contain significant amounts of T cells, many of which are in an activated state8 9 10 11 12 13 14 ; major histocompatibility complex class II molecules are expressed on endothelial and smooth muscle cells in the vicinity of activated T cells15 ; and B cells, immunoglobulins, and C5b-9 complement complexes are also present in the plaques.16 17 18 19 All these findings support the notion that atherosclerosis may be an immune-modulated disease.
Lipoprotein oxidation seems to play a critical role in the development of atherosclerosis.2 20 Highly reactive products from lipid peroxidation, such as malondialdehyde (MDA) and 4-hydroxynonenal, bind to free amino groups of lysines and other charged amino acid side chains of apoB.2 The phospholipids of LDL can also be oxidized,21 and cardiolipin is recognized by some autoantibodies reactive against oxidized LDL (oxLDL). Circulating autoantibodies to epitopes of oxLDL have been detected in the plasma of patients and experimental animals with atherosclerosis.13 22 23 24 25 26 27 28 29 It has recently been shown that the titer of autoantibodies to oxLDL is correlated with the extent of atherosclerotic lesions in LDL receptor–deficient mice.30 OxLDL present in atherosclerotic lesions23 24 31 32 33 is highly immunogenic11 23 34 and can stimulate the recruitment of immune cells.35 36 37 Antibodies isolated from atherosclerotic lesions recognize epitopes of oxLDL, and some of them form immune complexes with oxLDL.38 Approximately 10% of the T cells cloned from human atherosclerotic lesions respond specifically to oxLDL.11 Taken together, these findings suggest that humoral and cellular immune responses to oxLDL affect the atherosclerotic process. In addition, heat shock protein 65, Chlamydia pneumoniae, herpes simplex type I, and cytomegalovirus have also been suggested as possible immunogens in the plaque.6 39 40 Therefore, it seems that the atherosclerotic plaque might contain various antigens that are targeted by the immune system.
Recently, several groups have studied the effect of immunization on atherosclerosis. Palinski et al41 and Ameli et al42 showed that immunization of hypercholesterolemic rabbits with MDA-LDL41 or Cu2+-oxidized LDL42 reduced lesion formation. Similarly, immunization of LDL receptor knockout mice fed a Western diet43 and apoE-deficient (E0) mice fed normal chow inhibited the disease process.44 However, the mechanism of the protective effect is currently unknown.
To explore humoral and cellular immune reactions involved in this protection, we immunized E0 mice45 46 with either homologous plaque homogenates or homologous MDA-LDL. Immunization with either preparation reduced lesion development in proportion to rises in the titers of T-cell–dependent antibodies to oxLDL and oxidized phospholipids. This suggests an important role for antibodies and T-cell–B-cell interactions in the protection conveyed by immunization.
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Methods |
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Mice
Male E0 mice45 were backcrossed 10 times onto the C57BL/6J background (strain C57BL/6J-ApoEtm1Unc); these mice were obtained from M&B Breeding and Research Center, Ry, Denmark. Eight-week-old mice were fed a Western diet containing 0.15% cholesterol.12 13 Animal care was in accordance with national guidelines, and all experiments were approved by the local ethics committee.
Antigen Preparation
Homologous Lipoprotein Isolation
Blood was obtained by heart puncture from 6- to
8-week-old anesthetized male E0 mice
and pooled into vacuum tubes containing
Na2-EDTA. VLDL and LDL were isolated from plasma
by ultracentrifugation through a discontinuous NaCl
gradient of 1.006 to 1.065 mg/mL for 20 hours at 4°C in a Beckman
L8-80 ultracentrifuge with a 50.3-Ti Beckman fixed-angle
rotor.26 The lipoprotein
preparation with added Na2-EDTA (1 mg/mL) was
sterilely filtered, kept at 4°C under N2, and
used within 2 weeks. The modification of MDA-LDL and MDA-VLDL was
performed as described.13
Human LDL was prepared from venous blood obtained from healthy human
donors after an overnight fast, pooled into vacuum tubes containing
Na2-EDTA (1 mg/mL), and treated in the same way
as mouse LDL.
Plaque Homogenate
The heart and proximal aorta of aged male
E0 mice were briefly perfused with PBS,
dissected out, and put in ice-cold preservatives, which included 1
mg/mL Na2-EDTA, 2 mmol/L benzamidine,1
mmol/L phenylmethylsulfonyl fluoride, 0.01% aprotinin, and
0.008% gentamycin in PBS. The atherosclerotic plaques from the root of
the aorta were isolated under a dissection microscope within 1 hour in
ice-cold preservatives without EDTA and benzamidine and were frozen
immediately in liquid nitrogen. Plaques were then
homogenized in a Dismembrator (B. Braun Melsungen AG) and
suspended in PBS. The protein content was determined by the
Lowry method.
Immunization Protocol
At 6 weeks of age, male E0
mice were randomly divided into 3 groups (n=5 or 6 per group). They
were injected with homologous plaque homogenate (100 µg
protein per mouse), homologous MDA-LDL (100 µg protein per mouse), or
PBS in the foot pads, which was boosted 4 times at 2-week intervals
(ratio of antigen [or PBS] to adjuvant 3:2). The antigens used in the
first injection were emulsified with complete Freund’s adjuvant.
Incomplete Freund’s adjuvant was used in booster injections. All mice
were euthanized at 18 weeks of age after 10 weeks on the Western
diet.12
Quantification of Plaque Size and Cellular
Components
Because the correlation is strong between the extent
of atherosclerosis in the aortic root and in the entire
aortic tree in murine atherosclerosis
models,47 we measured lesions
in the aortic root by use or the method described by
Paigen.48 In brief,
the mice were euthanized in a CO2 chamber and
perfused transcardially with PBS. The heart was dissected out. The
tissue segment from the sinus aorticus to the lower tips of the right
and left atria was isolated and snap-frozen in liquid nitrogen and
embedded with OCT compound (Miles Laboratories). The tissue
block was sectioned with a thickness of 10 µm. For morphometric
analysis, 5 sections were cut at 100-µm intervals starting at
the level of the aortic valves. Sections were stained with oil red O
and counterstained with hematoxylin. The size of the plaque was
measured with Leica Q500 MC image analysis software. The mean
value of plaque cross-sectional areas from 5 sections was used to
estimate the lesion size of each mouse. To count the number of cells
infiltrating into the plaques, immunohistochemistry was performed as
described.13
Determination of Antibody Titer and
Specificity
Blood was obtained by heart puncture in conjunction
with
euthanasia.12 13
Mouse sera were centrifuged at
14 000g for 30 minutes to
remove chylomicrons and stored at -80°C until assay. ELISA was used
to quantify IgG and IgM antibodies against
MDA-LDL.13 Alkaline
phosphatase–labeled goat antibodies to mouse IgG and IgM were from
Southern Biotechnology. Mouse sera were diluted in PBS to 1:100 for IgM
and 1:200 for IgG.
To explore whether circulating IgG also recognizes the epitope(s) on oxidized phospholipids, cardiolipin (Sigma Chemical Co) or air-oxidized cardiolipin28 48 was coated on PETG EIA plates (Micronic).28 Mouse sera were diluted to 1:50 for IgG antibodies against oxidized cardiolipin. The ratio of absorbance in wells coated with oxidized cardiolipin to the absorbance in wells with native cardiolipin was calculated to correct for nonspecific binding of antibodies to cardiolipin. Because ß2-glycoprotein I is an important target for binding of antoimmune anti-phospholipid antibodies,49 50 51 the serum IgG anti–ß2-glycoprotein I antibodies were tested.51 Competitive inhibition assays were performed to confirm the specificity of the mouse IgG anti–MDA-LDL and to determine whether anti–oxidized cardiolipin antibodies and anti–MDA-LDL antibodies cross-react. A 1:200 dilution of the serum from MDA-LDL–immunized mice was added to equal volumes of dilution buffer containing serially increased amounts of MDA-LDL as a competitor. The results were given as a ratio of B to B0, where B is the amount of IgG antibodies bound to the plated antigens (MDA-LDL or oxidized cardiolipin) in the presence of competitor MDA-LDL, and B0 is the binding in the absence of competitor. To rule out the possibility that MDA-LDL as a competitor could bind nonspecifically to the proteins, sera from mice immunized with keyhole limpet hemocyanin (KLH, Pierce) were used as controls, in which KLH, instead of MDA-LDL, was used as the plated antigen.
SDS-PAGE and Western Blot
To analyze the protein profiles, LDL, VLDL,
MDA-LDL, and MDA-VLDL as well as plaque homogenates were
loaded (20 µg per lane) on SDS-PAGE gels consisting of 6% separating
and 4% stacking gels followed by Coomassie brilliant blue staining.
For immunoblotting, human MDA-LDL, mouse MDA-LDL, and
mouse MDA-VLDL (25 µg per lane) were separated on SDS-PAGE and
electrophoretically transferred to PVTC membranes (Amersham) at 4°C
overnight at 40 V plus 2 hours at 100 V. The membranes were blocked for
1 hour at room temperature with 3% gelatin in Tris-buffered saline
(500 mmol/L NaCl and 20 mmol/L Tris, pH 8.0). The membranes
were then incubated with mouse sera (1:80 in Tris-buffered saline
containing 1% gelatin and 0.05% Tween 20) for 2 hours at room
temperature. This was followed by a 1.5-hour incubation at room
temperature with alkaline phosphatase–conjugated goat anti-mouse IgG
(1:1000).
Flow Cytometry
Cells were prepared from freshly isolated inguinal
lymph nodes. A fraction of the cells was used to check the proportion
of T and B cells. They were stained with FITC-conjugated anti-CD3,
phycoerythrin-conjugated anti-CD19, and Cy-Chrome–conjugated anti-CD45
(PharMingen). The remaining cells were challenged with MDA-LDL for 6
hours to activate antigen-specific T cells. The very early
activation marker, CD69, was detected on T-cell subsets by staining for
30 minutes at 4°C with FITC-conjugated anti-CD69,
phycoerythrin-conjugated anti-CD8, and Cy-Chrome–conjugated anti-CD4
antibodies (all from PharMingen). The cells were analyzed with
a FACS Calibur flow cytometer (Becton
Dickinson).
Serum Cholesterol and
Triglyceride Analysis
Cholesterol and triglyceride
concentrations in mice sera were determined by use of enzymatic methods
(Unimate 5 Chol, Hoffman-La Roche; triglycerides/6B,
Boehringer-Mannheim) and a Cobas Mira
System.
Statistical Analysis
Results are expressed as mean±SEM. Data were
analyzed by the Wilcoxon nonparametric
test. The significance level was set at
P<0.05. Correlations were
estimated by use of the Spearman rank correlation
test.
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Results |
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Lesion Development in Immunized E0 Mice
At 18 weeks of age, E0 mice fed a Western diet showed fibrofatty plaques that were filled with macrophage-derived foam cells, smooth muscle cells, and CD4+ T cells as well as CD22+ B cells.12 16 52 In the present study, E0 mice were immunized with homologous MDA-LDL, homologous plaque homogenates, or PBS injections (controls). At 18 weeks of age, after 10 weeks on a Western diet, all mice had developed fibrofatty plaques with lipid-rich core regions covered by fibrous caps. Mice immunized with either plaque homogenate or homologous MDA-LDL showed a 39% and 46% reduction in lesion size, respectively, compared with the PBS-treated controls (Figure 1
). This is in agreement with the previous finding
that oxLDL immunization alleviates
atherosclerosis.41 42 43 44
It is interesting that plaque homogenate immunization also
had a protective effect.
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Immunohistochemistry showed that CD4+ T cells, CD8+ T cells, and CD22+ B cells were present in all sections (data not shown). CD22+ B cells and CD4+ cells were always more frequent than CD8+ T cells. For CD22+ and CD4+ cells, no differences were observed between groups. In contrast, CD8+ cells were significantly fewer in the MDA-LDL–immunized group (data not shown).
T-Cell–Dependent Antibody Response to MDA-LDL,
Oxidized Phospholipids, and ApoB-100/48
To characterize the specific immune response induced by
immunization, circulating IgM and IgG to MDA-LDL and oxidized
cardiolipin were determined by ELISA. No increase in the titer of IgM
against MDA-LDL could be detected after immunization
(Figure 2A). However, the titer of T-cell–dependent IgG
antibodies to MDA-LDL was elevated dramatically in mice immunized with
plaque homogenate and with MDA-LDL
(Figure 2A). The titer of circulating IgG to oxidized
cardiolipin was also increased significantly in mice immunized with
plaque homogenate or MDA-LDL
(Figure 2B). Competitive inhibition assays indicated that IgG
antibodies to either MDA-LDL or oxidized cardiolipin could be blocked
by MDA-LDL
(Figure 2C), This cross-reactivity could be due to the
presence of oxidized cardiolipin on MDA-LDL particles or could
represent antibodies to shared
epitopes.27 We also assessed
another potential cross-reactivity, which is caused by
ß2-glycoprotein I binding to oxidized
cardiolipin50 ; therefore,
some anti-phospholipid antibodies could react with
ß2-glycoprotein I rather than oxidized phospholipids.
However, no anti–ß2-glycoprotein I antibodies could be
detected in any of the groups (data not shown).
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The protein component in the plaque homogenates
was analyzed by SDS-PAGE. A major band at 210 kDa was observed;
it had the same apparent molecular mass as apoB-48
(Figure 3A). The circulating IgG antibodies from the plaque
homogenate–immunized group recognized epitopes on a 500-
and 210-kDa band from human and mouse MDA-LDL as well as mouse MDA-VLDL
(Figure 3B), which indicated that a significant amount of
MDA-LDL is present in plaques of E0 mice
and implied that the MDA-LDL epitopes of B cells may be located within
the sequence of apoB-48.
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T-Cell Response to MDA-LDL in Draining Lymph
Nodes of E0 Mice
Cells of draining lymph nodes were exposed to MDA-LDL
to detect T cells reactive with this antigen. The expression of CD69, a
T-cell marker for very early activation, was measured on the cells
after a 6-hour culture with homologous MDA-LDL. This permitted an early
detection of activated T cells before viability was reduced in
the primary cultures.
CD4+ and
CD8+ T cells of mice immunized with plaque
homogenate or MDA-LDL were activated by homologous
MDA-LDL, indicating the existence of cellular immune responses to the
immunogens
(Figure 4).
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Serum Lipids, Body Weight, Plaque Size, and
Induced IgG Antibodies
No significant differences in cholesterol
or triglyceride levels or in body weight were found between
the groups (data not shown). Serum cholesterol was
correlated with body weight
(Figure 5A) and plaque size
(Figure 5B). Importantly, higher titers of IgG antibodies to
MDA-LDL and oxidized cardiolipin were associated with lower serum
cholesterol levels
(Figure 5C and 5E) and with smaller plaques
(Figure 5D and 5F). MDA-LDL immunization was associated with
an increased proportion of
CD19+/CD45+ B
cells in draining lymph nodes (54.5±1.2% in MDA-LDL–immunized mice
versus 49.3±2.0% in PBS-injected controls) and a concomitant
reduction in the proportion of
CD3+/CD45+ T
cells (data not shown).
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Discussion |
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The results of the present study show (1) that immunization with homologous plaque homogenate as well as homologous MDA-LDL inhibits plaque growth, suggesting that the plaque is an autoimmune target in the disease process; (2) that the immunogens of the plaque share epitopes with MDA-LDL, MDA-VLDL, and oxidized cardiolipin; (3) that antibody responses to oxidized lipoproteins and plaque antigens are T-cell dependent; and (4) that IgG antibody titers against MDA-LDL and oxidized cardiolipin correlate negatively with plaque size and serum cholesterol levels in immunized animals.
These data confirm and extend previous findings that immunization with MDA-LDL and other preparations mimicking in vivo modified LDL reduce lesion size in hypercholesterolemic animals. This provides strong support for the oxidation as well as the inflammatory-immune hypothesis for the pathogenesis of atherosclerosis. The development of antibodies reactive with oxidized lipoproteins after immunization with a plaque homogenate reveals immunologic cross-reactivities between oxLDL and plaque components. Antibodies reactive with oxidized cardiolipin as well as MDA-modified protein components of oxLDL were detected in the sera of E0 mice immunized with plaque homogenate, and the most likely explanation is that oxLDL was present in the plaque material. An alternative possibility could be that oxidative modification occurring in plaques generate B-cell epitopes similar to those present in oxLDL.
Immunizations were carried out by use of Freund’s adjuvant, which is strongly proinflammatory and promotes antigen processing by macrophages and dendritic cells. Such an activation of macrophages might, per se, affect atherosclerosis. Immunizations with Freund’s adjuvant can also induce immune responses to heat shock protein 65, which may be proatherogenic.40 However, the addition of immunogens (MDA-LDL and plaque homogenate) conferred protection when lesions were compared with those in mice injected with a PBS/Freund’s adjuvant emulsion. This fact and the finding that antibody titers correlated inversely with plaque size strongly support the notion that immunization with MDA-LDL or plaque material ameliorates atherosclerosis.
Antibodies were developed against protein and lipid components of oxLDL. In both cases, IgG antibodies were formed. This implies that T-cell help was provided for B-cell responses and resulted in immunoglobulin isotype switching. Although such a switch is the rule on booster immunization with protein antigens, antibodies to lipid antigens often develop in a non–T-cell–dependent manner. However, the present finding of IgG anti–oxidized cardiolipin suggests that T cells recognize oxidized cardiolipin or molecular structures associated with it. The present data emphasize the importance of molecular analyses to identify the epitopes and mechanisms involved in atheroprotective immunization.
High IgG titers against MDA-LDL and oxidized cardiolipin were correlated with a reduction in the size of atherosclerotic lesions. In fact, oxidized cardiolipin antibody titers showed a stronger (negative) correlation with lesion size than (the positive correlation of) serum cholesterol. This clearly suggests that B-cell responses mediate protection against atherosclerosis. Because the immunoglobulin isotype switch implied T-cell help, T-cell–B-cell cooperation during immune responses may play a role, However, the most obvious interpretation would be that antibodies to components of oxLDL confer protection against atherosclerosis. This might occur by Fc-dependent removal of oxLDL from the circulation or by neutralizing the effects of oxLDL systemically or locally.
Our conclusions differ from those of Freigang et al,43 who immunized LDL receptor–deficient mice with LDL preparations. Although these authors also observed a negative correlation between anti–MDA-LDL titers and atherosclerosis in MDA-LDL–immunized mice, they did not observe such a correlation in mice immunized with native LDL and therefore concluded that the antiatherogenic effect was probably not dependent on antibodies.
In the present study, the negative correlation between anti–MDA-LDL titers and lesions in mice immunized with plaque homogenate and in mice receiving MDA-LDL support the notion that protective antibodies may play a role. Our analysis of anti–oxidized cardiolipin antibodies renders further support to this hypothesis, inasmuch as the negative correlation between these titers and lesion size was even stronger than that for anti–MDA-LDL titers. Therefore, although cellular immune responses may also be important, our data suggest that humoral immune responses toward the components of modified lipoproteins confer protection against atherosclerosis. It will now be important to evaluate whether transfer of specific antibodies and/or B cells can protect atherosclerosis-prone mice from disease.
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Acknowledgments |
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Our work was supported by the Swedish Medical Research Council (project No. 6816), the Swedish Heart-Lung Foundation, the Johnson, Wallenberg, and Hedlund Foundations, King Gustaf V 80th Anniversary and King Gustaf V and Queen Viktoria Foundations, and the AFA Research Fund. We thank Karin Danell-Toverud for LDL preparations and Anita Larsson for measuring serum cholesterol and triglycerides.
Received December 30, 1999; accepted May 16, 2000.
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