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© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Antibodies to Oxidized LDL in Relation to Carotid Atherosclerosis, Cell Adhesion Molecules, and Phospholipase A2
From the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden.
Correspondence to Johannes Hulthe, MD, PhD, Wallenberg Laboratory, Fack 16, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden. E-mail Johannes.Hulthe{at}wlab.wall.gu.se
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Abstract |
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Abstract—The role of the humoral immune response to oxidized low density lipoprotein (Ox-LDL) in atherogenesis is unclear and available studies are contradictory. The aims of the present study were (1) to compare antibody titers to modified LDL in a group of patients with hypercholesterolemia (n=102) with those in matched controls (n=102), (2) to analyze whether these titers were related to atherosclerosis development as measured by ultrasound, and (3) to analyze whether these titers were related to soluble cell adhesion molecules and secretory type II phospholipase A2 in plasma. The results showed that male patients with hypercholesterolemia had lower immunoglobulin G (IgG) titers compared with those in healthy controls. In the control group, there was an inverse correlation between intima-media thickness of the carotid artery bulb and IgM titers against Ox-LDL and malondialdehyde-LDL (r=-0.35, P=0.001; and r=-0.31, P=0.003, respectively). In the patient group, however, only weak associations were seen. IgG titers were positively associated with soluble intercellular adhesion molecule-1, soluble E-selectin, and secretory type II phospholipase A2. Taken together, the results of this study support the concept that the humoral immune response against Ox-LDL may be protective in early atherosclerosis. The pattern, however, is complex, and the role of the immune response may differ in different patient groups as well as at different stages of the disease.
Key Words: Ox-LDL • antibodies • atherosclerosis • intima-media thickness • inflammation
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Introduction |
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Immune mechanisms have been suggested to play a key role in atherosclerosis development.1 Several lines of evidence support the concept that oxidized (Ox)-LDL may be a key antigen in this process. T-cell clones responsive to Ox-LDL have been isolated from human lesions.2 Furthermore, in several studies, antibodies against epitopes of Ox-LDL have been found in both human and rabbit plasma3 and in atherosclerotic lesions.4 5 A relationship between circulating antibodies against Ox-LDL and atherosclerotic disease has, however, not been unequivocally shown. There are case-control studies suggesting an elevated antibody titer against Ox-LDL in patients with various manifestations of atherosclerotic disease.6 7 8 High titers of antibodies have also been found to be independent predictors of the progression of carotid atherosclerosis.9 In other recent studies, however, no such relationships have been found between atherosclerotic disease and antibody titers.10 11
Soluble forms of cell adhesion molecules (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and E-selectin) can be detected in serum, and these molecules have also recently been detected in several components of human atheroma12 ; in addition, cross-sectional and prospective data suggest that soluble forms of these proteins are elevated among patients with diverse manifestations of atherosclerosis.13 14
Another possible marker for atherosclerosis development is the secreted group IIa phospholipase A2 (snpPLA2), which has been described in association with local and systemic inflammation.15 snpPLA2 has been shown to stimulate oxidation of LDL by lipoxygenase.16 snpPLA2 has been found in human atherosclerotic lesions17 and has also recently been found to be correlated with coronary artery disease and to predict coronary events.18
Development of the B-mode ultrasound technique has made it possible to noninvasively study the atherosclerotic process. Intima-media thickness (IMT) of the carotid artery has been used as a noninvasive indicator for the atherosclerotic process in the coronary arteries.19
The aims of the present study were (1) to compare antibody titers to modified LDL in a group of patients with hypercholesterolemia (n=102) with those in matched controls (n=102); (2) to analyze whether these titers were related to atherosclerosis development, as measured by ultrasound; and (3) to analyze whether these titers were related to other inflammatory markers of possible interest in atherosclerosis development, eg, soluble cell adhesion molecules and snpPLA2, in plasma.
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Methods |
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Study Groups
Study Group With Primary Hypercholesterolemia
Subjects with primary hypercholesterolemia (n=105) were recruited from the screening of subjects from the general population performed at the Wallenberg Laboratory (n=50) and also from patients at the Lipid Clinic of the Sahlgrenska University Hospital (n=55). Inclusion criteria were willingness to participate, 20 to 70 years of age, serum cholesterol >6.5 mmol/L, LDL cholesterol >5.0 mmol/L, and serum triglycerides <4.5 mmol/L. Furthermore, the patients had to fulfill at least 1 of the following ultrasound criteria: (1) a maximum IMT in the common carotid artery >1.0 mm or (2) a measurable plaque in the carotid artery, arbitrarily defined as a 50% increase in IMT compared with that of neighboring sites. Lipids and ultrasound variables were measured twice before inclusion, and subjects had to fulfill inclusion criteria at both occasions. Because of technical reasons, 3 patients had no serum samples available; thus, the total number of patients included for the present report was 102. The study group has previously been well described.20
Study Group of Control Subjects
For each patient, 1 control subject was recruited
from the same screening examination as mentioned above. Control
subjects had no symptoms of or treatment for
cardiovascular disease. All control subjects had serum
cholesterol levels <6.5 mmol/L at the initial
screening examination. Control subjects were matched for sex, age,
height, weight, body mass index (BMI), and smoking
habits.20 The protocol was
approved by the ethics committee of Göteborg University, and informed
consent was obtained from all subjects.
Anthropometric Data, Serum Lipids, Blood
Pressure, IMT, and Plaque Occurrence in the Patient and Control
Groups
Patients and controls were well matched according to
age, body height, body weight, and BMI. As expected, patients had
higher serum cholesterol, LDL cholesterol, and
serum triglyceride levels compared with controls
(Table 1
). IMT in the carotid artery bulb was
significantly thicker in male patients compared with controls:
1.22±0.33 mm (95% confidence interval [CI], 1.13 to 1.31] and
1.03±0.34 mm (95% CI, 0.93 to 1.12), respectively, as well as in
female patients compared with controls: 1.37±0.46 mm (95% CI,
1.24 to 1.51) and 0.91±0.20 mm (95% CI, 0.85 to 0.97),
respectively. The frequencies of moderate to large plaques in male
patients and controls were 44.2% and 15.4%, respectively, and in
female patients and controls, 52% and 2%,
respectively.20
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Antibody Titers Against Modified
Lipoproteins
Determination of Antibody Titers Against
Modified Lipoproteins
Antibody titers were determined with a solid-phase
ELISA, as earlier
described.21 Antibody titer
was defined as absorbance=(patient serum-postcoat)/(internal
antibody titer standard serum-postcoat). For IgG, the postcoated
wells gave no absorbance; therefore, this correction was made only for
IgM.
Internal Antibody Titer Standard Used
On each plate, 2 different internal standard serum
samples were repeatedly tested. The absorbances for these 2 samples,
named the internal control sample (ICS) and the internal standard
sample (ISS), were used to calculate their ratio (ie, ICS/ISS), which
was used as the internal antibody titer, the variability has previously
been shown to be
satisfactory.21 Standard
deviations (SDs) for the mean value of the ratio ICS/ISS (ie, the
internal antibody titer standard used) from all plates were 0.06 and
0.05 for IgG titers against Ox-LDL and malondialdehyde (MDA)-LDL,
respectively, and 0.05 and 0.08 for IgM titers against Ox-LDL and
MDA-LDL, respectively, when earlier predefined criteria were
used.21
Ultrasonography
Examination was performed with an ultrasound scanner
(Acuson 128) with a 7-MHz linear transducer aperture of 38 mm, as
described
earlier.22 23 The
right carotid artery was scanned at the level of the bifurcation, and
images for IMT measurements were recorded from the far wall of the
common carotid artery and the carotid artery bulb. The images were
measured in an automated analyzing
system.24 As described
before, a subjective semiquantitative scale was used to grade the size
of plaques into grades 1, 2, and 3, where grade 1 corresponds to 1 or
more small plaques (less than 
10
mm2) and grade 3 corresponds to large
plaques causing a hemodynamic change in blood
flow.23 24
Reproducibility studies of blinded rereading of plaque occurrence in 53
male subjects showed that plaque size was assessed in the same way on
both occasions in 95% of the cases.
Quantification of Type II
snpPLA2 by ELISA
Levels of snpPLA2 in human
sera were measured by enzyme-linked capture antibody
immunoassay.25 The
antibodies used were a monoclonal antibody against human
snpPLA2 (1 µg/µL) from Cayman
Chemicals and a polyclonal antibody (IgG fraction) against human
recombinant snpPLA2 that was produced in our
laboratory and demonstrated no cross-reactivity with type V
PLA2 (Edward A. Dennis, personal communication)
or actin.26 ELISA plates
were read at 405 nm (Spectra MAX Plus microplate spectrophotometer
system, Molecular Devices). Purified human recombinant
snpPLA226
was used to generate a standard curve (62.5 to 2000 pg/50 µL per
well). The between-assay variation was determined by comparing the same
blood samples (n=15) on 3 different days. The coefficient of variation
was found to range between 8.6% and 9.6%.
Cell Adhesion Molecules
Circulating soluble VCAM-1, E-selectin, and ICAM-1
levels were determined by commercially available ELISA kits and
standards (R&D Systems Europe Ltd). The between-assay variation was
determined by comparing the same blood samples (n=41) on 2 different
plates. The coefficient of variation was found to be 3.3%, 5.1%, and
4.8% for VCAM-1, E-selectin, and ICAM-1 levels,
respectively.
Biochemical Analysis
Blood samples for serum cholesterol,
serum triglycerides, and lipoprotein fractions were drawn
after a fasting period of 10 to 12 hours. Cholesterol and
triglyceride levels were determined by fully enzymatic
techniques.27 28
HDL was determined after precipitation of apolipoprotein (apo)
B–containing lipoproteins with MnCl2 and
dextran sulfate. LDL cholesterol was calculated as
described by Friedewald et
al.29 All lipid
analyses were performed at the Wallenberg
Laboratory.
Statistical Analysis
All statistical analyses were performed with
SPSS 8.0 for Windows. The Mann-Whitney test was used when comparing
mean values of antibody titers in patients and controls. Furthermore, a
t-distributed variable was
used to calculate 95% CIs for differences. Comparisons between groups
for anthropometric and ultrasound data were not formally tested for
significance. Only 95% CIs for mean values are presented
because patients and controls had been selected and matched on the
basis of anthropometric and ultrasound variables. Mantel’s test
for linear association was used to test the relationship between
antibody titers and Ox-LDL and plaque occurrence and size in the
carotid artery.
Partial correlation (adjusted for sex) coefficients were used to investigate the relationships between antibody titers against Ox-LDL, IMT, cell adhesion molecules, and snpPLA2 in the patient and control groups.
Probability values <0.05 (2-sided) were regarded as statistically significant.
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Results |
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Antibody Titers Against Modified Lipoproteins in Patients With Hypercholesterolemia and Controls
Male patients with hypercholesterolemia had significantly lower IgG titers against Ox-LDL and MDA-LDL compared with control subjects. No other significant differences were observed (Table 2
). When patients and controls were analyzed
together, women had significantly higher mean values for IgM titers
against Ox-LDL and MDA-LDL compared with men
(P=0.016 and 0.010,
respectively).
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Partial Correlations Between Antibody Titers,
Cell Adhesion Molecules, and snpPLA2 in Patients
With Hypercholesterolemia and Controls
When adjusted for sex, IgG titers against both Ox-LDL
and MDA-LDL in the patient group were significantly associated with
ICAM, E-selectin, and snpPLA2. In addition, IgG
titers against MDA-LDL were also associated with VCAM in the patient
group
(Table 3). Otherwise there were no significant relationships
observed in the patient and control groups
(Table 3).
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IMT in Relation to Antibody Titers in the
Patient and Control Groups
When adjusted for sex, no significant relationships
were observed in the patient group between IMT of the common carotid
artery or the carotid artery bulb and antibodies (both IgG and IgM)
against Ox-LDL and MDA-LDL, respectively
(Table 4). However, in the control group, common carotid
artery IMT tended to be negatively associated with IgM titers against
Ox-LDL (r=-0.19,
P=0.055). Furthermore, IMT of
the carotid artery bulb was significantly and negatively associated
with IgM titers against both Ox-LDL and MDA-LDL
(r=-0.35,
P=0.001; and
r=-0.31,
P=0.003, respectively). IgG
titers in the control group were not significantly associated with IMT
(Table 4).
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Plaque Occurrence and Size in Relation to
Antibody Titers Against Modified Lipoproteins in the Patient and
Control Groups
For men in the patient group, decreasing IgG titers
against MDA-LDL were significantly associated with plaque occurrence
and size in the carotid artery
(P=0.041). For women in the
patient group, increasing IgG titers against Ox-LDL were significantly
associated with plaque occurrence and size in the carotid artery
(P=0.045). Otherwise no
significant relationships were found between antibody titers and plaque
occurrence and size in the patient group
(Table 5). In the control group, there were no significant
relationships between IgG titers and plaque occurrence and size
(Table 5). However, decreasing IgM titers against Ox-LDL
were significantly associated with plaque occurrence and size for men
in the control group
(the
Figure). Decreasing IgM titers against MDA-LDL were
also significantly associated with plaque occurrence and size in both
men and women in the control group
(P=0.003 and
P=0.010, respectively;
Table 5).
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Discussion |
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The main finding in the present study was the association between subclinical atherosclerosis and low antibody titers against Ox-LDL or MDA-LDL. Male patients with hypercholesterolemia and signs of early atherosclerosis had lower IgG titers compared with those in healthy controls. Furthermore, in the control group, there was a significant inverse correlation between IMT of the carotid artery bulb and IgM titers against Ox-LDL and MDA-LDL (r=-0.35, P=0.001; and r=-0.31, P=0.003, respectively). There was also a highly significant inverse correlation between plaque occurrence and size and IgM titers in the control group. In the patient group, only weak associations were seen. IgG titers against both Ox-LDL and MDA-LDL were significantly and positively associated with ICAM, E-selectin, and snpPLA2 levels in the patient group but not in the control group.
The above-mentioned observations between subclinical atherosclerosis and antibody titers are confusing but interesting. So far, the general hypothesis has been that high antibody titers to Ox-LDL predispose to atherosclerosis.6 7 8 On the other hand, there are recent reports indicating that immunization of experimental animals with Ox-LDL, leading to dramatically increased IgG levels, may inhibit the progression of atherosclerosis.30 31 32 In this context, the role of humoral immune reactions in atherogenesis is not clear.33 The protective role of the humoral immune response is supported by a recent study by Nicoletti et al.34 In that, study a spleen-associated immune response could protect against atherosclerosis in apoE-deficient mice. B cells can produce IgM without T-cell help, and the high titer of IgM to Ox-LDL in the present study may reflect T-cell–independent B-cell activation.
In general, it may be hypothesized that the physiological role of antibodies against Ox-LDL and related compounds is to trigger removal of the compounds from the circulation and possibly also from the arterial wall. Accordingly, Shoji et al35 recently showed that there was a negative correlation between antibody titers to Ox-LDL and plasma levels of Ox-LDL. Also in clinical studies there are reports supporting an association between low antibody titers and increased atherosclerosis. We have reported earlier on patients with familial hypercholesterolemia that those with a previous myocardial infarction had lower IgM titers compared not only with patients without a previous myocardial infarction but also with controls.21 A low antibody titer has also been reported in subjects with borderline hypertension.36
Another explanation for the inverse relationship between antibody titers to Ox-LDL and atherosclerosis could be the formation of soluble antigen-antibody complexes. Lopes-Virella et al37 recently showed that there was a significant negative correlation between free Ox-LDL antibodies and immune complexes in subjects with insulin-dependent diabetes mellitus. Hence, the possibility that immune complex formation may affect antibody titers, as determined in the present study, should be considered.
The above-mentioned explanations for the inverse relationship between atherosclerosis and antibody titers (eg, removal of antigen from the circulation and complex formation) do not explain why there was a relationship between IgM titers (but not IgG titers) and atherosclerosis in the control group (but not in the patient group). We find methodological inconsistencies less likely as an explanation for the varying results, since we in earlier studies have shown that the measurement of subclinical atherosclerosis as well as the determination of antibody titers have good reproducibility and specificity.21 38
The discrepancies may instead indicate differences in the character of atherosclerotic disease between patients and controls. The patient group was characterized by hypercholesterolemia and a high prevalence of sub-clinical atherosclerosis. On the other hand the control group was normocholesterolemic and had a low prevalence of sub-clinical atherosclerosis. In this context it may be suggested that the humoral immune response play a different role in different stages of the development of atherosclerosis as well as in the presence of various other risk factors. In the above mentioned study by Shoji et al35 the subjects were all healthy. Also, the animals immunized with modified LDL30 31 32 were free from significant atherosclerosis at the time of immunization. Furthermore, Fukumoto et al39 recently showed a negative relationship between common carotid IMT and antibody titers to Ox-LDL in a healthy population. The results from the present study are in line with these latter findings.
Because the composition of immune-competent cells in atherosclerotic plaques is quite different between early and advanced lesions,33 the biological role of immune responses against Ox-LDL probably differs in various stages of atherogenesis. This might explain why we found an inverse correlation in the control group but not in the patient group.
Another difference between the patient and control groups that could have affected the results is that some of the patients had been on lipid-lowering therapy. The drugs were withdrawn before inclusion to the study, but one may hypothesize that treatment could have long-term effects on antibody titer formation. Furthermore, it is not known whether the withdrawal of lipid-lowering medication may lead to an acute increase in antigen (ie, LDL cholesterol) formation, which in the present study might have caused short-term changes in antibody titers.
In the control group, IgM–Ox-LDL was associated with subclinical atherosclerosis in the carotid bulb only but not with IMT in the common carotid artery. Atherosclerotic changes are first seen in the carotid bulb, and subclinical atherosclerosis in this region, as measured by ultrasound, has also previously been shown to be associated with coronary atherosclerosis, as measured by coronary angiography.40 It is therefore not surprisingly to find a relationship between atherosclerotic changes in the carotid bulb and antibody titers in this group of healthy subjects.
IgG titers against Ox-LDL and MDA-LDL were positively correlated with cell adhesion molecule levels and snpPLA2 levels in patients but not in controls. Again, this could be due to different responses in different stages of the atherosclerotic process. The role of these inflammation markers and whether they are regulated by the immune response or nonspecific inflammatory stimulation in atherosclerosis cannot be concluded from the present study. However, inflammation may trigger LDL oxidation. Furthermore, the degradation of LDL by snpPLA2 may make the lipoprotein particles more sensitive to oxidation. These factors may therefore participate in triggering the immune response against Ox-LDL.
Taken together, the findings of this study support the concept that the humoral immune response against Ox-LDL may be protective in early atherosclerosis. The pattern, however, is complex, and the role of the immune response may be different in different patient groups as well as at different stages of the disease.
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Acknowledgments |
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This study was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (projects 10880, 4531), Doctors Educational Agreement grants for clinical research, and Astra Hässle, Mölndal, Sweden. We thank laboratory technologists Aira Lidell, Anna Frödén, and Caroline Schmidt for excellent research assistance.
Received December 13, 1999; accepted September 29, 2000.
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