© 1998 American Heart Association, Inc.
Original Contributions |
Lysophosphatidylcholine Is Involved in the Antigenicity of Oxidized LDL
From the Department of Medicine, Unit of Rheumatology and CMM, Karolinska Hospital (R.W., Y.H.H., J.F.); and the Department of Medicine, King Gustaf V Research Institute, Karolinska Institute (L.S.E.), Stockholm, Sweden.
Correspondence to Johan Frostegard, Department of Medicine, Karolinska Hospital, 17177 Stockholm, Sweden.
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Abstract |
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Abstract—Lysophosphatidylcholine (LPC) is formed by hydrolysis of PC in low density lipoprotein (LDL) and cell membranes by phospholipase A2 or by oxidation. Oxidized (ox) LDL activates endothelial cells, an effect mimicked by LPC. oxLDL also has the capacity to activate T and B cells, and antibody titers to oxLDL are related to the degree of atherosclerosis. The antigen in oxLDL responsible for its immune-stimulatory capacity is not well characterized, and we hypothesized that LPC was involved. We demonstrate herein the presence of antibodies against LPC, both of the IgG and IgM isotype, in 210 healthy individuals. This antibody reactivity was not specifically related to oxidation of the fatty acid moiety in LPC, since LPC containing only palmitic acid showed antibody titers equivalent to those of LPC containing unsaturated fatty acids. Antibody titers to PC were low compared with LPC, and hydrolysis of PC at the sn-2 position is thus essential for immune reactivity. There was a close correlation between anti-oxLDL and anti-LPC antibodies. Furthermore, LPC competitively inhibited anti-oxLDL reactivity, which indicates that LPC may explain a significant part of the immune-stimulatory properties of oxLDL. LPC, being a lipid, is not likely to be an antigen itself. Instead, LPC could form immunogenic complexes with peptides, which may induce and potentiate immune reactions in the vessel wall. This study adds to the evidence that LPC is an important component of oxLDL and emphasizes the potential role of phospholipase A2 in atherosclerosis.
Key Words: lysophosphatidylcholine • antibodies • oxidized LDL • autoimmune diseases • atherosclerosis
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Introduction |
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Anti-phospholipid antibodies have been found in a variety of inflammatory and autoimmune diseases such as SLE and are related to cardiovascular disease.1 Antibodies have been shown to be directed mainly against CL, a diphosphatidylglycerol, as well as phosphatidylethanolamine and phosphatidylserine.2 It is generally believed that phospholipids with antigenic properties bind to plasma proteins like ß2-glycoprotein, thereby creating neoantigens,2 which are recognized by the so-called anti-phospholipid antibodies. Patients with significant amounts of anti-phospholipid antibodies may develop autoimmune thrombocytopenia and have an increased risk for thrombotic events.3 4
According to a leading hypothesis, oxLDL plays a pivotal role in atherosclerosis.5 The early stages of atherosclerosis are characterized by the presence of activated macrophages and T lymphocytes,6 and oxLDL may play a role in this activation.7 8 9 Antibodies against oxLDL are present both in healthy individuals and in atherosclerotic plaques and are related to atherosclerosis progression.10 11 12 Furthermore, anti-oxLDL antibodies have been correlated with titers against CL in SLE patients.13 One of the active components of oxLDL is LPC, which may be formed during oxidation of LDL14 or from PC by enzymes with PLA2 activity.15 Recently we identified secretory PLA2 type II (ie, sPLA2-II, nonpancreatic type) expression and activity in both normal and atherosclerotic arterial walls, being mainly expressed by medial smooth muscle cells.16 This finding opens the possibility that significant amounts of LPC may be generated in the arterial wall by hydrolysis of phospholipids in retained LDL. In several autoimmune diseases like rheumatoid arthritis and SLE, elevated plasma PLA2 activity has been demonstrated.17 18 Therefore, in these disorders, elevated amounts of LPC could be produced in the blood compartment. On the basis of this evidence, we wondered whether antibodies were produced in vivo against LPC. In the present article we present evidence that antibodies against LPC are present in normal, healthy individuals and that their titers can be correlated closely with antibody titers to oxLDL.
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Methods |
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Study Group
Sera from the blood bank at the Karolinska Hospital was used in this study and consisted of sera from 210 healthy volunteering blood donors with a mean age±SD of 46.6±11.5 years. There were 150 males (46.81±9.32 years) and 60 females (46.21±13.52 years).
Lipids and Reagents
L-
-LPC (from egg yolk type 1, produced by
PLA2 treatment), L-- 16:0 (LPC
16:0, also produced by PLA2 treatment),
L--PC (from egg yolk type 1), and CL (from bovine brain)
were from Sigma Chemical Co.
LDL was isolated from the plasma of healthy donors by sequential preparative ultracentrifugation in a Beckman 50.3 Ti fixed-angle rotor (Beckman L8–80 ultracentrifuge) for 48 hours at 1°C and collected in the density interval 1.025 to 1.050 kg/L.19 The protein content was determined according to the method of Lowry et al20 and adjusted to 200 µg/mL. The LDL was dialyzed against PBS (pH 7.4) for 24 hours and then oxidized by exposure to 5 µmol/L CuSO4 for 18 hours at 37°C. This procedure has previously been shown to result in extensive oxidation of LDL.21 Antigen PPD (2.5 mg/mL) was from Statens Seruminstitut, and antigen EB-Na was from Blotest.
Determination of Antibodies Against LDL, Lipids, and EB-Na
IgG and IgM antibodies against oxLDL and native LDL were
determined by an ELISA essentially as
described.22 OxLDL and LDL were diluted to 2
µg/mL in coating buffer (carbonate/bicarbonate buffer, 50
mmol/L, pH 9.7), and a volume of 100 µL per well was used to coat the
ELISA plates (Costar 2581). The plates were kept at 4°C overnight,
washed three times with PBS containing 0.05% Tween-20, and then
blocked with 20% ABS-PBS for 2 hours at room temperature. The plates
were then incubated with 100 µL serum, diluted 1:30 in 20% ABS-PBS
at 4°C overnight.
Antibodies against CL, PC, LPC, and LPC 16:0 were analyzed essentially as described, with CL as the antigen.23 In brief, Titertek 96-well polyvinylchloride microplates (Flow Laboratories) were coated with 50 µL per well of 50 µg/mL lipid dissolved in ethanol and allowed to dry overnight at 4°C. Blocking was accomplished with 20% ABS-PBS for 2 hours. Serum samples (50 µL each), diluted 1:30 in 20% ABS-PBS, were added to each well.
Antibody reactivity to the EB-Na component in Epstein-Barr virus was detected with an ELISA according to the manufacturer's instructions (Blotest). In brief, 100 µL per well of 50 ng/mL EB-Na was used to coat the ELISA plates (Costar 2581). The plates were then incubated with 100 µL serum, diluted 1:30 in 20% ABS-PBS at 4°C overnight.
After three washes with PBS, the plates were incubated with 50 µL/mL of alkaline phosphatase–conjugated goat anti-human IgA (Sigma A-3400), diluted 1:10000; IgG (Sigma A-3150), diluted 1:9000; or IgM (Sigma A-3275), diluted 1:7000 with PBS at 37°C for 2 hours. After three washes, 100 µL of substrate (phosphatase substrate tablets, Sigma 104; 5 mg in 5 mL diethanolamine buffer, pH 9.8) was added. The plates were incubated at room temperature for 30 minutes and read in an ELISA Multiskan Plus spectrophotometer at 405 nm. Each determination was done in triplicate. The coefficient of variation between triplicate tests was <5%.
Cross-reactivity Between Antibodies to LPC and oxLDL
To investigate whether there was any immunological
cross-reactivity between the antibodies tested, competition assays were
performed. Sera at a dilution that yielded 50% of maximal binding to
the compound coated were preincubated with different concentrations of
oxLDL, LPC, CL, or EB-Na. The sera were incubated overnight with
different competitors at 4°C, and inhibition of binding to oxLDL was
tested. The percentage of inhibition was calculated as follows: percent
inhibition=ODcontrol-ODwith
competitorx100/ODcontrol, where OD
is the optical density in nanometers.
Statistical Methods
Conventional methods were used for calculation of means and SDs.
Parallelism between dilution curves was determined by correlation
coefficient analysis and Fisher's test. Simple regression was
used to analyze the correlations between the antibodies and
between age and the antibodies.
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Results |
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Antibody Titers Against LDL, oxLDL, CL, and LPC
The levels of IgA, IgG, and IgM antibodies against LDL, oxLDL, CL, and LPC were determined. In general, antibodies of the IgA isotype to these antigens were very low (data not shown). The levels of both IgG and IgM antibodies are shown in Table 1
.
Antibodies against oxLDL were significantly higher
(P<.[r]001) than those against LDL. The IgG
and IgM antibody titers against both LPC and CL were clearly detectable
in the group as a whole, although marked individual variation was
noted. There was no correlation between antibody titer and age (data
not shown).
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Analysis of Antibodies Against LPC
To identify the characteristic feature of LPC that induces
antibody formation, we tested the antigenicity of PC obtained from the
same source as LPC (egg yolk) and that of LPC 16:0, ie, LPC containing
only saturated palmitic acid in the sn-1 position. For
this purpose, 20 serum samples with the highest antibody titers against
LPC were chosen. The levels of antibodies against PC, LPC, and LPC
16:0, are shown in Fig 1. The levels of
antibodies against LPC (IgM, 0.302±0.092; IgG, 0.335±0.2; mean±SD)
and against LPC 16:0 (IgM, 0.342±0.14; IgG, 0.325±0.15) were both
significantly higher (P<.[r]001) than the
levels of antibodies against PC, which were quite low (IgM,
0.11±0.077; IgG, 0.075±0.11). There was no significant difference
between the levels of antibodies against LPC and those against LPC
16:0. There was a strong, linear correlation between antibody titers
against LPC and LPC 16:0 (IgG, r=.841,
P<.0001; IgM, r=.784,
P<.0001). The distribution of antibody titers against
LPC for the whole group was almost normal, as shown in Fig 2.
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To further characterize antibody reactivity to LPC, different dilutions
of sera from four high- and four low-titer individuals were
investigated. The curves for the individuals with high titers were
parallel, since correlation coefficients between them were >.91 and
P values were <.002 in all comparisons between the curves
(Fig 3).
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The correlation between antibodies against LPC and antibodies
against LDL, oxLDL, and CL are shown in Table 2. There was a significant correlation
(P<.0001) between antibody titers against oxLDL and
LPC for both the IgG and IgM isotypes. Likewise, antibody titers were
correlated between LPC and CL, particularly those of the IgM isotype
(P<.0001). Other significant correlations were found
between LDL and oxLDL (data no shown). No significant association was
found between IgG antibody titers against oxLDL and CL, but for IgM,
there was a comparatively weak correlation (Table 2).
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Cross-reactivity of Antibodies to LPC and oxLDL
To study possible cross-reactivity between the antibodies,
we performed competition experiments with LPC, CL, and oxLDL at a
dilution that yielded 50% of maximal binding to oxLDL. As a control,
the unrelated antigen PPD was used. Fig 4
shows that LPC and oxLDL had the same capacity to inhibit serum binding
to oxLDL-coated plates (P<.01 when compared with PPD;
P<.05 when compared with CL). CL had an intermediate
capacity in this respect (P<.05 when compared with
PPD), whereas PPD showed no inhibitory effect.
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), LPC (
),
cardiolipin (
), and PPD (
) of serum binding to oxLDL-coated
plates. Sera were incubated with different antigens and concentrations
as indicated at 4°C overnight. After incubation, binding to
oxLDL-coated ELISA plates was investigated. Results are mean±SD of
four donors.
To exclude the possibility that LPC has a general ability to
interfere with antibody binding, the antibody reactivity (very common
in the population) to EB-Na, a component of Epstein-Barr virus, was
studied. When ELISA plates were coated with EB-Na, oxLDL, or LPC and
EB-Na was used as the competitor, antibody binding to EB-Na itself was
strongly reduced, whereas there was no effect on binding to LPC or
oxLDL (Fig 5A). However, when LPC instead
of EB-Na was used as a competitor, binding to LPC and oxLDL was
strongly reduced, whereas binding to EB-Na was not influenced (Fig 5B).
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Discussion |
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A new finding of the present study is that healthy subjects produce antibodies against LPC, a major component of oxLDL. Lysophospholipids are also produced by a heterogeneous group of enzymes with PLA2 activity.24 Since PC is the most abundant phospholipid in cellular membranes, LPC would be the dominant lysophospholipid formed. This may have far-reaching implications for a variety of immunological/inflammatory diseases, like rheumatoid arthritis and SLE, which are characterized by an elevated PLA2 expression and activity.17 21 Our finding of antibodies to this ubiquitous lysophospholipid in healthy humans may reflect the circumstance that several types of PLA2s are constitutively expressed in many tissues and leukocytes at a low level. Several inflammatory cytokines have been shown to increase the activity and expression of PLA2s, whereas glucocorticoids (dexamethasone) inhibit the enzyme.24
Phospholipids that have previously been demonstrated to function as antigens are CL, phosphatidylethanolamine, and phosphatidylserine. Elevated levels of such antibodies are found in patients with the anti-phospholipid syndrome and are common in SLE, where they are related to enhanced risk of cardiovascular disease.1 It is generally believed that these phospholipids form a complex with peptides or proteins, whereby a neoantigen may be created that can be recognized by B cells.25 A recently published study investigating the nature of anti-CL antibodies in high-titer sera by Hörkkö et al26 presented evidence that antibodies were directed against epitopes created as a result of oxidation of fatty acids in CL during overnight adherence of the lipid to the ELISA plates. The antigenicity of LPC demonstrated herein was not investigated in high-titer sera but in sera from healthy individuals. LPC-antigenicity is not likely to depend on oxidative reactions, since there was no significant difference between antibody titers to LPC and the completely saturated LPC 16:0. Furthermore, antibody titers against PC, which has two fatty acids of which one is usually unsaturated, were lower than titers against LPC and the completely saturated LPC 16:0. However, LPC and oxidized CL may share antigenic epitopes in high titer sera, a possibility presently under investigation.
We found a strong correlation between antibody titers against LPC and CL, indicating that the antigenicity of CL may also be related to hydrolysis of one or more of its four fatty acids. Thus, antigenicity in our case seems to depend on the special structure of LPC with an empty sn-2 position. Whether this structure per se is sufficient to elicit an antibody response or whether a protein-LPC complex is needed remains to be shown. It has recently been suggested that C-reactive protein binds to LPC in membranes of injured cells, thereby activating the complement cascade.27 Thus, C-reactive protein, which is elevated in the blood in inflammatory conditions, is a potential candidate for an LPC-complexing protein, a possibility presently under investigation.
This study confirms findings by other investigators that antibodies against oxLDL are present in normal, healthy individuals.10 11 12 Antibodies to native LDL were also detected but at much lower concentrations, and it is thus clear that a B-cell antigen is formed or enhanced during oxidation of LDL. We have observed that LDL often has similar effects on T-cell and monocyte/macrophage activation as does oxLDL, but that these effects in general are lower and that higher concentrations of LDL are needed.7 9 The most likely explanation is that LDL and oxLDL contain the same antigenic compound(s) but at different concentrations and that this may be formed during oxidation. Large amounts of LPC are produced during in vitro oxidation of LDL.16 We have demonstrated here that LPC is as effective as oxLDL in inhibiting serum binding to oxLDL. Furthermore, highly significant statistical correlations between antibody titers against native oxLDL and against LPC were found. To exclude the possibility that LPC has a capacity to inhibit antibody interaction with antigen in general, an unrelated and common antigen from Epstein-Barr virus, EB-Na, was used. In contrast to EB-Na itself, neither LPC nor oxLDL interfered with serum binding to EB-Na. Likewise, EB-Na had no capacity to inhibit serum binding to LPC or oxLDL. Furthermore, LPC inhibited binding to LPC. Taken together, our findings show that a significant part of the antigenicity of oxLDL may be explained by LPC.
Our findings may be relevant to all disorders characterized by elevated production of LPC by PLA2 or by oxidation,5 28 because LPC may mediate several of the proinflammatory effects ascribed to oxLDL. Other reports support the notion of LPC as a proinflammatory factor in atherogenesis. LPC potentiates protein kinase C–mediated T-cell activation,29 stimulates smooth muscle cell proliferation,30 activates protein kinase C in intact vascular segments leading to increased superoxide production,31 and induces monocyte mRNA expression of heparin-binding endothelial growth factor.32 Furthermore, LPC has been shown to be chemotactic for T lymphocytes and monocytes.33 34 An interesting possibility is that antibodies to LPC/oxLDL could form immune complexes, which could be taken up by phagocytosis in the artery wall, leading to foam cell formation. In line with this, PLA2-modified LDL is taken up by macrophages, which develop into foam cells.35 In principle, antibodies to LPC produced by PLA2 in LDL may therefore form immune complexes, leading to both endothelial activation and possibly foam cell formation.
PLA2 and its product, LPC, free or bound to LDL, could thus be part of a comprehensive systemic as well as localized defense system against microorganisms and injured cells, which is upregulated during infection and inflammatory disorders.27 Clearly, studies of the role of anti-LPC antibodies in chronic inflammation and atherosclerosis could shed light on this issue.
Taken together, it is possible that LPC, produced during oxidation or enzymatically by PLA2, may activate B cells to antibody secretion and thus participate in and promote the chronic inflammatory reactions seen in atherosclerosis and several types of immunological disorders.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by King Gustaf V 80th Birthday Fund, the Swedish Society of Medicine, Ostermans Fund, The Swedish Rheumatism Association, Wibergs Fund, Börje Dahlin's Fund, Saléns Fund, the Nanna Svartz Fund, and the Swedish Heart Lung Foundation (all grants were awarded to J.F.).
Received September 3, 1997; accepted November 25, 1997.
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