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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Objective

To determine the prevalence of anti–high-density lipoprotein (anti-HDL) antibodies and to establish a possible relationship between anti-HDL, anticardiolipin antibodies (aCL), anti–β2-glycoprotein I (anti-β2GPI), and paraoxonase (PON) activity in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS).

Methods

Thirty-two patients with SLE and 36 with primary APS were enrolled in a cross-sectional study. Twenty age- and sex-matched healthy subjects were used as controls. Serum levels of IgG and IgM aCL, anti-β2GPI, and antiprothrombin antibodies and IgG anti-HDL were measured by enzyme-linked immunosorbent assay. Total cholesterol, HDL cholesterol, HDL2, and HDL3 were determined by standard enzymatic techniques. PON activity was assessed by quantification of nitrophenol formation, and total antioxidant capacity (TAC) by chemiluminescence.

Results

Levels of total HDL, HDL2, and HDL3 were reduced in patients with SLE compared with controls (mean ± SD 0.51 ± 0.3, 0.37 ± 0.3, and 0.14 ± 0.1 mmoles/liter, respectively, versus 1.42 ± 0.9, 1.01 ± 0.7, and 0.40 ± 0.2). Patients with SLE and primary APS had higher titers of anti-HDL antibodies and lower PON activity than controls. In the SLE population, PON activity was inversely correlated with IgG anti-HDL titers (r = −0.48, P = 0.005) whereas in the primary APS population, IgG anti-β2GPI was the only independent predictor of PON activity (r = −0.483, P = 0.003). In the SLE group, anti-HDL was inversely correlated with TAC (r = −0.40, P < 0.02), and PON activity was positively correlated with TAC (r = 0.43, P < 0.02).

Conclusion

IgG anti-HDL and IgG anti-β2GPI antibodies are associated with reduced PON activity in patients with SLE and primary APS. Since the physiologic role of PON is to prevent low-density lipoprotein oxidation with its attendant atherogenic effects, the reported interactions may be relevant to the development of atherosclerosis in SLE and primary APS.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by systemic inflammation and increased production of a wide range of autoantibodies directed against a multiplicity of antigens (1). Premature atherosclerosis has recently been recognized as an important cause of morbidity and mortality in SLE (2), and coronary artery disease accounts for up to 30% of all deaths in some reported series (3). Classic risk factors for cardiovascular disease in SLE appear to be similar to those in the general population, but specific factors such as steroid treatment, chronic inflammation, and renal disease could account for enhanced atheroma formation (4).

Dyslipoproteinemia is a major factor in the development of atherosclerosis in SLE (5, 6). Low levels of high-density lipoproteins (HDL) and apolipoprotein A-I (Apo A-I) have been related to disease activity and the presence of anticardiolipin antibodies (aCL) (7). Anticardiolipin antibodies, a hallmark of the antiphospholipid antibody syndrome (APS), can also be found in a wide range of different conditions and are present in 30–40% of patients with SLE (8). Cross-reactivity between these autoantibodies and plasma lipoproteins, particularly when the latter are oxidized, has been described to occur in SLE and APS and could contribute to the increased risk of atherosclerosis found in both conditions (9). Oxidation is a major process in atherosclerosis (10), and oxidative stress has been described in both SLE and APS (11). Paraoxonase (PON) is an enzyme with antioxidant activity, which circulates in plasma attached to HDL. Its function is to prevent oxidation of low-density lipoprotein (LDL), accounting thus for the antioxidant effect of HDL and explaining why HDL has a protective effect against atherosclerosis (12, 13). PON activity has been shown to decrease with age (14) and increase with intake of lipid-lowering drugs (15).

This study was undertaken to explore whether the activity of PON is impaired in patients with SLE and primary APS (contributing to enhanced atherosclerotic progression in these conditions), and, if so, whether the impairment could be dependent on the presence of autoantibodies against cardiolipin, β2-glycoprotein I (anti-β2GPI), prothrombin, and HDL.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients.

Sixty-eight consecutive patients (32 with SLE and 36 with primary APS) attending the outpatient clinic of the Centre for Rheumatology, University College of London, the Haematology Department of the Middlesex Hospital (London), and the Coagulation Unit of the Cardarelli Hospital (Naples, Italy) (referred by Dr. V. Brancaccio) were enrolled in this cross-sectional study. None of the SLE patients had APS, and the APS was primary in all of the APS patients. Twenty age- and sex-matched healthy controls served as a control group.

Demographic data on the patients and controls, and clinical data on the patients are shown in Table 1. All of the SLE patients met the American College of Rheumatology revised criteria for classification of the disease (16, 17), and all of the APS patients met the Sapporo revised criteria for primary APS (18). None of the patients in the study was taking lipid-lowering agents or antioxidant drugs. None of the SLE patients had a history of thrombosis or other atherosclerosis-related events. On the day of serum sampling the lupus patients' disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) scoring system (19). The individual disease activity assessments in the 8-organ/systems classification were combined to provide a global score of 0–9, with 9 representing the most active disease. Clinical data obtained on patients with SLE and primary APS included information regarding steroid dose, antimalarial drug use, antiplatelet agents, and anticoagulation status.

Table 1. Demographic and clinical data on the patients and controls*
 Controls (n = 20)SLE (n = 32)APS (n = 36)
  • *

    SLE = systemic lupus erythematosus; APS = antiphospholipid syndrome; BILAG = British Isles Lupus Assessment Group (19) (global score of 0–9, with 0 representing no disease activity and 9 representing the most severe disease); NA = not applicable; HCQ = hydroxychloroquine.

Age, mean ± SD years33.3 ± 3.635.5 ± 14.431.3 ± 14.2
No. (%) female/male17 (85)/3 (15)28 (87.5)/4 (12.5)32 (88.9)/4 (11.1)
Disease duration, median (range) yearsNA5.8 (1–12.3)5.2 (1–8.5)
Global score (BILAG), mean ± SDNA6.7 ± 4.5NA
Taking steroids, no. (%)NA23 (71.9)
Steroid dosage, mean ± SD mg/dayNA10.3 ± 10.0
Taking HCQ, no. (%)NA16 (50.0)
Had thrombotic event, no. (%)NA24 (66.7)
Had miscarriage, no. (%)NA14 (38.9)
Taking aspirin, no. (%)NA10 (31.3)16 (44.4)
Taking warfarin, no. (%)NA20 (55.6)

Sera from patients and controls were kept at −80°C until laboratory tests were performed. The study was carried out according to the Declaration of Helsinki, and informed consent was obtained from all patients before their participation in the study.

Anticardiolipin antibodies.

IgG and IgM aCL were measured by enzyme-linked immunosorbent assay (ELISA) using microtiter plates (Polysorp; Nunc, Life Technologies, Paisley, UK) half-coated overnight at 4°C with cardiolipin (bovine heart; Sigma-Aldrich, Poole, UK) (50 μg/ml cardiolipin in 70% ethanol). Blocking with phosphate buffered saline (PBS) was performed for 1 hour at room temperature. Plates were then washed once with PBS. Samples were diluted 1:100. Positive control serum (100 μl) was added to duplicate wells for 1 hour at room temperature. After 3 washes, 100 μl of alkaline phosphatase–conjugated anti-human IgG (1:1,000 in blocking agent) was added for 1 hour. Then, 100 μl of p-nitrophenyl phosphate (Product 104/105; Sigma-Aldrich) in diethanolamine buffer (pH 9.8) was added, followed by incubation at 37°C for color development. Absorbance at 405 nm was read after 1 hour. Assays were standardized with sera calibrated against the appropriate International Reference Material (20), and the results were reported as phospholipid units.

Anti-β2-GPI antibodies.

IgG β2GPI was measured by ELISA, using a commercial kit (Diastat anti-β2GPI; Axis-Shield Diagnostics; Dundee, UK) based on a method previously developed in our laboratory (21). IgM anti-β2GPI was assayed by an adaptation of the IgG kit components to accommodate the detection of IgM antibodies using a μ-specific conjugated secondary antibody. Both assays were standardized using serum with a known high concentration of antibody; units were expressed in mg/dl. The cutoff point for the upper limit of normal had been previously determined as the geometric mean + 95% confidence interval of values obtained in 30 healthy adults.

Antiprothrombin antibodies.

IgG and IgM antiprothrombin was analyzed by ELISA using γ-irradiated microtiter plates (Maxisorp; Nunc, Life Technologies) coated overnight at 4°C with 10 μg/ml human prothrombin (Enzyme Research Laboratories; Swansea, UK) in PBS. Blocking was performed using PBS containing 0.1% Tween 20 and 1% bovine serum albumin (BSA) (A7030; Sigma-Aldrich) for 1 hour at room temperature. Plates were than washed once using PBS containing 0.1% Tween 20. A standard curve was prepared from reference plasma with a known high antiprothrombin activity. Test samples were diluted 1:50 in PBS containing 0.1% Tween 20 and 1% BSA. Standard or test sample (100 μl) was added to duplicate wells for 1 hour at room temperature. After 3 washes, 100 μl of alkaline phosphatase–conjugated anti-human IgG or IgM was added for 1 hour, followed by addition of 100 μl p-nitrophenyl phosphate in diethanolamine buffer (pH 9.8). Incubation for color development was performed at 37°C, and was stopped using 3M NaOH. Absorbance at 405 nm was read. All assays were validated by the inclusion of internal quality control samples of known activity, and the units were expressed in optical density, as a percentage of control activity. The cutoff point for the upper limit of normal had been previously determined as the geometric mean + 95% confidence interval of values obtained in 30 healthy adults.

Anti-HDL antibodies.

IgG anti-HDL antibodies were measured by ELISA using γ-irradiated microtiter plates (Polysorb) half-coated overnight at 4°C with 20 μg/ml human HDL in 70% ethanol. HDL was isolated from healthy subjects as previously described (22). Blocking with PBS containing 1% BSA (A7030) was performed for 1 hour at room temperature. Plates were then washed once with PBS. Samples were diluted 1:100 in PBS containing 1% BSA. Positive control serum (100 μl) was added to duplicate wells for 1 hour at room temperature. After 3 washes, alkaline phosphatase–conjugated anti-human IgG was added, followed by addition of p-nitrophenyl phosphate in diethanolamine buffer, and incubation as described above for aCL and antiprothrombin antibodies. Absorbance at 405 nm was read. All assays were validated by the inclusion of internal quality control samples of known activity. The results were expressed as a percentage of the positive control in each plate.

Total cholesterol, total HDL, and HDL subfractions 2 and 3.

Plasma total cholesterol and HDL cholesterol were determined by the cholesterol oxidase–peroxidase antipyrine method with the use of an enzymatic test reagent (Infinity cholesterol test reagent; Sigma Diagnostics, Poole, UK). HDL was first isolated by selective precipitation of LDL from plasma using heparin-Mn2+. Specifically, 1 ml of plasma was treated with 75 μl of heparin, briefly vortexed, and allowed to incubate at room temperature for 2 minutes. Following addition of 100 μl of MnCl2, samples were again vortexed and incubated at 4°C for a further 30 minutes. Samples were then centrifuged at 12,000g for 5 minutes to pellet precipitated LDL particles and the supernatant collected for HDL cholesterol measurements. Aliquots of plasma or HDL-containing supernatant (10 μl) were then mixed with 1 ml of enzyme assay reagent, and the resultant mixture incubated at room temperature for 20 minutes and then assayed spectrophotometrically at 500 nm. Triplicate determinations were made, and the average value taken.

HDL subfractions 2 and 3 were obtained according to the method described by Gidez et al (23). Briefly, HDL3 was isolated by precipitation after addition of 50 μl dextran sulfate (14.3 mg/ml in saline) to 500 μl of total HDL prepared as described above. After incubation for 30 minutes at room temperature, samples were centrifuged at 12000g for 2 minutes. Supernatants (HDL3-containing) were removed and values were obtained by spectrophotometry at 500 nm, (multiplied by 1.225 to correct for additions). HDL2 values were obtained by subtracting the value for HDL3 from that for total HDL.

PON activity.

Serum PON activity was measured as described by Eckerson et al (24), with some modifications. Briefly, PON (1.0 mM), freshly prepared in 300 μl of 50 mM glycine buffer containing 1 mM calcium chloride (pH 10.5), was incubated at 37°C with 5 μl of serum, for 15 minutes in 96-well plates (Polysorp). Formation of p-nitrophenol was monitored at 412 nm, and activity expressed as nmoles p-nitrophenol per ml serum per minute. The cutoff point for the upper limit of normal had been previously determined as the mean + 3 SD of values obtained in 35 healthy adults.

Total antioxidant capacity of plasma.

Total antioxidant capacity (TAC) was assessed by the capacity of a sample to scavenge peroxynitrite formed by the reaction between superoxide and nitric oxide released from 50 μl of 10 mmoles/liter of SIN-1, using an ABEL (Analysis by Emitted Light) antioxidant test kit (Knight Scientific, Plymouth, UK) with Pholasin for peroxynitrite, according to the instructions of the manufacturer (Knight Scientific). TAC was expressed in minutes, measured from the time of the injection of SIN-1 into each sample well until luminescence occurred.

Statistical analysis.

Statistical analysis was performed using the Statistical Package for Social Sciences (Chicago, IL). Nonparametric tests were used to compare differences between groups (Kruskal-Wallis test) and to evaluate associations between variables (Spearman's rank test). Stepwise multiple regression was used to test the independence of the associations detected by univariate analysis.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Levels of aCL, anti-β2GPI, and antiprothrombin antibodies in patients and controls.

Median levels of IgG aCL, IgM aCL, IgG anti-β2GPI, IgM anti-β2GPI, and IgG antiprothrombin were always higher in patients with SLE and primary APS than in controls, whereas median levels of IgM antiprothrombin were not different across the 3 groups (Figure 1).

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Figure 1. Levels of IgG anticardiolipin (aCL) (A), IgM aCL (B), IgG anti–β2-glycoprotein I (anti-β2GPI) (C), IgM anti-β2GPI (D), IgG antiprothrombin (anti-PT) (E), and IgM anti-PT (F) in controls (CTRL), patients with systemic lupus erythematosus (SLE), and patients with primary antiphospholipid syndrome (PAPS). Bars show the medians. P values refer to the overall analysis of variance result, as determined by Kruskal-Wallis test. GPL = IgG phospholipid units; MPL = IgM phospholipid units.

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PON activity, TAC of plasma, and anti-HDL in patients and controls.

PON activity was low in SLE patients and even lower in primary APS patients compared with controls (P < 0.0001) (Figure 2A), but TAC did not differ across the 3 groups (Figure 2B). Anti-HDL antibody levels were significantly higher in SLE patients than in controls or primary APS patients (P < 0.0001) (Figure 2C).

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Figure 2. Levels of paraoxonase (PON) activity (A), total antioxidant capacity (TAC) of plasma (B), and IgG anti–high-density lipoprotein (anti-HDL) (C) in controls (CTRL), patients with systemic lupus erythematosus (SLE), and patients with primary antiphospholipid syndrome (PAPS). Bars show the medians. P values shown in the figure refer to the overall analysis of variance result, as determined by Kruskal-Wallis test. Other P values, determined by Dunn's post hoc test, were as follows: P < 0.01, PON levels in SLE patients versus controls; P < 0.001, PON levels in PAPS patients versus controls; P < 0.001, IgG anti-HDL levels in SLE patients versus controls; P < 0.005; IgG anti-HDL levels in SLE patients versus PAPS patients.

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Levels of cholesterol, HDL, and HDL subfractions and their relationship to PON levels in SLE patients and controls.

Levels of total cholesterol were similar in the SLE group and the controls (mean ± SD 4.39 ± 1.6 mmoles/liter and 4.55 ± 1.0 mmoles/liter, respectively). Patients with SLE had reduced levels of total HDL (0.51 ± 0.3 mmoles/liter, versus 1.42 ± 0.9 in controls; P < 0.001), HDL2 (0.37 ± 0.3 mmoles/liter, versus 1.01 ± 0.7; P < 0.001), and HDL3 (0.14 ± 0.1 mmoles/liter, versus 0.40 ± 0.2; P < 0.004). In controls, PON levels correlated with levels of HDL (r = 0.7, P = 0.0005) (Figure 3A), HDL2 (r = 0.78, P < 0.0001) (Figure 3C), and HDL3 (r = 0.44, P = 0.04) (data not shown). These relationships were not identified in the SLE group (Figures 3B and D).

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Figure 3. Correlation (by Spearman's rank test) between PON activity and HDL levels in controls (A) and SLE patients (B), and between PON activity and HDL2 levels in controls (C) and SLE patients (D). There were significant correlations in the control group but not in the SLE group. See Figure 2 for definitions.

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Relationship between oxidation markers, disease activity, and treatment.

HDL, HDL2, and HDL3 levels, anti-HDL titers, PON activity, and TAC levels did not differ between SLE patients receiving steroids or antimalarial agents and those not taking the medications. There was no correlation between the global BILAG score, the scores for any of the organ systems within the BILAG, C3 levels, or erythrocyte sedimentation rate and anti-HDL titers, PON activity, or TAC levels (data not shown). In the primary APS group, none of the variables was significantly different between patients receiving oral anticoagulation treatment and patients taking aspirin alone. Likewise, no significant differences in IgG anti-HDL levels, PON activity, and TAC levels were noted among patients with arterial or venous thrombosis and/or those who had had miscarriages (data not shown).

Relationship between PON and antibody titers.

In the SLE group, PON activity showed a strong inverse correlation with IgG anti-HDL levels (Figure 4A) (even after correction for age and steroid and antimalarial drug intake), but not with any other autoantibody investigated. In addition, IgG anti-HDL was negatively correlated with TAC (r = −0.40, P < 0.02), and TAC was positively correlated with PON (r = 0.43, P = 0.02). In the primary APS group, PON activity was inversely correlated with IgG aCL (Figure 4B), IgG anti-β2GPI (Figure 4C), and IgM anti-β2GPI (Figure 4D).

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Figure 4. Correlation (by Spearman's rank test) between IgG anti–high-density lipoprotein (anti-HDL) and paraoxonase (PON) activity in SLE patients (A) and between PON activity and IgG aCL levels (B), PON activity and IgG anti-β2GPI levels (C), and PON activity and IgM anti-β2GPI levels (D) in PAPS patients. See Figure 1 for other definitions.

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Multiple regression model.

To evaluate which antibody was most strongly associated with a decrease in PON activity in the primary APS group, we used stepwise multiple regression. PON activity was entered as the dependent variable and IgG aCL, IgG anti-β2GPI, and IgM anti-β2GPI, which correlated with PON in the univariate analysis, were entered as independent variables and corrected for age, sex, and warfarin intake. In this model, IgG anti-β2GPI was found to be the only independent predictor of decreased PON activity (r = −0.483, P = 0.003).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Systemic lupus erythematosus and the antiphospholipid syndrome are both characterized by an enhanced risk of thrombosis and atherosclerosis. Even though some pathogenic pathways might be shared, there are different factors that ultimately account for the development of vascular damage in the 2 conditions.

In SLE, prolonged steroid treatment seems to be the major cause in that it induces an atherogenic lipid profile, characterized by increased levels of very low-density lipoprotein and LDL and decreased levels of HDL, together with hypertension and diabetes (25). In the present study, HDL was reduced in SLE patients compared with controls, as has been reported previously (26). This reduction was quite significant for the HDL2 subfraction. A decrease in HDL2 in patients with SLE has not been reported previously, and is particularly important because this subfraction contains the higher percentage of Apo A-I, which partly accounts for the protective effect of HDL against atherosclerosis (27). The importance of Apo A-I in the context of SLE is further enhanced by the recent observation that Apo A-I exerts antiinflammatory properties by blocking the contact-mediated activation of monocytes by T lymphocytes (28).

Other pro-atherogenic factors include chronic inflammation (29) and enhanced lipid peroxidation (30). Both conditions have been found in patients with SLE (11, 31), whereas a strong link between lipid peroxidation and IgG aCL titers has been demonstrated in APS (32). Furthermore, aCL antibodies have also been related to atherosclerosis (33, 34). This may occur either via direct activation of the vascular endothelium or by the increased uptake of anti-oxidized LDL–LDL immune complexes by macrophages (35). In this context, anti-β2GPI antibodies could also be of importance, because they hinder the protective role of β2GPI in preventing oxidized LDL uptake by macrophages (35). In our study, patients with SLE and primary APS had higher titers of aCL, anti-β2GPI, and IgG antiprothrombin antibodies than controls, as expected. Interestingly, we found higher titers of IgG anti-HDL in patients with SLE than in those with primary APS. This difference and the lack of correlation between IgG anti-HDL and aCL antibodies suggest that the former represent a specific antibody subset and are not the result of cross-reactivity with aCL antibodies.

Antibodies to lipoproteins have been detected both in patients with SLE (36) and in those with APS (37). Whether these antibodies are specifically directed against an antigen present in the lipoproteins or are simply cross-reactive aCL or anti-β2GPI antibodies is still unclear. Previous studies have shown that both situations may coexist (38). However, most studies to date have investigated antibodies to LDL, and few have explored HDL as a possible target (39). Dinu et al reported the presence of antibodies against Apo A-I in SLE patients and found that these antibodies were more frequent in aCL-positive patients (39), suggesting the possibility of cross-reactivity. More recently, anti–Apo A-I antibodies were reported by Abe et al, and a human anti–Apo A-I monoclonal antibody was described (40). However, there are no data regarding the impact of these antibodies on clinical and biologic markers of atherosclerosis. One of the most important of these markers is lipid peroxidation, and one of the main defense mechanisms against lipid peroxidation is PON. PON is an antioxidant enzyme found in the liver, arterial wall, and plasma, where it travels attached to HDL (41). It has an important action in preventing LDL oxidation by peroxynitrite, in turn preventing the generation of oxidized LDL in plasma (12). Apo A-I stabilizes the enzyme (41), hence, interference with Apo A-I or with the HDL molecule itself could cause a reduction in the activity of the enzyme.

PON activity has not previously been assessed in patients with SLE, but a decrease in its activity in patients with different autoimmune conditions and with aCL antibodies has been described (42). However, no correlation between clinical or biologic variables and the enzymatic activity was detected, nor was a mechanism suggested to explain this finding. Our data show that PON is reduced in patients with SLE and, to an even greater extent, in patients with primary APS. In the latter group, PON activity was inversely correlated with IgG anti-CL and IgG and IgM anti-β2GPI titers. No correlation with antiprothrombin antibodies was found. This is not unexpected since prothrombin is not associated with HDL and has no reported interaction with PON, while β2GPI and cardiolipin can be present in the HDL complex (43). That antibodies against HDL (or one of its components) may decrease PON activity is suggested by the strong inverse correlation between IgG anti-HDL and PON activity found in patients with SLE. Therefore, IgG anti-HDL may indirectly affect the oxidant/antioxidant balance in SLE via an inhibitory effect on PON.

Total antioxidant capacity quantifies the overall antioxidant defense of plasma. A higher TAC would suggest an increased resistance to oxidation. Recently, Nuttall et al demonstrated a decrease in TAC along with a pro-atherogenic lipid profile (elevated cholesterol, triglycerides, and lipid peroxides) in SLE (44). TAC levels in patients with SLE and primary APS in our cohort did not differ significantly from levels in the control group. However, in the SLE group, TAC was correlated positively with PON activity and inversely with anti-HDL, suggesting that IgG anti-HDL may decrease TAC by reducing PON activity.

Interestingly, no correlation between aCL, anti-β2GPI, anti-HDL, and TAC was found in the primary APS population. This suggests that other mechanisms might be affecting TAC in primary APS. A possible explanation could be that the decrease in PON activity found in primary APS is due to a higher prevalence of the RR polymorphism, known to be associated with decreased enzymatic activity (45), which could be less affected by the presence of these autoantibodies. In fact, Lambert et al described an increased incidence of this PON polymorphism in patients with aCL antibodies and arterial thrombosis (42).

In conclusion, our findings highlight the relevance of HDL, IgG anti-HDL, and PON in patients with SLE. Total HDL, and in particular HDL2, are decreased in SLE. This lipoprotein or some of its components may represent target (auto)antigens, since elevated IgG anti-HDL titers were noted in the patients investigated. More importantly, we have demonstrated that PON activity is markedly reduced in both SLE and primary APS and that this reduction correlates with the presence of IgG anti-HDL, IgG aCL, and IgG and IgM anti-β2GPI antibodies. However, only IgG anti-β2GPI was independently associated with decreased PON in the primary APS group. This complements the observation that β2GPI prevents the oxidation of LDL (46), and hence, antibodies against β2GPI may deprive β2GPI of its antioxidant properties. Because PON is important for the prevention of LDL oxidation, we suggest that IgG anti-HDL and IgG anti-β2GPI, via an inhibitory effect on PON activity, contribute to the oxidation of LDL and thus differential atherogenic routes in SLE and primary APS.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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