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Abstract

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

Objective

To demonstrate the binding of bovine lipoprotein lipase (LPL) by IgG from sera obtained from patients with systemic lupus erythematosus (SLE) and other rheumatic diseases, and the relationship of anti-LPL to triglyceride levels in SLE.

Method

Binding of LPL by IgG from sera obtained from patients with SLE and other rheumatic diseases was measured by an enzyme-linked immunosorbent assay technique. Lipid profiles for fasting blood samples obtained from SLE patients and control subjects were determined.

Results

Sera obtained from 105 patients with SLE were assessed for reactivity with LPL, and 49 (47%) of the results were positive. Sera obtained from patients with rheumatoid arthritis (RA) (n = 80), Sjögren's syndrome (n = 30), polymyositis and dermatomyositis (n = 30), and progressive systemic sclerosis (n = 31) were also studied, and 10 (13%), 3 (10%), 12 (40%), and 13 (42%), respectively, were positive for reactivity with LPL. It was determined that all affinity-purified anti–double-stranded DNA (dsDNA) antibodies and 4 of 5 monoclonal anti-dsDNA antibodies bound to LPL. The binding of IgG depleted of anti-dsDNA to LPL indicates a second anti-LPL activity in SLE. Measurements of fasting lipid levels in SLE patients with anti-LPL revealed a strong positive correlation of antibody levels and total serum triglycerides, apolipoprotein B, and apolipoprotein E concentrations.

Conclusion

Antibodies to LPL occurred in 47% of SLE patients and in a similar percentage of patients with polymyositis or systemic sclerosis. The prevalence of these antibodies was less in patients with RA or Sjögren's syndrome. It is hypothesized that the elevated triglyceride levels in SLE patients are in part attributable to anti-LPL, and this lipid abnormality could contribute to the premature atherosclerosis known to be present in patients with SLE.

The development of premature atherosclerosis has been recognized since 1976 as a clinical problem in patients with systemic lupus erythematosus (SLE) (1). Numerous subsequent studies have confirmed these initial observations, with reported frequencies of coronary artery disease (CAD) ranging from 2% to 19.8% in clinical prospective studies and from 10% to 54% in autopsy studies (2). Questions raised by these observations are many and focus on the identification of risk factors in this SLE population. As in other populations, traditional risk factors that are predictive of CAD in patients with SLE include age, male sex, elevated homocysteine levels, obesity, hypertension, diabetes mellitus, and creatinine levels (2). However, as reported by Esdaile et al, even when these traditional risk factors were taken into account in a group of SLE patients, the risk of myocardial infarction was still increased 8.3-fold because of the disease process itself (3). In addition, although chronic steroid intake has been blamed for an increased risk of CAD, Petri concluded, after careful study and use of longitudinal regression analysis, that the effects of steroids are indirect and affect the magnitude of 3 traditional risk factors: elevated cholesterol level, hypertension, and obesity (2).

In studies of SLE, a specific pattern of dyslipidemia has been noted in both pediatric and adult cases (4, 5). This pattern, which is best appreciated in patients with active disease who are untreated, consists of elevated levels of very low-density lipoproteins (VLDL) and triglycerides, and decreased levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 (Apo A1). As stated above, this pattern was noted in both untreated pediatric (4) and adult (5) cases of active SLE. In 2 case reports, extremely high triglyceride levels were associated with decreased lipoprotein lipase (LPL) activity in the plasma (6, 7). In 1 case, the patient's triglyceride level decreased from >2,100 mg/dl to 95 mg/dl with steroid treatment (6), suggesting a role for autoimmunity in patients with very high triglyceride levels. Other investigators have reported higher total cholesterol (201 mg/dl) and higher serum triglyceride levels (134 mg/dl) in SLE patients compared with those in matched controls (168 mg/dl and 74 mg/dl, respectively) (8).

These data stimulated further analysis by Borba et al, who evaluated clearance of artificial chylomicrons labeled with tritiated triglyceride (3H-TG) and cholesteryl ester (14C-CE) in 7 untreated female patients with active SLE and 7 age-matched female controls (9). The SLE group demonstrated a marked decrease of the 3H-TG fractional catabolic rate (FCR) (mean ± SD 0.024 ± 0.014 versus 0.049 ± 0.010 minute−1; P = 0.04) and of 14C-CE FCR (0.005 ± 0.008 versus 0.022 ± 0.008 minute−1; P = 0.007) compared with the control group. In addition, a striking reduction of LPL activity, measured as area under the curve of the remaining triglycerides determined after thin-layer chromatography, was observed in the SLE patients. These results suggested that both lipolytic catabolism of chylomicrons and removal of chylomicron remnants by the liver are impaired in SLE. Such inhibition of lipolysis could be one of the factors contributing to the elevated triglyceride and VLDL levels observed in untreated patients with active SLE. This inhibition would presumably implicate decreased activity of the enzyme LPL as a major factor responsible for the catabolism of chylomicrons.

These data stimulated our efforts to determine whether immunologic responses directed to LPL are present in SLE patients, and if there is any relationship of autoantibody to LPL and triglyceride levels in patients with SLE.

PATIENTS AND METHODS

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

Patient selection.

Lupus patients were identified through physician referrals throughout the US and Puerto Rico, rheumatology clinics at the University Hospital in Oklahoma City and Texas Scottish Rite Hospital for Children at Dallas, or the media. Each pedigree enrolled was required to contain at least 1 family member affected with SLE, although the emphasis of another ongoing research program headed by Dr. John B. Harley was on studying multiplex families with SLE. Thus, SLE patients from both simplex and multiplex families were available for study. All patients with SLE met at least 4 of the 1982 American College of Rheumatology (ACR) classification criteria for SLE (10). Age at the time of onset of SLE was determined using the date at which the patient first met at least 4 of the ACR criteria. All patient families were of European-American, African-American, or Hispanic ethnic origin. Ethnicity was defined as identification of 3 generations of the same ethnic background. The demographic characteristics of the SLE patients and control subjects are listed in Table 1.

Table 1. Characteristics of SLE patients and control subjects*
 SLEControl
  • *

    SLE = systemic lupus erythematosus.

Sex, %  
 Female8989
 Male1111
Age, mean ± SD years34.9 ± 14.734.6 ± 14.7
Ethnicity, %  
 White4343
 Hispanic4141
 African American1515
 American Indian11

The patients were enlisted to recruit unrelated control subjects, who were matched for age, sex, and race. The age of each control subject was supposed to be within 5 years of the age of the matched SLE patient. This pairing was successful, as indicated by the fact that the mean ± SD age of SLE patients was 34.9 ± 14.7 years, and that of the control subjects was 34.6 ± 14.7 years. Among both the SLE group and the control group, 89% of subjects were women, 11% were men, 43% were white, 41% were Hispanic, 15% were African American, and 1% were American Indian.

Determination of clinical criteria.

All available medical records for the SLE patients were reviewed. Patients usually completed an extensive questionnaire and were also interviewed. Clinical data were abstracted using a standardized case review form. To verify the presence or absence of each ACR criterion, the following scoring method was used: a score of 3 was assigned if the patient's medical record or self-report convincingly supported the criterion; a score of 2 was assigned if the medical record or self-report strongly suggested the presence of the criterion but did not establish it; a score of 1 was assigned when the evaluator doubted that the criterion was present, but some evidence could be interpreted to support it; and a score of 0 meant there was no evidence supporting the presence of the criterion. Only the criteria with a score of 3 were considered in selecting patients for this study.

Serology.

After informed consent was given, blood samples were collected from all participants. All of the serology tests were performed in our clinical immunology laboratory. Autoantibodies were assayed using standard methods. Antinuclear antibodies were detected by standard immunofluorescence staining. Anti–double-stranded DNA (anti-dsDNA) was detected by immunofluorescence on a Crithidia Lucilia substrate.

Enzyme-linked immunosorbent assay (ELISA) for antibody to LPL.

The ELISA for antibody to LPL used pure bovine LPL purchased from Sigma (St. Louis, MO). Maximal activity was achieved with coating concentrations of 5–10 μg/ml LPL on Immulon plates (Dynex Technologies, Chantilly, VA). IgG binding was assessed by incubation of reactive plates with alkaline phosphatase–conjugated goat anti-human IgG (Sigma) followed by the addition of p-nitrophenyl phosphate and the reading of optical density (OD) at 405 nm with a Dynatech scanner (Guernsey, Channel Islands, UK). All assays were performed with sera diluted 1:100.

Determination of isotype-specific anti-LPL.

IgM and IgA anti-LPL were determined by using goat anti-μ chain–specific and goat anti-α chain–specific conjugates, respectively. Other details of the assay are the same as those for the determination of IgG anti-LPL.

Characterization of bovine LPL by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE).

The LPL preparation was characterized by 15% SDS-PAGE, as described previously (11). A complementary DNA encoding the human LPL sequence of 448 amino acids has previously been isolated (12); the calculated molecular weight for the mature protein is 50,394, and with 3 glycosylation sites, a total molecular weight of 60,000 is expected. A 15% SDS gel revealed 2 bands of 60 kd and 55 kd, respectively. Both were positive by immunoblot with lupus sera that bound the LPL preparation strongly in ELISA. A reasonable hypothesis is that the 55-kd protein is a degradation product of the 60-kd LPL molecule.

Detection of LPL activity in immune complexes in SLE sera.

A volume of 10 μl human serum was mixed with 1.0 cc of a rabbit anti-human IgG serum that had been shown to quantitatively precipitate the IgG in the 10-μl aliquot. The precipitate was allowed to form at 4°C overnight, and then the precipitate was centrifuged at 3,000 revolutions per minute for 10 minutes at 4°C. The precipitate was washed 3 times with 1.0 cc of cold 0.15M NaCl in 0.02M PO4, pH 7.2 buffer, with intervening centrifugations. SLE sera were compared with normal sera that had negligible LPL binding in the ELISA. Thus, an SLE serum and a normal serum were treated in a parallel manner, resulting in a pair of precipitates, one (the SLE serum) presumably containing LPL bound to IgG, the other with negligible amounts of LPL bound to IgG. The resuspended precipitates were then incubated with substrate (p-nitrophenyl butyrate) for 10 minutes, and the precipitate was centrifuged and the supernatant OD read at 400 nm to assess enzyme activity.

Inhibition ELISA.

Experiments were designed to assess the ability of dsDNA to inhibit the reactivity of polyclonal IgG anti-dsDNA antibodies in whole sera as well as with monoclonal anti-dsDNA antibodies. In such experiments, the antisera or isolated IgG preparations were preincubated with dsDNA, with final concentrations of 10 μg/ml or 100 μg/ml, for 1 hour at room temperature. Such antibody–dsDNA solutions were then transferred to LPL-coated plates for binding assessment. The DNA used in these experiments was calf thymus DNA (Sigma).

Lipid determination.

Lipids were fractionated from serum to yield HDL and a mixture of VLDL and LDL. The following approach was used: 0.25 ml of 0.9% NaCl was added to 0.25 cc of serum in an Eppendorf tube (Madison, WI) at 4°C. Heparin (10 μl, 5,000 USP units/ml) and 15 μl of 1.0M MnCl2 were added to the diluted serum. This was allowed to stand at 4°C overnight and was then vortexed. The solution was centrifuged at 10,000 rpm in a Sorvall SA 600 rotor (Wilmington, DE) for 30 minutes. The supernatants (HDL) were transferred to clear Eppendorf centrifuge tubes. The precipitates (VLDL–LDL) were dissolved by the addition of 0.25 ml of phosphate buffered saline (0.02M phosphate, 0.15M NaCl, pH 7.2). Supernatants and redissolved precipitates were analyzed for cholesterol, triglycerides, and apolipoproteins, as were whole sera before fractionation.

Method for cholesterol.

The cholesterol reagent used was purchased from Roche Laboratories (Mannheim, Germany). According to this method, cholesterol esters are hydrolyzed to free cholesterol by the enzyme cholesterol esterase. The cholesterol produced is oxidized by cholesterol oxidase in a reaction that results in the formation of hydrogen peroxide. Hydrogen peroxide reacts with 4-amino antipyrine and phenol in the presence of peroxidase to yield a quinone imine dye that absorbs light at 500 nm. Cholesterol standards are provided by the manufacturer (Roche Laboratories). Those reactions were applied to whole serum, the supernatant (HDL) fraction, and the redissolved precipitate (LDL–VLDL).

Method for triglycerides.

A kit manufactured by Bayer (Tarrytown, NY) was used. The principle of this method is the conversion of triglycerides to free glycerol by LPL. Virtually all of the serum glycerol is present as triglycerides, but the small amount of free glycerol can be determined by measuring glycerol using the technique described below, without prior treatment with LPL. Thus, it is a 2-part assay.

Once the free glycerol and free fatty acids are generated by LPL, the glycerol is converted to glycerol-3-phosphate by glycerol kinase in the presence of ATP. The glycerol-3-phosphate is reacted with glycerol-3-phosphate oxidase in the presence of oxygen to form hydrogen peroxide. This in turn forms a colored complex with 4-amino antipyrine and chlorophenol in the presence of peroxidase. The terminal color reactions for this reaction are very similar to those used in the cholesterol assay described above. The triglyceride level is calculated by subtracting the values determined without lipase treatment from the value determined after lipase treatment. The manufacturer (Bayer) provides standards for triglycerides.

Immunoturbidimetric assays for apolipoproteins.

The basic principle of this assay is measurement of turbidity after mixing known volumes of diluted serum with monospecific goat or sheep anti-apolipoproteins, which are available as kits from various manufacturers (e.g., Bayer). Standard samples of known concentration are also available from the manufacturer (Bayer). The method used was that described by Brustolin et al (13). This method was used for the determination of Apo A1, Apo B, and Apo E levels in all the serum samples obtained from our cohort of SLE patients and controls.

RESULTS

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

Sera obtained from groups of patients with SLE, rheumatoid arthritis (RA), polymyositis and dermatomyositis, Sjögren's syndrome, and from normal, unrelated control subjects were assessed for their ability to bind LPL-coated plates. The results are listed in Table 2. As shown, antibodies to LPL are not disease-specific, occurring as frequently in patients with polymyositis and progressive systemic sclerosis as in those with SLE. Although there appear to be many positive results in the normal population, details of the assay must be explored to elucidate this finding. For each 20 disease sera assayed, a panel of 4 normal human sera were run on each plate. Positive results were defined as those with a value exceeding the mean ± 2 SD of the OD units from the panel of 4. The group of unrelated control subjects (n = 75) were matched with patients for age, race, and sex. To illustrate the quantitative differences in anti-LPL activity between the disease groups and controls, the percentages of sera with anti-LPL values >0.6 OD units are listed in Table 3.

Table 2. Prevalence of anti-LPL in disease sera*
 No. testedNo. (%) positive
  • *

    Anti-LPL = anti–lipoprotein lipase.

Systemic lupus erythematosus10549 (46.7)
Polymyositis3012 (40.0)
Progressive systemic sclerosis3113 (41.9)
Rheumatoid arthritis8010 (12.5)
Sjögren's syndrome303 (10.0)
Control7521 (28.0)
Table 3. No. (%) of sera with anti-LPL >0.60 OD units*
Disease groupAnti-LPL >0.6 OD units
  • *

    Anti-LPL = anti–lipoprotein lipase; OD = optical density.

Systemic lupus erythematosus (n = 105)20 (19.1)
Polymyositis (n = 31)5 (16.1)
Progressive systemic sclerosis (n = 30)5 (16.7)
Rheumatoid arthritis (n = 80)6 (7.5)
Sjögren's syndrome (n = 30)2 (6.6)
Normal (n = 75)1 (1.3)

As shown, the number of sera with anti-LPL levels >0.6 OD units is very low in the normal population and clearly distinguishes patients with SLE, polymyositis, and progressive systemic sclerosis from controls. Although the levels in patients with RA and Sjögren's syndrome are higher than those in controls, the difference is not statistically significant.

We used 2 approaches to address the issue of whether any part of the antibody activity with LPL resides in the anti-dsDNA antibodies, which are so characteristic of SLE—particularly active disease. First, we tested the ability of dsDNA to inhibit the reactivity of sera positive for anti-LPL activity. Table 4 lists 10 SLE sera reactive with LPL and the inhibition of a 1:100 dilution of serum by dsDNA (100 μg/ml and 10 μg/ml) in their reactivity with LPL-coated plates. From 35% to 70% of the LPL activity was inhibited by dsDNA at a final concentration of 100 μg/ml. This suggests that part of the anti-LPL binding activity resides in the anti-dsDNA population. Conversely, for sera that were anti-Sm–positive, anti-Ro–positive, or anti–U1 RNP–positive, attempts to inhibit reactivity with LPL by affinity-purified Sm, Ro, and U1 RNP, respectively, were unsuccessful, indicating no relationship of these antibody specificities to inhibition of LPL activity. However, normal sera with elevated values for anti-LPL were inhibited in their binding by dsDNA in a manner quite similar to that of SLE sera with anti-LPL activity.

Table 4. Inhibition of SLE sera reactivity with LPL by dsDNA*
Patient% inhibition by dsDNA
100 μg/ml10 μg/ml
  • *

    SLE = systemic lupus erythematosus; LPL = lipoprotein lipase; dsDNA = double-stranded DNA.

  • Mean ± SD 50.8 ± 10.4%.

  • Mean ± SD 33.8 ± 14.8%.

14947
25847
35233
43517
55328
6388
74525
86051
97050
104832

Experiments were then designed to test directly the possibility that at least part of the anti-LPL activity of SLE sera is attributable to cross-reactivity with anti-dsDNA antibodies. Affinity-purified anti-dsDNA antibodies were prepared from sera obtained from 5 SLE patients, and all 5 at concentrations of 25 μg/ml reacted with LPL-coated plates, yielding OD values of 0.3–0.7 in the standard assay at 1-hour incubation with the substrate. Moreover, the reactivity was blocked 75–95% by 100 μg/ml of dsDNA. Even more impressive were the reactivities of human monoclonal anti-dsDNA antibodies with LPL-coated plates, as shown in Table 5.

Table 5. Reactivity of monoclonal anti-dsDNA with LPL*
Human monoclonal antibodyConcentrationOD value at 1 hour% blocked by 100 μg/ml dsDNA
  • *

    Anti-dsDNA = anti–double-stranded DNA; LPL = lipoprotein lipase; OD = optical density.

B31 μg/ml0.70383
D53 μg/ml0.24180
RH1415 μg/ml0.1010
33C93 μg/ml0.88978
32B93 μg/ml0.80976

Four of the 5 human monoclonal anti-dsDNA antibodies at concentrations of 1–3 μg/ml reacted strongly with LPL-coated plates, and these reactions were efficiently blocked by dsDNA. Monoclonal anti-dsDNA RH14, even at a concentration of 15 μg/ml, reacted weakly and was not blocked by dsDNA.

Clearly, at least part of the antibody activity directed to LPL resides in the anti-dsDNA antibody population. This reactivity of anti-dsDNA antibodies is not attributable to contamination of the LPL preparation with dsDNA, because treatment of LPL with DNase has no effect on the reactivity of anti-dsDNA antibodies with LPL. Comparable treatment of dsDNA solutions by DNase ablated its ability to coat plates for an anti-dsDNA reaction. The ability of dsDNA to block, on average, only 50.8% of the anti-LPL activity of SLE sera suggests that there is an antibody to LPL that is independent of anti-dsDNA antibodies and is of comparable importance. Direct evidence for the existence of IgG with anti-LPL activity other than anti-dsDNA was obtained by passing SLE IgG from anti-dsDNA–positive sera over a DNA cellulose column. In 4 of 4 instances, effluent IgG from DNA cellulose columns devoid of anti-dsDNA activity bound LPL-coated plates. Such data suggest the existence of at least 2 types of anti-LPL in SLE sera, one being anti-dsDNA and the other IgG without dsDNA-binding activity. Not surprisingly, anti-LPL and anti-dsDNA titers frequently cofluctuated, reflecting the cross-reactivity of anti-dsDNA antibodies with LPL.

Finally, 26 SLE sera had elevated levels of anti-LPL but normal levels of anti-dsDNA; conversely, 9 SLE sera were reactive with dsDNA by ELISA and negative for anti-LPL. Thus, several lines of evidence indicate that there are 2 types of anti-LPL, one of which is specific for LPL and nonreactive with dsDNA, and a second type that reacts with both LPL and dsDNA.

Ig isotypes of anti-LPL activity.

All the data presented thus far represent IgG anti-LPL activity. To assess anti-LPL activity in the IgM and IgA classes, isotype-specific activity was assessed with appropriate conjugates. A sample of 89 SLE sera that had previously been studied with an anti-IgG reagent were also studied with anti-IgM and anti-IgA reagents. Using the anti-IgG reagent, 44 (49.4%) of 89 sera were positive. When the anti-IgM and anti-IgA reagents were used, 29.2% and 18.0% of sera, respectively, were positive. Of the total sera, 54 (60.7%) were positive for antibody of 1 or more isotypes.

Presence of LPL in immune complexes.

The technique for measuring immune complexes containing LPL was described in Patients and Methods. Using 5 SLE sera with high anti-LPL activity in ELISA and 5 normal sera with negligible anti-LPL activity in ELISA, precipitates from SLE sera had 0.023–0.170 OD differences at 400 nm compared with precipitates from normal sera run in parallel manner. These data suggest that SLE sera have LPL bound to IgG in immune complexes.

Relationship of lipid levels and anti-LPL.

The existence of an immune response to LPL raises the question of whether there is an association of such antibodies and an effect on lipid levels. This was investigated by studying fasting lipid levels and the level of anti-LPL as measured by the OD of a 1:100 dilution of serum on LPL-coated plates in 85 SLE patients. The data are shown in Table 6 and illustrate the correlation of the lipid levels with the OD achieved in the anti-LPL assay.

Table 6. Relationship of anti-LPL activity and serum lipids in SLE*
LipidPearson's correlation coefficientP
  • *

    Anti-LPL = Anti–lipoprotein lipase; SLE = systemic lupus erythematosus; LDL = low-density lipoprotein; HDL = high-density lipoprotein; Apo = apolipoprotein.

Total cholesterol0.052770.6315
Triglycerides0.46860.0001
LDL cholesterol0.132530.2412
HDL cholesterol−0.206400.0581
HDL triglycerides0.190460.0808
LDL triglycerides0.494780.0001
Apo A1−0.178750.2969
Apo B0.440480.0072
Apo E0.460230.0047

As seen, highly significant relationships exist between anti-LPL levels and total triglycerides, triglyceride LDL, Apo B, and Apo E levels. Notably, no relationships are seen between anti-LPL levels and total cholesterol, triglyceride HDL, or Apo A1 levels. A further refinement of these data can be achieved by partitioning the SLE patients into 2 groups: those with elevated levels of anti-LPL (>0.17 OD units), and those with normal levels of anti-LPL (<0.17 OD units). These data are shown in Table 7 and, as can be seen, the correlation coefficients for triglycerides, LDL triglycerides, Apo B, and Apo E in the anti-LPL–positive group are higher than those in the total group of SLE patients. There are no statistically significant positive correlations between lipid levels and anti-LPL in the SLE patients with OD values <0.17 units. Interestingly, in the anti-LPL–positive group, there is a positive correlation coefficient of 0.46501 and a P value of 0.0192 between total cholesterol and LPL activity that was not apparent in the total SLE patient group, as shown in Table 6. There is no immediately obvious explanation that would relate decreased LPL activity with elevations of serum cholesterol, but the finding poses an important challenge for understanding these relationships.

Table 7. Lipid levels in SLE patients with anti-LPL values <0.17 and >0.17 OD units*
LipidAnti-LPL <0.17 OD units (n = 47)Anti-LPL >0.17 OD units (n = 25)
Pearson's correlation coefficientPPearson's correlation coefficientP
  • *

    OD = optical density (see Table 6 for other definitions).

Total cholesterol−0.166660.26290.465010.0192
Triglycerides−0.208880.15880.842960.0001
LDL cholesterol−0.072770.63880.092080.6687
HDL cholesterol0.035940.8105−0.088510.6740
HDL triglycerides−0.159960.28280.231070.2664
LDL triglycerides−0.216680.14350.851170.0001
Apo A10.019020.9348−0.075910.8146
Apo B−0.495590.02230.815130.001
Apo E−0.129800.57500.876160.0002

The data in Table 7 further strengthen the possible mechanistic role of antibody to LPL in the hyperlipidemia seen in SLE patients.

DISCUSSION

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

These observations raise the possibility that antibodies to LPL could be a factor leading to elevated levels of triglycerides, Apo B, and Apo E. Studies on the ability of IgG with anti-LPL activity to inhibit LPL enzyme activity are underway but are thus far unrevealing. Conversely, early preliminary measurements of serum LPL activity show an inverse relationship to anti-LPL activity, suggesting either an inhibitory effect of antibody on LPL activity or the facilitation by antibody of enhanced turnover of the enzyme, either or both of which could be responsible for lower serum LPL activity. Only detailed studies that are underway can reveal the mechanisms of these observed relationships.

One must address the issue of the role of hyperlipidemia in the development and/or progression of CAD. Although all investigators agree that elevated cholesterol levels increase the risk of CAD, the data have not been as clear for elevated triglycerides and the risk of CAD. In 1991, a review of the literature revealed that triglyceride levels were frequently associated with CAD in univariate analysis (14). However, the same studies showed that the relationship between triglycerides and CAD less frequently survived multivariate analysis. Subsequent studies found more compelling data, even after multivariate analysis, relating elevated triglyceride levels and the risk of CAD (15, 16). Moreover, it has been reported that the elevated triglyceride level characteristic of familial LPL deficiency is associated with premature atherosclerosis (17). It has also been reported that mutations in the LPL gene that are not associated with complete LPL deficiency nonetheless increase the risk of ischemic heart disease (18) and progression of CAD (19). Finally, it has been reported that LPL activity is inversely related to the severity of angina pectoris in patients with CAD (20).

It is becoming clear that elevated triglyceride levels can contribute to the risk and/or progression of CAD, and that decreases of LPL activity can play a significant role in such triglyceride elevations. In any case, the presence of a positive correlation between triglyceride levels and anti-LPL activity supports a continuing analysis of this correlation and its relationship to premature myocardial infarction and stroke in patients with SLE.

Acknowledgements

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

The monoclonal anti-dsDNA antibodies B3, D5, and RH14 were generously provided by Dr. David Isenberg of University College, London. The monoclonal anti-dsDNA antibodies 33C9 and 32B9 were generously provided by Drs. Thomas Winkler and Joachim Kalden of Erlangen University, Germany.

REFERENCES

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