Elsevier

Atherosclerosis

Volume 188, Issue 1, September 2006, Pages 160-166
Atherosclerosis

Antibodies of IgM subclass to phosphorylcholine and oxidized LDL are protective factors for atherosclerosis in patients with hypertension

https://doi.org/10.1016/j.atherosclerosis.2005.10.017Get rights and content

Abstract

Objective

To determine the importance of antibodies against phosphorylcholine (PC) and oxidized low density lipoprotein (OxLDL) for development of atherosclerosis.

Methods and results

Two hundred and twenty six individuals with established hypertension (diastolic pressure >95 mmHg) were from European Lacidipine Study on Atherosclerosis. Antibodies of IgG and IgM subclass were tested by ELISA against PC (aPC), cupper-oxidized (ox)- or malondialdehyde (MDA)-modified LDL. High-sensitivity C-reactive protein was measured by nephelometry.

As a surrogate measure of atherosclerosis, we used the mean of the maximum intima-media thicknesses (IMT) in the far walls of common carotids and bifurcations was determined by ultrasonography at the time of enrolment, and 4 years following enrolment.

aPC could be competed out by PC and OxLDL, while cardiolipin (CL) and β2-glycoprotein I (β2GPI) were less effective and phosphatidylserine (PS) not at all. Increases in IMT at follow-up were less common in subjects which at the time of enrolment had high IgM aPC (both 75th and 90th; odds ratios: 0.46; CI: 0.25–0.85; 0.36; CI: 0.15–0.87) and high IgM aOxLDL and aMDA-LDL (90th; odds ratios 0.27; p = 0.01; CI: 0.11–0.69 and 0.27; p = 0.01; CI: 0.11–0.69). CRP was unrelated to IMT-changes. The relationship between IgM aPC, aOxLDL and aMDA-LDL and changes in IMT was independent of age, treatment with atenolol or lacidipine, smoking and lipids. Women had higher levels of IgM antibodies tested (p < 0.05).

Conclusions

High levels of IgM-antibodies against PC and OxLDL predict a favourable outcome in the development of carotid atherosclerosis in hypertensive subjects. Whether these antibodies could be used therapeutically deserves further study.

Introduction

Atherosclerosis can be described as an inflammatory disease characterized by activation of immune competent cells and production of inflammatory cytokines in the atherosclerotic lesions in the artery wall [1]. Established risk factors like hypertension, blood lipids, diabetes and smoking are likely to promote this inflammatory reaction, but the mechanism by which this occurs is not well characterized and different non-mutually exclusive possibilities exist. Several different autoantigens that could elicit this immune reactivity have been proposed, including oxidized low density lipoprotein (OxLDL) and heat shock proteins (HSP) [2], [3]. Available data on the role of immune reactions in atherosclerosis indicate a complex relationship. One example of this is immunization in animal models to influence atherogenesis. When HSP 60/65 is used as an antigen, atherosclerosis increases but decreases when animals are immunized with OxLDL [4], [5].

The role of aOxLDL in human disease appears to be complex. In humans, we previously demonstrated that aOxLDL were higher in healthy controls than in men with borderline hypertension, an example of early cardiovascular disease [6]. Recent studies are also in line with this observation, suggesting a protective function in humans [7], [8]. Other observations indicate, however, that aOxLDL are raised in human cardiovascular disease (CVD), especially at later stages [2], [3], [9], [10]. One example is systemic lupus erythematosus (SLE) an autoimmune disease associated with a very high risk of CVD. We recently demonstrated that SLE-patients with a history of CVD have clearly raised aOxLDL—levels as compared with SLE-patients without CVD [11]. It is thus possible that aOxLDL plays different roles during different disease stages. Methodological differences may also be of importance and OxLDL is a complicated compound, difficult to standardize.

OxLDL itself has many proinflammatory properties including activation of T cells [12], [13], monocytes/macrophages and endothelial cells [14], [15], [16]. OxLDL promotes inflammation also in immune competent cells from atherosclerotic lesions [17]. However, it should be noted that OxLDL may also ameliorate acute inflammatory reactions and instead promote a more low-grade chronic inflammation as that seen in atherosclerosis [18]. Many biological effects of OxLDL are caused by platelet activating factor (PAF)-like lipids and/or lysophosphatidylcholine (LPC) in OxLDL [19], [20], [21]. It is interesting to note that phosphorylcholine (PC) is a major component not only in PAF and PAF-like lipids (where it is essential for interaction with the PAF-receptor) but also in OxLDL. PC is also an immunogenic component of many bacteria including Streptococcus pneumoniae [22]. Furthermore, PC is expressed by apoptotic cells [2], [23]. Indeed, some antibodies against OxLDL in mice are genetically identical with TI5 antibodies, which protect against lethal pneumococcal infection [23] and recently immunization with pneumococcal vaccine that induced IgM aPC antibodies was demonstrated to protect against atherosclerosis development [24].

The European Lacidipine Study on Atherosclerosis (ELSA) is a 4-year prospective hypertension treatment study where the development of carotid artery wall alterations are studied [25], [26]. We here report that IgM aPC and aOxLDL predict a favourable outcome in atherosclerosis as detected by carotid IMT measurements in hypertensive subjects, from the ELSA study. The implications of these findings are discussed.

Section snippets

Subjects

Serum samples were obtained from 226 subjects with established hypertension (diastolic pressure >95 mmHg) prior to their entry into the Swedish component of the European Lacidipine Study on Atherosclerosis (ELSA) [25], [26]. Samples were collected following a 4-week washout period with no medication to minimize the effects of treatment on the measured parameters. Blood pressure, cholesterol and triglyceride levels were determined as described previously [25], [26]. One hundred and fifteen of the

Results

Basic characteristics of the subjects at the time of enrolment into the study have been detailed elsewhere [27] and are presented in Table 1.

Competition studies reveal that aPC of IgM and IgG subclass was competed out by preincubation with PC-BSA, while cardiolipin had a weak and phosphatidylserine no competitive capacity (Fig. 1a and b). β2-glycoprotein I competed to some extent with IgG binding to PC-BSA but not so much with IgM (Fig. 1a and b). PC-BSA had a low capacity to compete out

Discussion

The main finding in this report is that high levels of IgM autoantibodies to PC, OxLDL and MDA-LDL predict a decreased rate of progression of carotid IMT in patients with hypertension. IgG autoantibodies against these antigens were also higher in patients with less progression of IMT, but this difference did not reach statistical significance.

The existence of antibodies against PC in humans has been known for decades [22] and have been linked to pneumonia [28] and also, interestingly, IgG aPC

Acknowledgements

We acknowledge the study coordinator of the European Lacidipine Study on Atherosclerosis (ELSA) for permission to use the Swedish patients from Lund and Stockholm for these analyses.

Sponsorship: This study has been supported by the Swedish Heart Lung Foundation, the King Gustav V 80th Birthday Fund, the Swedish Society of Medicine, The Torsten and Ragnar Söderberg Foundation and The Swedish Science Fund.

References (38)

  • Q. Xu et al.

    Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65

    Arterioscler Thromb

    (1992)
  • R. Wu et al.

    Autoantibodies to OxLDL are decreased in individuals with borderline hypertension

    Hypertension

    (1999)
  • J. Hulthe et al.

    Antibodies to oxidized LDL in relation to carotid atherosclerosis, cell adhesion molecules, and phospholipase A(2)

    Arterioscler Thromb Vasc Biol

    (2001)
  • J. Karvonen et al.

    Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis

    Circulation

    (2003)
  • C. Bergmark et al.

    Patients with early-onset peripheral vascular disease have increased levels of autoantibodies against oxidized LDL

    Arterioscler Thromb Vasc Biol

    (1995)
  • E. Svenungsson et al.

    Risk factors for cardiovascular disease in systemic lupus erythematosus

    Circulation

    (2001)
  • J. Frostegård et al.

    Induction of T-cell activation by oxidized low density lipoprotein

    Arterioscler Thromb

    (1992)
  • S. Stemme et al.

    T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein

    Proc Natl Acad Sci USA

    (1995)
  • J.A. Berliner et al.

    Minimally modified low density lipoprotein stimulates monocyte endothelial interactions

    J Clin Invest

    (1990)
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