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