doi: 10.1161/01.CIR.0000143225.07377.EA
(Circulation. 2004;110:2552-2558.)
© 2004 American Heart Association, Inc.
Editorial |
Are Anti–Oxidized Low-Density Lipoprotein Antibodies Pathogenic or Protective?
From the Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Israel (Y.S.); RDL Reference Laboratory, Los Angeles, Calif (R.W.); Specialty Laboratories, Santa Monica, Calif (L.D.D.); and Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (E.M.).
Correspondence to Y. Shoenfeld, MD, FRCP, Head, Department of Medicine B, Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail shoenfel{at}post.tau.ac.il
Key Words: Editorials • lipoproteins • atherosclerosis • cardiovascular diseases • antibodies
Despite a recent decline, atherosclerosis remains the most common cause of death in the Western world. The disease course of atherosclerosis is characterized by its chronicity, with progression in its initial stages being particularly insidious. Chronic inflammation is the pathological hallmark of atherosclerosis,1–4 and inflammatory processes are instrumental at all stages of this disease. Even before the development of detectable intimal lesions, the expression pattern of the endothelium has been shown to be inflammatory in nature, conforming to the response-to-injury hypothesis first postulated by the late Russell Ross.5 Thus, in lesion-prone sites of the arterial tree, the endothelial expression of adhesion molecules is upregulated, reflecting endothelial dysfunction secondary to unfavorable blood rheology6 and/or hypercholesterolemia.7–9
Atherosclerosis is known today to be associated with the burden of infection as well.10 The presence of infectious/inflammatory pathogeneses raises the autoimmune aspect of the condition.11–14
Anti–oxidized LDL (oxLDL) antibodies are exceptional among the autoantibodies prevalent in atherosclerosis: on the one hand, a correlation was found between the existence and titers of anti-oxLDL antibodies and the extent of atherosclerosis and cardiovascular disease (CVD) (Table 1). On the other hand, experimental data indicate that anti-oxLDL antibodies may be protective.
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OxLDL: A Notorious Molecule That May Play a Role as an Autoantigen
oxLDL frequently presents in the sera of patients with autoimmune conditions, acute coronary syndrome, or stable coronary artery disease (CAD).15–18 OxLDL has been associated with both subclinical atherosclerosis and inflammatory variables.19 A large amount of oxLDL accumulates in atherosclerotic plaques,20–22 and the serum concentrations of circulating oxLDL may correlate with the severity of CAD23 and acute coronary syndrome.24 OxLDL seems to be an immunogenic molecule that stimulates the induction of anti-oxLDL antibodies. Thus, it is not surprising that an association was found between the presence of anti-oxLDL antibodies and atherosclerosis and CVD.25–31
OxLDL as an Agent in the Development of Atherosclerosis and CVD
LDL can be oxidatively modified in vivo to be an immunogen associated with the progression of atherosclerosis and CVD.32,33 In a study using a mouse model of experimental antiphospholipid syndrome (APS), mice immunized with oxLDL exhibited a significantly more severe form of the disease compared with native LDL-immunized mice, as expressed by lower platelet counts, longer activated partial thromboplastin time, and higher fetal resorption rates.34 The interaction of IgG anti-ß2GP-I antibody from the spontaneous mouse model of APS, ie, NZW x BXSB F1 mouse, with the ß2GP-I–oxLDL complexes significantly enhanced oxLDL uptake by macrophages.35,36 The results34 indicate that oxLDL aggravates the clinical manifestations of APS and suggest that autoantibodies cross-reactive with oxLDL may provide a pathogenic mechanism for accelerated atherosclerosis in APS.
The accumulation of oxLDL in the vessel wall stimulates the overlying endothelial cells to produce a number of proinflammatory molecules, including adhesion molecules such as the intercellular adhesion molecule-1, the vascular cell adhesion molecule-1, and endothelial selectin (E-selectin), as well as growth factors such as macrophage colony-stimulating factor. These active molecules seem to contribute to the recruitment of leukocytes to the affected area.20 A vast number of T cells, primarily CD4+ CD45RO+ memory cells (a large proportion of which express HLA-DR and very late activation antigen-1), have been found within the atherosclerotic lesions.37 The presence of those cells in the atherosclerotic plaques is because of a direct response to the oxLDL accumulation in the arterial wall.38 The high concentrations of oxLDL in the vessel wall are recognized and phagocytosed by macrophages, thereby contributing to a cascade of events characterized as immunoinflammatory reactions of atherosclerosis.39
Dual Effects of Anti-oxLDL Antibodies
OxLDL stimulates the production of autoantibodies by B cells.11,40 Anti-oxLDL antibodies are present in healthy individuals (Table 2) as well as in patients with atherosclerosis and CVD.25,27,41 Because antibodies may protect or neutralize pathogens and immunogens,42–44 humoral immunity to oxLDL can reduce the incidence of atherosclerosis. The protective role of T cell–dependent antibody was demonstrated in rabbits and mice immunized with oxLDL. The reduced atherosclerosis correlated with the levels of immunoglobulin G (IgG) anti-oxLDL antibodies.11,42–45 Transfer of B cells from atherosclerotic apolipoprotein E (apoE)–knockout mice to young, disease-prone apoE-knockout mice appeared to protect the latter from developing advanced disease. Protection to a lesser extent was observed when B cells from young apoE-deficient mice were transferred, implying a role for development of adaptive immunity in the protective response. Interleukin-10 may play a crucial role in anti-oxLDL pathogenicity. Interleukin-10–deficient mice had significantly more advanced disease.46 Therapy with intravenous immunoglobulin (IVIG) induced interleukin-10 upregulation and protection from atherosclerosis.47
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A monoclonal IgM anti-oxLDL antibody (EO6) derived from apoE-deficient mice, which binds intact oxLDL, blocked the macrophage scavenger receptors CD36 and SR-B1 for oxLDL binding; thus, the innate immune response may have a protective role via macrophages.33
The above-mentioned experiments clearly demonstrate that anti-oxLDL antibodies potentially bear an immunoprotective function against the development of atherosclerosis and CVD.
Protective Role of Anti-oxLDL Antibodies in Humans
Human anti-oxLDL antibodies play an important role in the regulation of oxLDL levels. These antibodies have been found in children,48 healthy adults, and patients with coronary heart disease.27 Circulating antibodies recognizing oxLDL are present in cardiovascular risk–free children. The levels of the antibody in children are significantly higher than in adults,48 suggesting that the antibodies may not necessarily be related to atherosclerosis and CVD. It is probable that the high levels of antibodies in children modulate the antigen and thus protect against the development of atherosclerosis and CVD. A study investigating anti-oxLDL antibodies in patients with early CVD found that anti-oxLDL antibodies were decreased in patients with borderline hypertension.49 The results of a survey on complications of diabetic CAD support this fact.50
In another study51 that explored the relationship between oxLDL and its antibody, the plasma oxLDL concentrations in 130 healthy subjects were inversely correlated with the levels of anti-oxLDL antibodies. Yet another study in a healthy population with no clinical signs of atherosclerosis52 showed that anti-oxLDL antibody levels were inversely related to the intima-media thickness of the carotid arteries. As mentioned previously, the binding activity of anti-oxLDL IgG is significantly higher in children than in adults.48 These studies seem to support the idea that anti-oxLDL antibodies have a protective function against the development of atherosclerosis and CVD in healthy individuals. Table 3 lists85–94 several studies that found negative associations between anti-oxLDL antibodies and CVD and other conditions.
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The role of anti-oxLDL antibodies in hypertension was also analyzed. The levels of anti-oxLDL antibodies were significantly lower in borderline stages, whereas the concentrations of oxLDL were not. The concentrations of oxLDL were higher in subjects with hypertension than in those who were normotensive. There was no difference in the levels of anti-oxLDL antibodies between hypertensive subjects and controls.17,49
Pathogenic Role of Anti-oxLDL Antibodies in Humans
Atherosclerotic lesions contain immunoglobulins53 that specifically recognize oxLDL. Elevated anti-oxLDL antibody concentrations may be a predictor for the development of atherosclerosis and CVD.25,28,29 These antibodies are the most effective parameters for predicting the extent of coronary atherosclerosis.54 Their presence is also associated with a higher risk for coronary restenosis after percutaneous transluminal coronary angioplasty.55 Higher levels of the antibodies in patients with peripheral occlusive arterial disease portend more extensive atherosclerotic lesions.56 Elevated levels of anti-oxLDL antibody are related to hypertension, systemic vasculitis, peripheral arterial disease, endothelial dysfunction, atherosclerosis, and CVD.25,28,29,56–66 Table 1 lists several studies that found associations between anti-oxLDL antibodies and CVD-related conditions.
Conversely, antibodies can also induce other immune effects, such as immune opsonin-associated antigen binding to phagocytes, complement activation, and presentation of antigens to T lymphocytes, to trigger an adaptive immune response. Anti-oxLDL antibodies involved in these immune functions can induce an immune injury.21,41,53,67
Human anti-oxLDL antibodies41,68 can possess different classes and subclasses, including IgA, IgG1, IgG2, IgG3, and IgM, as well as specific idiotypes.69 The multiple classes and subclasses of anti-oxLDL antibodies may result in heterogeneous effects: namely, oxLDL contains phospholipids; IgG2 is the dominant subclass to respond to epitopes containing phospholipids; and the IgG3 subclass fixes complement better and binds Fc receptors more avidly and thus has more pathogenic properties than the IgG2 subclass.70,71 However, these differences in anti-oxLDL antibody characteristics and their correlation with clinical manifestations have not yet been analyzed.
Anti-oxLDL antibodies are extensively prevalent in diseases other than CVD. Elevated levels of anti-oxLDL antibodies were found in patients with autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and APS,16,26,30,72–84 as well as in other conditions such as diabetes mellitus,71 uremia,77 chronic periaortitis, hepatocellular carcinoma, ß-thalassemia, psoriasis, and preeclampsia and eclampsia (Table 2).
Immune Regulation of Anti-oxLDL Antibodies and the Innate Immune Response
The anti-oxLDL antibodies in healthy normotensive individuals seem to be native antibodies51 that neutralize and catabolize oxLDL.52
Native antibodies and anti-idiotypic antibodies with IVIG could affect atherosclerosis and CVD progression. The administration of IVIG to apoE-deficient mice modulated both the development of fatty streaks and the progression to fibrofatty atherosclerotic plaques and resulted in reduced atherosclerosis.95 The IVIG treatment was associated with T-cell anergy and reduction of IgM anti-oxLDL antibody titers.95 Human IVIG from different manufacturers contains both protective anti-oxLDL antibodies and anti-idiotypic antibodies to anti-oxLDL antibody.69
To investigate the presence of anti-idiotypes against anti-oxLDL antibodies within IVIG, F(ab')2 fragments of IVIG IgG were used to absorb IgG F(ab')2 fragments from the pool of sera with high anti-oxLDL levels. The decreased binding to oxLDL of the absorbed supernatants shows that IgG F(ab')2 fragments of the IVIG preparations had high inhibitory capacities, ranging from 65% to 90%. Therefore, we could conclude that IVIG preparations contain both anti-oxLDL and anti–anti-oxLDL activity.69 These results go along other studies pointing to the fact that IVIG exerts its beneficial effect mainly via its anti-idiotypic characteristics.86,96
The natural anti-oxLDL antibodies might exert an effect by modulating oxLDL, whereas the anti-idiotypes may play a role in neutralizing the excess pathogenic anti-oxLDL antibodies through the idiotypic network, ie, an immunomodulatory role.97
A recent study demonstrated that phosphorylcholine, a component of Streptococcus pneumoniae, is a major antigen in oxLDL, which is recognized by anti-oxLDL antibodies that have protective properties. Furthermore, immunization with pneumococcal vaccine in a mouse model of atherosclerosis also protected against atherosclerosis.98 It is therefore possible that some infections, eg, agents with phosphorylcholine as a major antigen, can indeed be protective.
Anti-oxLDL antibodies bind oxLDL and generate immune complexes. Circulating immune complexes are not in themselves harmful. They cause damage only if they are deposited in tissues. The pathogenesis of atherosclerosis and CVD involves different mechanisms, including the response of the vessel wall to injury,3 the damaging effects of immune complexes,99 and the effects of oxLDL.100 These mechanisms supplement each other: oxLDL may trigger an immune reaction,100 with one of the consequences being the production of immune complexes.
Conclusions and Future Directions
To better evaluate the role of the anti-oxLDL antibodies (IgG, IgM) in health and disease, several factors should be explored. The significance of the classes and subclasses of anti-oxLDL antibody Ig has to be determined. Indeed, Karvonen et al101 recently reported an inverse association between IgG and IgM autoantibody titers to malondialdehyde-LDL. Similarly, Show et al102 isolated a panel of oxLDL-specific B-cell lines from apoE-deficient mice that secreted IgM antibodies that specifically bound to oxidized phospholipids. These antibodies blocked the uptake of oxLDL by macrophages. The antibodies were found to be structurally and functionally identical to classic "natural" F15 anti-phosphocholine antibodies that are of B1 cell origin. Thus, the isotope (IgM) may play an important role in determining the function of anti-oxLDL.102
Anti-oxLDL antibodies should be isolated into each class and/or subclass by several subsequent biochemical/immunochemical purification steps (ie, ion-exchange column, protein A-Sepharose column, size exclusion column, etc) from sera of normal subjects and from patients with disease that may be related to anti-oxLDL antibodies and from different sources of commercially available IVIG preparation, as well as from sera of hyperlipidemic mice (ie, APOE–/– and Ldlr–/–) and from mice immunized with IVIG. The specificity of the antibodies has to be characterized by ELISA, using an oxLDL or its derived lipid-coated microtiter plate and also using a silica plate on which oxLDL-derived lipids are chromatographically isolated. Furthermore, the antibody fractions should be used in in vitro culture systems to evaluate their effect on macrophage uptake of oxLDL.
Additional options of future ways to evaluate the question of pathogenicity or protectivity of anti-oxLDL is by analyzing monoclonal antibody structures;
Recently, isolated human anti-oxLDL monoclonal antibodies by a phage display method from the peripheral blood of 2 patients with atherosclerosis were generated, and the nucleotide and amino acid sequences of the heavy- and light-chain variable regions (VH and VL) of these antibodies should be determined. The high frequencies and pattern of the somatic mutations of the V regions may suggest the occurrence of affinity maturation by an antigen-driven B-cell activation during anti-oxLDL autoantibody-producing B-cell development. Structural differences may point to a pathogenic or protective role.
Furthermore, the characteristics of the deposited anti-oxLDL antibodies and/or their immune complexes in the atherosclerotic lesions should be analyzed. Does anti-oxLDL antibody inhibit or increase macrophage uptake of oxLDL to form foam cells?
Is the avidity of the anti-oxLDL to oxLDL important in protection? Are there different epitopes on oxLDL that determine protection or pathogenicity? Are there cross-reacting epitopes between infecting agents (eg, phosphorylcholine) and oxLDL that are more important in protection? Only after clearly defining the characteristics of protective anti-oxLDL antibodies and the conditions of their generation will we know whether we can immunize patients with oxLDL as a means to stimulate an immune therapeutic response,103 especially in patients with accelerated atherosclerosis, ie, systemic lupus erythematosus, rheumatoid arthritis, and APS104,105 and for the prevention of restenosis.
Footnotes
*The first 2 authors contributed equally to this work. 
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