Clinical significance of the humoral immune response to modified LDL

doi:10.1016/j.clim.2009.04.001

Clinical Immunology

Volume 134, Issue 1, January 2010, Pages 55-65

https://doi.org/10.1016/j.clim.2009.04.001 Get rights and content

Abstract

Human low density lipoprotein (LDL) undergoes oxidation and glycation in vivo. By themselves, oxidized LDL (oxLDL) and AGE-LDL have proinflammatory properties and are considered atherogenic. But the atherogenicity of these lipoproteins are significantly increased as a consequence of the formation of immune complexes (IC) involving specific autoantibodies. OxLDL and AGE antibodies have been shown to be predominantly of the IgG1 and IgG3 isotypes. OxLDL antibodies are able to activate the complement system by the classical pathway and to induce FcR-mediated phagocytosis. In vitro and ex vivo studies performed with modified LDL-IC have proven their pro-inflammatory and atherogenic properties. Clinical studies have demonstrated that the levels of circulating modified LDL-IC correlate with parameters indicative of cardiovascular and renal disease in diabetic patients and other patient populations. The possibility that spontaneously formed or induced modified LDL antibodies (particularly IgM oxLDL antibodies) may have a protective effect has been suggested, but the data is unclear and needs to be further investigated.

Introduction

While there is general consensus about the inflammatory nature of atherosclerosis [1], [2], [3], understanding the multitude of insults that initiate and perpetuate the inflammatory process is far from clear and very much in its infancy. This review will focus on the proposed and still controversial role of modified LDL antibodies (mLDL Abs), which have been characterized in great detail from both the structural and biological points of view. The involvement of humoral immune processes in atherosclerosis is not likely to be limited to mLDL Abs. In this issue of CI others will discuss the role of antiphosphorylcholine antibodies, and special mention needs to be made of the literature suggesting that heat shock proteins and their corresponding antibodies may also play a significant role in cardiovascular disease [4], [5], [6].

Section snippets

The immunogenicity of modified lipoproteins

In vitro-modified human lipoproteins are immunogenic when injected into rabbits and rodents [7], [8], [9], [10]. They are also recognized by autoantibodies that seem to exist virtually in every single human adult [10], [11]. It is possible that the antibodies that are detected in normolipemic and hyperlipemic individuals recognize LDL with different degrees of modification [12] but the precise nature of the modifications and epitopes recognized by human antibodies is not totally clear.

Structural and biological characteristics of modified LDL antibodies

Circulating human oxLDL antibodies were the first to be purified by affinity chromatography using immobilized oxLDL [29]. By 2002 we had isolated oxLDL antibodies from 46 patients with type 1 diabetes and found that IgG was the predominant isotype, followed by IgM and IgA. Within the IgG isotype, ox LDL antibodies were predominantly of subclasses 1 and 3 [19], [29], [30]. The predominance of IgG over IgM in isolated circulating oxLDL antibodies is not a characteristic of diabetic patients; it

Pathogenicity of modified LDL antibodies in humans

Initially, the attention of clinical investigators concentrated on finding evidence supporting a pathogenic role for oxLDL and MDA-LDL antibodies, using them as a surrogate measurement of LDL with different degrees of modification. The results of these studies were rather disappointing, because the results were often conflicting and failed to produce a clear cut indication of the clinical value of modified lipoprotein antibody assays as biomarkers for the development and/or progression of

The flip side: is the humoral immune response to modified lipoproteins protective against the development of atherosclerosis?

In 1995 Palinski et al. reported that the immunization of LDL receptor-deficient [LDLr^−/−] rabbits with homologous MDA-LDL reduced atherogenesis [88]. This report triggered multiple animal studies in rabbits and mice, well summarized by Binder et al. [89]. Apo-E deficient mice immunized with homologous MDA-LDL also showed a reduction in the development of atheromatous lesions[88], [90]. Similar observations were reported in hypercholesterolemic rabbits immunized with autologous oxLDL [91].

Conclusions

The immunogenicity of autologous modified LDL in humans has been established by numerous studies summarized in this review. There is also considerable and conclusive evidence suggesting that the humoral immune response to modified LDL is pathogenic in humans. The predominant isotypes of modified LDL antibodies are IgG, of subclasses 1 and 3, classically considered as proinflammatory [34], [35]. More important is the fact that in vitro and ex vivo data have proven that IC containing oxidized LDL

Acknowledgments

This work was supported by the Research Service of the Ralph H. Johnson Department of Veteran Affairs Medical Center, by a Program Project Grant funded by the National Institutes of Health/NHLBI (PO1-HL55782), by a grant funded by NIH/NIDDK (R01 DK081352), and by a grant from the Juvenile Diabetes Research Foundation (1-2006-49).

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ReviewClinical significance of the humoral immune response to modified LDL

Abstract

Introduction

Section snippets

The immunogenicity of modified lipoproteins

Structural and biological characteristics of modified LDL antibodies

Pathogenicity of modified LDL antibodies in humans

The flip side: is the humoral immune response to modified lipoproteins protective against the development of atherosclerosis?

Conclusions

Acknowledgments

J. Am. Coll. Cardiol.

J. Lipid Res.

J. Biol. Chem.

J. Lipid Res.

Atherosclerosis

Atherosclerosis

J. Lipid Res.

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

Clin. Immunol.

Clin. Immunol.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Clin. Immunol. Immunopathol.

Clin. Immunol.

J. Lipid Res.

J. Lipid Res.

Clin. Immunol. Immunopathol.

Immunol. Lett.

J. Lipid Res.

Atherosclerosis

Atherosclerosis

Lancet

Clin. Chim. Acta

Atherosclerosis

Clin. Immunol.

Atherosclerosis

Atherosclerosis

J. Am. Coll. Cardiol.

Atherosclerosis

J. Diabetes Complicat.

Atherosclerosis

J. Lipid Res.

Mol. Immunol.

Inflammation in atherosclerosis

Nature

Atherosclerosis—an inflammatory disease

N. Eng. J. Med.

Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime

Nat. Med.

Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis

Circulation

Role of heat shock proteins in atherosclerosis

Arterioscler. Thromb. Vasc. Biol.

Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein

Arteriosclerosis

Lipoprotein autoantibodies: measurement and significance

Clin. Diagn. Lab. Immunol.

The autoantibody repertoire against copper- or macrophage-modified LDL differs in normolipidemics and hypercholesterolemic patients

J. Clin. Immunol.

Use of polyethylene glycol (PEG) to concentrate immune complexes from serum or plasma samples

Ann. rheum. Dis.

Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL

Arterioscler. Thromb. Vasc. Biol.

Natural antibodies against phosphorylcholine as potential protective factors in SLE

Rheumatology (Oxford)

Immunogenic oxidized low-density lipoprotein/beta2-glycoprotein i complexes in the diagnostic management of atherosclerosis

Clin. Rev. Allergy Immunol.

Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man

J. Clin. Invest.

Oxidation of LDL by myeloperoxidase and reactive nitrogen species: reaction pathways and antioxidant protection

Arterioscler. Thromb. Vasc. Biol.

Immunologic detection and measurement of hypochlorite-modified LDL with specific monoclonal antibodies

Arterioscler. Thromb. Vasc. Biol.

Review
Clinical significance of the humoral immune response to modified LDL