Elsevier

Atherosclerosis

Volume 201, Issue 1, November 2008, Pages 17-32
Atherosclerosis

Review
The autoimmune origin of atherosclerosis

https://doi.org/10.1016/j.atherosclerosis.2008.05.025Get rights and content

Abstract

Atherosclerosis is a chronic inflammatory disease. Many studies and observations suggest that it could be caused by an immune reaction against autoantigens at the endothelial level, the most relevant of which are oxidized LDL and heat shock proteins (HSP) 60/65. Endothelial dysfunction plays a fundamental role. The first antigen is related to the increased leakage and oxidation of LDL; the second to cellular reaction to stress. Experimental and clinical observations confirm the pathogenetic role of these antigens. Both innate and adaptive immunity and impaired regulatory mechanisms of the autoimmune reaction are involved. Different triggering factors are examined: infectious agents, smoking, air pollution, diabetes and hypercholesterolemia. Analogies and differences between systemic atherosclerosis and transplant-related coronary atherosclerosis help to understand their respective nature. Immune mechanisms might be responsible for the passage from stable plaque to unstable and rupture-prone plaque. Finally, prospects of treatment and prevention are linked to the induction of tolerance to responsible antigens, activation of immune regulatory response and the use of immunomodulatory drugs.

Introduction

Atherosclerosis is a chronic inflammation affecting the intima of arteries [1], [2]. The origin of this inflammation is still under discussion [1], [3], [4]. However, according to a many investigators, one hypothesis prevails: that it is an autoimmune disease [5], [6], [7], [8], [9], [10].

Section snippets

On what ground is such a hypothesis based?

Observations suggesting an autoimmune origin of atherosclerosis.

Atherosclerotic lesions start when low-density lipoprotein (LDL) molecules are trapped in the arterial wall, the first step in the evolution of atheroma being the generation of a “fatty streak” due to retention of LDL in the subendothelial extracellular matrix [1]. At this stage lymphocytic T cells are already present in the lesion, before development of the plaque [5], [11]. Later on, an abundant sub-endothelial infiltration of

What antigens can be responsible for the autoimmune reaction and where do they come from?

Autoantigens considered responsible for the autoimmune reaction at the origin of atherosclerosis: mechanisms causing their expression at the endothelial level.

The main autoantigens are: the HSP and the oxidized low-density-lipoproteins (oxLDL). The secondary autoantigens are: the β2 glycoprotein and the structural components of some micro-organisms [1], [14], [15], [20], [32], [39].

Some of them arise from so-called “endothelial dysfunction” [15], [32], [39], [40], [41], which consists in the

What are HSPs and what is their function in the organism?

Nature and role of HSPs.

The name is derived from their isolation in a small fly, the Drosophila, which was utilized for pioneer research on chromosomes. After exposure to heat, the induction of genes for the synthesis of HSP was observed in the Drosophila salivary glands [32], [54].

These stress proteins are present in all living organisms [55]. Many of them, like the HSP60, are localized in the mitochondria (of which they are considered “bodyguards” as they play an important role in their

What is the role of HSPs in the pathogenesis of atherosclerosis?

The antigenic role of HSPs in the pathogenesis of atherosclerosis.

It has been amply demonstrated in the literature that HSPs can play a primary antigenic role in the autoimmune pathogenesis of atherosclerosis [1], [10], [13], [14], [32], [41], [56], [59], [67], [68], [69].

When rabbits are fed a cholesterol-rich diet, the atherosclerotic lesions that consequently arise contain the “HSP factor-1” (the transcription factor of HSP) in significantly higher levels than in normal vessel walls [57]. In

What about the oxidized LDL, the other protagonists of this pathogenetic scenario?

Nature and role of the oxLDL.

Oxidized LDL are the product of oxidation of their polyunsaturated fatty acid component due to the increased concentration of ROS at the subendothelial level [79], [80], [81]. Two aldehydes with strong immunogenic properties (immunogenic epitopes) are formed: malondialdehyde and 4-hydroxynonenal with anionic valence [82], [83]. By such alteration of their chemical structure these self-proteins are transformed into auto-antigens [5], [9]. The uptake of oxLDL by

By what mechanisms is the autoimmune reaction set off at the site of atherosclerosis?

Ways of activation of the immune response by the involved antigens.

The vascular system is considered part of the immune system [15]. The endothelium occupies a strategic position, as it is positioned between the circulatory stream and the tissues [15].

The immune system acts in two phases: identification of non-self and reaction against it. The first phase consists of two components: “innate” and “adaptive” [15], [95].

The innate component represents the defensive outpost. It is germline encoded

What about the association between infectious agents and atherosclerosis?

Infectious agents and atherosclerosis: role of the HSPs.

Numerous studies have demonstrated a pathogenetic relationship between atherosclerosis and some micro-organisms (bacteria and viruses) causing chronic infections [104], [105]. This relationship seems to be particularly important in countries where conventional (“Western”) cardiovascular risk factors are less relevant [106]. The involved bacteria include: Chlamydia pneumoniae, Helicobacter pylori[107] and Porphyromonas gingivalis[39], [108]

Are autoimmune mechanisms involved in the smoking-related atherogen effects?

Possible autoimmune nature of smoking-related atherogenesis.

As known, smoking is an important risk factor for atherosclerosis. Although the molecular mechanism of the vascular damage is still unclear, smoking causes oxidative stress-related pro-inflammatory alterations of endothelial cells, their dysfunction and consequent expression of HSPs on their surface [32], [77], [139], [140], [141]. In addition, LDL are more prone to become oxidized by smoking-related substances [140]. Consequently,

Is the immune response somehow moderated?

Defective curbing mechanisms at the origin of autoimmune reactions. Nature and role of regulatory T lymphocytes.

Excessive Th1-response to specific antigens might, if not curbed, lead to autoimmune diseases [39], [145], [146]. For this reason, a balancing system regulates the intensity of the reaction and raises the triggering threshold of T cell responses [147], particularly in the presence of a persistent stimulus [56], [148]. This regulation is carried on principally by the T “regulatory”

Is this also valid for atherosclerosis?

Treg cell dysfunction in atherosclerosis.

Like other chronic inflammatory diseases of autoimmune origin, also atherosclerosis appears to depend on the deficiency of Treg function [56], [150], [160], [161], [162]. Reactions against HSPs are normally curbed by active regulating natural immunity accomplished by Treg cells [163]. Moreover, TGF-β, one of the cytokines produced by Treg, has been shown to play an important role in dampening atherosclerosis development [164], [165]. Finally, it has been

Could autoimmune mechanisms play a role in acute vascular events?

Mechanisms of altered immune control and autoimmune reaction at the origin of unstable plaques and of their rupture.

It has been ascertained that most of the acute arterial occlusions are due to the rupture of unstable (inflamed) plaques [162]. In fatal myocardial infarction, analysis of the culprit atherosclerotic lesion shows that inflammation is crucially determinant in provoking the superficial erosion and rupture of the coronary plaque [145].

Plaque inflammation and instability, when it

Do HSPs also play a role in inducing tolerance?

HSP-activated immunotolerance.

HSP60/70 are able to regulate Treg-related immune tolerance by attracting these lymphocytes toward the sites of inflammation where the HSPs are expressed [60], [177]. The epitope of HSP responsible for the Treg function, is the 256–265 peptide [56].

How can HSPs be, at the same time, triggers of aggressive immune responses and factors of tolerance? The possibility of an antigen stimulating either tolerance or an active immune response is governed by several factors,

What is the role played by hypercholesterolemia?

Relationship between auto-immune reactions and hypercholesterolemia in atherosclerosis.

In humans, atherosclerosis is practically absent below a certain level of cholesterolemia (150 mg%) and the risk of its appearance gradually increases by increasing the cholesterol levels [145]. Besides, the immune reaction against LDL, as described, depends on their infiltration in the sub-endothelial space which is conceivably proportional to the level of cholesterolemia [181]. Atherosclerosis does not

Could autoimmunity also play a significant role in diabetes-related atherosclerosis?

Autoimmunity and atherosclerosis in diabetic patients.

As known, atherosclerosis and its consequences is more frequent, precocious and severe in diabetes. It represents its main cause of morbidity and mortality [186], [187], [188]. Other diabetes-linked cardiovascular risk factors (like hypertension, dyslipidemia, pro-thrombotic tendency) do not completely account for the excess of mortality. Consequently, specific (and still undefined) diabetes-related risk factors are assumed to play a role

Are there any prospects of prevention or cure for atherosclerosis from an immunomodulatory point of view?

Treatment prospects and prevention of atherosclerosis through modulation of immune responses.

There are several interesting routes of intervention that have been covered so far. The principal are: induction of tolerance, active immunization, passive immunization, activation or expansion of Treg cells and use of drugs with immunomodulatory effect [145].

Conclusions

There are, at the moment, different theories concerning the nature of the inflammation at the origin of atherosclerosis. The autoimmune hypothesis appears to be one of the most realistic and attractive. Future studies may add other elements to the data illustrated in this review (Table 1 and Fig. 1). Vaccination against atherosclerosis, through the induction of tolerance against self-antigens (or external epitopes) and amplification of the regulatory response, may hopefully pave the way to the

Acknowledgement

The author wishes to thank Prof. Mariella Trovati of Turin University, without whose moral support and encouragement this paper would never have been written. Dr. Alessio Tommasetti is the careful and patient designer of the figure.

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