Elsevier

Autoimmunity Reviews

Volume 5, Issue 3, March 2006, Pages 195-201
Autoimmunity Reviews

Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases

https://doi.org/10.1016/j.autrev.2005.06.005Get rights and content

Abstract

Atherosclerosis (AT) is a chronic autoimmune inflammatory disease, characterized by lipoproteins metabolism alteration leading to formation of pro-inflammatory and pro-oxidative lipids and immune response. Identification of macrophages, T cells, pro-inflammatory cytokines, adhesion cell molecules in atherosclerotic lesions support the hypothesis that innate and adaptive immune response participate in the atherogenesis mechanism. Multiple factors such as inflammatory, infectious and immune system, among others participate in this process. The principal antigens identified in atherogenesis are: oxidized LDL (oxLDL), HSPs and β2GPI. During LDL oxidation, multiple neoantigens are formed (anti-EO). These antibodies seem to be protective. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have accelerated AT. The association of both diseases with AT suggests a common pathogenic mechanism. SLE and atherosclerosis are immune-complex mediated diseases. Participation of complement activation, and CD40, CD40 ligand interactions have been demonstrated in AT and SLE. AT may be the initial presentation or the consequence of primary antiphospholipid syndrome. The similarities between AT, SLE, and APS and the identification of protective antibodies offer opportunities for new immunomodulation treatment strategies.

Introduction

Atherosclerosis (AT) is a chronic autoimmune inflammatory disease, characterized by lipoproteins metabolism alteration that leads to formation of pro-inflammatory and pro-oxidative lipids and immune response. Atheroma is a consequence of chronic inflammation and it contains immune system cells, principally macrophages and T cells. Macrophages (foam cells) are full of lipids, especially oxidized LDL (oxLDL). Identification of immune/inflammatory infiltration and experimental models support the hypothesis that immune system participates in atherogenesis mechanism [1].

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), have accelerated AT. This concept is based on epidemiological, clinical, laboratory and experimental studies. The present review will discuss the role of inflammatory, infectious, and immune response in AT and their relationship with APS and SLE.

Endothelial dysfunction is the initial process of AT and it is associated with oxidative stress that produces an imbalance between superoxides and nitric oxide (NO) on endothelial cells, with an increase of cell adhesion molecules (CAM), active platelets and leucocytes recruitment. The interaction of active endothelial cells, platelets and leucocytes participate in the plaque structure with chemokines deposit. Presence of pro-inflammatory cytokines (IL-6, TNF-α), chemokines (MCP-1) and other molecules (CRP, CD40 L) in the atherosclerotic plaque is a clear evidence of inflammatory response. Interestingly enough, two anti-inflammatory cytokines, IL-10 and transforming growth factor β (TGF-β) act as protective factors in AT. Removal of these regulators accelerates the process. Considering these data altogether, it is clear that the balance between inflammatory and anti-inflammatory activity controls the AT progression. However, the initial factors for the endothelial cells activation in AT are not completely understood [2].

Infectious agents (virus and bacterias) can promote directly or indirectly AT. There are evidences that infectious agents directly participate in the atherosclerotic plaque rupture. The indirect effect depends on a cross reaction of immune system against infectious agents, and artery wall. The infectious agents involved in AT are: Chlamydia pneumoniae, Cytomegalovirus, oral pathogen agents (Porfiromona gingivalis), Helicobacter pylori, etc. These agents infect and activate endothelial cells and leucocytes. Infected vessels develop oxidative stress and increase of CAM expression. Nevertheless, the definitive evidence that these infectious agents are enough for AT initiation are scarce. In humans the data are not conclusive. Antibiotic and antiviral treatment are controversial in relation with AT improvement. “Toll-like receptors” (TLR) are expressed by macrophages. Their function is protective, stimulating innate immunity against pathogen agents. TLR may have a role in AT development, increasing the production of pro-inflammatory cytokines [3], [4].

Since several types of pathogens may contribute to coronary artery disease, it is unlikely that a single microbe causes AT. It is possible that infection at various sites may affect the AT progression. On the other hand, there is controversy regarding antibiotic and antiviral treatment and AT improvement [3].

T cells are present in atherosclerotic plaques, especially in plaque rupture. The majority of T cells presenting in plaques are CD3 and CD4 positive and have TCR-αβ + receptors. This profile of surface molecules implicate the recognition and presentation of antigenic proteins by macrophages or dendritic cells to T cells. These cells represents 2 / 3 of all T cells CD3+ in advanced human atherosclerotic lesions and more than 90% of T cells in apoE- knockout (KO) AT model [5], [6].

Adaptive immunity is composed by T cells, antibodies and immunoregulatory cytokines that modulate activity and progression of atherosclerotic disease. The principal antigen identified in atherosclerotic plaques is oxLDL. In fact, T cells response, and detection of anti-oxLDL antibodies in patients with AT and experimental models support the hypothesis that immune response against oxLDL is present in atherogenesis [5].

Heat shock proteins (HSP) are produced during tissue lesion and they act as chaperons to avoid the denaturalization of other cell proteins. The AT animal models have HSP60 antibodies and their immunization with HSP60 accelerates AT and activates TLR4 like endotoxins. Therefore, HSP60 induces specific antibodies and may active innate immunity [7].

β2-glycoprotein I (β2GpI), is present in platelets, endothelial cells and atherosclerotic plaques. Anti-β2GpI has been identified in sera of patients with AT, SLE and APS. Immunization of transgenic mice with ß2GPI increases AT [8].

Antibodies anti-oxLDL, anti-cardiolipin, anti-ß2GPI, anti-HSPs, anti-lipoprotein lipase (anti-LPL) and anti-oxLDL/ ß2GPI complex have been found in patients with SLE and primary antiphospholipid syndrome (PAPS) with AT clinical manifestations [9].

The pathogenic role of these antibodies is under investigation. Protective role of antibodies in AT has been suggested. During LDL oxidation, multiple neoantigens are formed (anti-EO). These antibodies seem to be protective and they are linked to IL-5. An experimental study demonstrated that a change in Th1 to Th2 response reduces AT with an increase of anti-EO antibodies [6], [10]. In contrast, anti-cardiolipin antibodies and anti-ß2GPI may contribute to LDL oxidation by inhibition of paraoxonase activity, an enzymatic family with anti-oxidant activity [11].

Section snippets

Atherosclerosis as initial manifestation of PAPS

Studies in humans with APS have reported a wide spectrum of signs of AT, from AT manifestation as the first APS symptom to manifestations presented during long-term follow up of APS. Premature AT of the lower limbs as the first symptom of APS has been reported [12]. Spronk, et al. [13] described three patients with severe systemic AT, including aortic occlusion, associated with high levels of aCL and hyperhomocysteinemia and other risk factors without features of SLE and PAPS. Patients with

Systemic lupus erytematosus and atherosclerosis

SLE is a prototype inflammatory autoimmune disease affecting any organ and system including the blood vessels. Accelerated AT is now recognized as a major cause of morbidity and mortality in young women with SLE. The association of both diseases suggests a common pathogenic mechanism. The similarities between AT and SLE may provide new treatment strategies and understanding of vascular disease in these patients [24]. Very recently, it was demonstrated an association between C reactive protein

Conclusions

  • 1.

    Atherosclerosis is an inflammatory/immune disease.

  • 2.

    Atherosclerotic lesions especially unstable plaques contain active immune cells. This finding suggests that inflammatory immune activation in coronary arteries initiates acute coronary syndromes.

  • 3.

    Ox-LDL, HSPs and ß2GPI are the main antigens identified.

  • 4.

    Similarities between atherosclerosis, SLE, and APS as well as the identification of protective antibodies offer opportunities for new immunomodulation treatment strategies.

Take home messages:

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