Pathogenic immunity in systemic lupus erythematous and atherosclerosis: common mechanisms and possible targets for intervention

Abstract

Systemic lupus erythematous (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including the kidneys, skin, joints, blood, and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in SLE patients compared to age- and gender-matched control subjects and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies.

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder of unclear etiology that primarily affects women of child-bearing age. Patients affected by this condition can present with clinical damage to many organs including the kidneys, skin, joints, blood, and nervous system. Although the pathogenesis of SLE is not well understood, several predisposing factors are likely involved and play crucial roles in the initiation and maintenance of aberrant immune responses. These factors include genetic predisposition, gender, and the environment.

Both innate and adaptive immune responses appear to be involved in the development and perpetuation of SLE. Enhanced cell death and decreased clearance of dead cells have been observed in this disease, and are considered key in promoting prolonged exposure of modified autoantigens and in triggering abnormal immune responses such as enhanced type I interferon (IFN) synthesis. Several types of immunological perturbation have been described in murine and human lupus, including B cell and T cell abnormalities, autoantibody and immune complex production, complement activation, and dysregulation of synthesis of many cytokines and chemokines [1, 2]. This activation of self-reactive immune cells results in chronic sterile inflammation and tissue damage. SLE disease mechanisms are summarized in Fig. 1.

Figure 1.

Systemic lupus erythematous (SLE) disease mechanisms. Autoantigens released by apoptotic cells or other modified self-molecules can be taken up by antigen-presenting cells (APCs) or activating neutrophils, initiating different immune responses. Activated APCs will then activate T cells that start to produce cytokines, pro- or anti-inflammatory, and express co-stimulatory molecules to further activate other immune cells. Continued release of proinflammatory cytokines can induce damage of the surrounding tissue. T cells activated by autoantigens can further activate B cells leading to autoantibody production. Autoantibodies can then form immune complexes (ICs) with the respective autoantigen; after depositing the IC in tissues, inflammatory cells are recruited leading to tissue damage at the site of IC deposition. Activated neutrophils release proteins and reactive oxygen species with bactericidal properties. In addition to this, activated neutrophils extrude neutrophil extracellular traps (NETs) that have bactericidal functions, and the actions of activated neutrophils will lead to tissue damage during continued release of these lattices. Furthermore, NETs promote thrombosis leading to an increased risk of thrombus formation during inflammation. N, neutrophil; B, B cell; T, T cell; OxLDL, oxidized LDL; IFN; interferon; CD40L, CD40 ligand; FcR.

Although the diagnosis and treatment of SLE have significantly improved, the 5- and 10-year survival rates are significantly reduced in patients with this disease compared to the general population [3]. Of note, whereas deaths due to lupus manifestations have decreased, those due to cardiovascular disease (CVD) in SLE have not; in some studies, the latter represent more than one-third of all deaths in SLE patients [4] and a leading cause of mortality [5]. Indeed, patients with SLE have a 5- to 10-fold increased risk of myocardial infarction, as compared to age- and sex-matched control subjects, even after adjusting for traditional Framingham CVD risk factors [6, 7]. In the Framingham Offspring Study, 35- to 44-year-old women with SLE were found to have a 50-fold increased risk of myocardial infarction [8]. The increased CVD risk in SLE has also been associated with a more aggressive development of atherosclerosis, as assessed by carotid ultrasound [9], coronary calcium scoring by computerized tomography [10], positron emission tomography analysis of coronary flow reserve [11], and myocardial perfusion imaging [12].

Given that the Framingham risk equation cannot account for the enhanced CVD risk in SLE, it has been proposed that immune dysregulation characteristic of this disease has a fundamental role in vascular damage and accelerated development of plaque [13]. Nevertheless, it should be noted that identification and treatment of traditional risk factors for CVD, such as dyslipidemia, smoking, hypertension, and diabetes, are essential in this patient population, in order to decrease any additional burden on the vasculature. There are several features that make CVD in SLE atypical: the presentation in young women, the lack of a clear protective effect by statins, and the lack of a ‘classical’ inflammatory burden typically associated with atherosclerosis in the general population [14, 15]. Therefore, there is a need to clearly understand the mechanisms leading to premature vascular damage in SLE to better identify and treat this potentially devastating complication. In this review, we will focus on potential therapeutic strategies in SLE that target the immune system, and their impact on atherosclerosis and CVD.

The immune system and atherosclerosis

Inflammation triggered by aggregation and oxidation of LDL in the arterial wall plays a key role in the development of atherosclerosis [16]. This inflammation drives a fibrotic remodeling of the arterial intima resulting in plaque development and, in more advanced stages of the disease, plaque rupture. Danger signals generated by LDL oxidation and the tissue injury caused by oxidized LDL activate inflammation through interaction with Toll-like receptors (TLRs) and other types of innate immune receptors [17]. The level of inflammation in the plaque is also affected by a complex array of adaptive immune responses against oxidized LDL and other plaque antigens. These immune responses may dampen inflammation and promote vascular repair through the action of regulatory T (Treg) and regulatory B (Breg) cells as well as specific autoantibodies that facilitate the removal of oxidized LDL. In the absence of hypercholesterolemia and other CVD risk factors, this regulatory immunity will normally protect the arterial wall from atherosclerosis. However, chronic exposure to high levels of LDL is associated with a risk for loss of tolerance against oxidatively modified LDL antigens and activation of proinflammatory Th1 immune responses. Consequently, the balance between regulatory and proinflammatory immune plaque antigens may determine whether the atherosclerotic disease process will regress or progress [18]. The mechanisms responsible for the failure to maintain tolerance against plaque antigens in atherosclerosis remain to be fully understood. Presentation of LDL antigens in lymph nodes and the spleen is likely to primarily induce tolerogenic responses. However, when presentation of LDL antigens occurs in atherosclerotic lesions, factors such as concomitant activation of TLRs, expression of cytokines favoring Th1 maturation, and/or inhibition of dendritic cell migration to draining lymph nodes are likely to shift local immune responses toward proinflammatory immunity and aggravate the disease process.

Impaired efferocytosis: a common link between SLE and atherosclerosis

The loss of tolerance against LDL and other plaque antigens in atherosclerosis shares many characteristics with the loss of tolerance against self-antigens associated with disease development and organ damage in SLE. In particular, an impaired capacity to clear apoptotic cells and necrotic debris has been implicated as an important factor in both diseases. In SLE patients, apoptotic cells accumulate in various tissues including germinal centers where they may trigger inflammatory responses and breakdown of B cell tolerance [19]. Advanced atherosclerotic plaques not only accumulate significant numbers of apoptotic cells but also contain elevated levels of cells undergoing secondary necrosis [20]. Atherosclerotic plaques also contain large amounts of oxidized LDL, which competes with apoptotic cell ligands in the binding to phagocyte scavenger receptors, further reducing the local capacity for efferocytosis. In addition to uptake by scavenger receptors, opsonins such as milk fat globule epidermal growth factor 8 (MFG-E8), Gas-6, Protein-S, and complement factors (e.g. C1q and C3b) play important roles in mediating binding of apoptotic cells to various endocytic receptors on phagocytes. MerTK, a receptor for Gas-6 and Protein-S on M2 macrophages, appears to be particularly important in the activation of anti-inflammatory responses by apoptotic cells. Experimental evidence indicates that some of these pathways may be impaired in SLE (reviewed in [21]). Recent studies have suggested that these pathways may also play an important role in atherosclerosis, as a shift toward a proinflammatory Th1 phenotype accompanied by increased plaque necrosis has been demonstrated in apolipoprotein (apo)E−/− mice deficient in MFG-E8, MerTK, and C1q [22–24]. Table 1 summarizes the common disease mechanisms in CVD and SLE.

Table 1.

Common disease mechanisms in cardiovascular disease and systemic lupus erythematous

• Impaired clearance of apoptotic cells

• Skewed Th1 activation

• Increased/changed activation of T cells

• B cell activation

• LDL oxidation

Autoantibodies and vascular dysfunction

Endothelial dysfunction is an early marker of atherogenesis and the result of damage to endothelial cells that can no longer maintain the normal balance between vasodilation and vasoconstriction, blood clot formation and fibrinolysis, and smooth muscle cell proliferation and migration. Damaged endothelium promotes atherogenesis via increased endothelial permeability, leukocyte adhesion and transmigration, cytokine production, and platelet aggregation. Endothelial dysfunction can be induced by several conditions, many of them risk factors for atherosclerosis, such as diabetes, hypertension and hypercholesterolemia [25]. Rajagopalan et al. showed that patients with SLE have impaired endothelial function and that this is associated with an increased number of circulating apoptotic endothelial cells [26], suggesting the presence of an autoimmune response against the endothelium in SLE. This notion is further supported by the finding of anti-endothelial cell antibodies in patients with SLE [27]. However, SLE is also characterized by the generation of many other autoantibodies that can affect endothelial function [28]. Antiphospholipid (aPL) antibodies, including lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and beta 2-glycoprotein (b2-GPI), are present in 20–30% of all patients with SLE [29] and have been linked to an increased risk of venous and arterial thrombosis [30]. The pathophysiological role and mode of action of aPL antibodies remain to be fully elucidated but the results of cell culture studies suggest that these antibodies enhance expression of adhesion molecules on endothelial cells and increase monocyte adhesion. Although some studies have demonstrated increased levels of aPL antibodies in SLE patients with prevalent CVD [31, 32], this association is still a matter of controversy.

The role of autoantibodies in atherosclerosis remains to be clarified. Most studies have focused on the association between autoantibodies against oxidized LDL and CVD [33]. The results of these studies have been inconsistent, possibly due to difficulties in standardizing the antigen used in the antibody detection assay [34]. However, the findings of studies analyzing antibodies against specific antigens in oxidized LDL have been more consistent and are generally in line with a protective role of such antibodies. One of the most important antigens in oxidized LDL is a phospholipid, oxidized phosphatidylcholine, which is recognized by germline-encoded natural immunoglobulin (Ig)M released by B1 cells [35]. This class of IgM also recognizes phospholipid epitopes on the surface of apoptotic cells and several types of microorganisms. They are considered to play an important role in the first-line defense against infections as well as in tissue homeostasis by facilitating removal of cellular debris. It has been shown that increasing the level of circulating natural IgM by active or passive immunization reduces the development of atherosclerosis in hypercholesterolemic mice [36, 37], whereas atherosclerosis is aggravated in mice lacking circulating IgM [38]. Similarly, lupus-prone MRL/lpr mice develop more severe autoimmunity when deficient in circulating IgM [39]. Furthermore, a low level of natural IgM antibodies against phosphorylcholine was associated with the prevalence of plaques in the carotid arteries of SLE patients [40]. Taken together, these findings suggest that natural IgM could have an atheroprotective role in SLE. Other LDL autoantibodies, IgG and IgM against the apoB-100 peptides p45 (amino acids 661–680) and p210 (amino acids 3136–3155), have also demonstrated an association with CVD. Low levels of these antibodies have been associated with more severe atherosclerosis and an increased risk for development of myocardial infarction [41–43]. Treatment of hypercholesterolemic mice with recombinant IgG directed against malondialdehyde-p45 has been shown to inhibit the development of atherosclerosis and to promote plaque regression when combined with lowering of plasma cholesterol levels [44, 45]. It remains to be determined whether these antibodies can also protect against atherosclerosis in the setting of SLE. Table 2 summarizes the cardiovascular complications observed in SLE patients.

Table 2.

Cardiovascular complications in systemic lupus erythematous

• Endothelial dysfunction

• Increased thrombosis

• Myocarditis, pericarditis, and endocarditis

• Increased cholesterol levels

Immune cells in atherosclerosis and SLE

Neutrophils

Neutrophils are the most abundant immune cells in the circulation and they have the ability to release peptides and reactive oxygen species with bactericidal properties when activated. Recent evidence has indicated that neutrophils are important in both atherogenesis and plaque destabilization [46]. The alarmins S100A8, A9, and A8/A9 are secreted by activated neutrophils and in a recent prospective study their presence in plasma was found to correlate with neutrophil count, CVD risk factors, and CVD incidence [47]. Similar studies have been performed in SLE patients; plasma levels of S100A8/A9 and S100A12 were found to be elevated in patients compared to healthy control subjects. Furthermore, SLE patients with a history of CVD have increased levels of these proteins compared to patients without CVD [48]. This suggests that detection of S100 proteins could be used as a tool to determine risk of CVD in individuals with and without SLE.

Chromatin-containing fibers with bactericidal function, termed neutrophil extracellular traps (NETs), are extruded by neutrophils into the extracellular space [49]. Furthermore, endothelial cytotoxicity induced by NETs is a cause of vascular damage [50] and these lattices of fibers are strong promoters of thrombosis. As NET formation is more common in SLE patients, this phenomenon may be important for the induction of vascular damage in this disease. A distinct, proinflammatory type of neutrophils, so-called low-density granulocytes (LDGs), was first described in SLE. LDGs are cells with increased capacity to release NETs leading to enhanced externalization of autoantigens and induction of type I IFN responses. It has been shown that NETs are cytotoxic to endothelial cells through matrix metalloproteinase (MMP-9) and histone-associated processes [51, 52] and promote endothelial dysfunction, thrombosis, and vascular damage [53, 54]. Furthermore NETs carry all the oxidative machinery to modify HDL, rendering it proatherogenic [55]. Recent evidence indicates that inhibition of NET formation in vivo in animal models of lupus and atherosclerosis can improve vascular function, decrease plaque formation, and abrogate thrombosis [56]. Inhibition of NET formation might therefore be a useful future option for the treatment of CVD in SLE; however, no such treatment strategies are in clinical testing at present.

Monocytes and macrophages

In SLE, monocytes and macrophages are characterized by enhanced activation with increased expression of co-stimulatory molecules, an altered number and types of Fc gamma receptors, and overproduction of proinflammatory cytokines such as IL-6, tumor necrosis factor-α and type I IFNs [57]. In patients with SLE, compared to healthy control subjects, macrophages are reduced in number and show a reduction in the uptake of apoptotic cells leading to accumulation of apoptotic material. Apoptotic material does not normally induce inflammatory responses but when presented in an inflammatory context it can cause the activation of autoreactive T cells. The function of monocytes and macrophages in atherosclerosis development in patients with SLE is not fully understood but human monocytes and macrophages primed with type I IFNs are more prone to take up lipids, which leads to increased foam cell formation [58]. Furthermore, in vitro experiments with human macrophages have shown that plasma from SLE patients increases foam cell formation compared to plasma from healthy control subjects, which can be linked to increased expression of the scavenger receptor CD36 [59, 60]. Fc gamma receptors are expressed on monocytes and their expression is dysregulated in SLE. Findings from experiments using mouse models indicate that lack of the inhibitory Fc gamma receptor IIb promotes both SLE and atherosclerosis development; this suggests that dysregulation of Fc receptors may be an important factor contributing to increased CVD in SLE [61, 62].

Neopterin, a purine nucleotide produced by macrophages activated by IFN-γ, is a marker of macrophage activation. In atherosclerosis, a high neopterin concentration is associated with increased disease severity. Neopterin levels are also increased in SLE, but are not correlated with the severity of coronary atherosclerosis [63]. The cytokine macrophage migration inhibitory factor (MIF) plays a role in activation of macrophages and lymphocytes and has been shown to be increased in SLE, both in patients and in mouse models of the disease [64]. Moreover, it has been shown that a single-nucleotide polymorphism in the MIF gene is associated with an increased prevalence of SLE, indicating that this cytokine might have an important role in disease development [65]. Using mouse models of atherosclerosis, it has been demonstrated that there is a reduction in plaque development and monocyte recruitment when MIF is absent [64]. As MIF seems to have a central role in disease development, blocking or inhibiting the function of this factor could provide a potential novel therapeutic target for both SLE and atherosclerosis.

Lymphocytes

B cells are often considered to have an important role in SLE. As the functions and activities of B cells are often controlled by T cells, this heterogeneous group of cells is also important in SLE pathogenesis. B and T cells also have central roles in atherosclerosis, and both protective and disease-promoting functions have been described.

A key function of B cells and plasma cells in SLE is the production of autoantibodies which is a central feature of the disease and also used as a diagnostic marker. B cells are also antigen-presenting cells and can secrete cytokines with immunomodulatory functions. Studies of B cells in mouse models of SLE have shown that B cell deficiency inhibits disease development whereas defective antibody secretion has a minor role in SLE progression, suggesting that the antibody-producing role of B cells may not be as important as first considered [66]. Recently, understanding of the role of B cells in atherosclerosis has increased. Based on results from mouse studies it was previously believed that B cells are protective in atherosclerosis, mainly because of the protective autoantibodies they produce. However, more recent studies in which mature B cells were depleted in atherosclerotic mice have shown that B cells also have proatherogenic functions [67]. These findings emphasize the complexity of the functions of B cells, as well as other immune cells, in both atherosclerosis and SLE. As cells with regulatory capacity exist among both B and T cells, therapies need to be specific for the disease-promoting cells while maintaining the pool of immunoregulatory/protective cells and their functions. In SLE, therapies targeting B cells include general B cell depletion via blockade of CD20 or CD22 with monoclonal antibodies (anti-CD20 is used in SLE although not an approved for that indication) and inhibition of co-stimulatory pathways or neutralizing growth factors, such as B cell activation factor (BAFF), important in B cell activation [66]. The effect of these B cell-targeting therapies in atherosclerosis is essentially unknown. As described above, blockade of B cells with antibodies against CD20 reduces atherosclerosis in mice, but whether this is also true in humans with SLE needs to be explored.

In SLE, T cells display abnormal phenotypes, an altered activation threshold, and triggering of signaling pathways that lead to increased activation and expression of co-stimulatory molecules such as CD40 ligand (CD40L) [68]. T cell expression of CD40L is important in B cell differentiation, proliferation, class switch, and antibody production via CD40 interactions on the B cell. Increased CD40L–CD40 interactions lead to enhanced B cell activity and increased production of disease-promoting autoantibodies [69]. CD40L signaling is also important for atherosclerosis development, and inhibition of CD40L–CD40 interactions results in a more stable plaque phenotype [70]. Blockade of CD40L could therefore provide a potential therapeutic target for both SLE and atherosclerosis; however, the role of this therapeutic modality in SLE remains unclear [68].

T cell activation is dependent on interactions between the T cell receptor and its associated molecules that are concentrated to lipid rafts. When T cells become activated, the lipid rafts are clustered to allow the signaling molecules to come into close contact [68]. However, in SLE, the lipid rafts appear to be already clustered in the inactivated state, resulting in a lower activation threshold of the T cell [71]. Statins can disrupt lipid rafts and may promote abrogation of the T cell signaling abnormalities in SLE [72]. Statins were therefore considered as potentially beneficial in SLE, both as lipid-lowering therapy and with regard to their action on T cells. However, the vasculoprotective role of statins in SLE remains to be determined and trials to this date have not shown a major beneficial role to reduce CVD risk and immune dysregulation in SLE [73, 74].

Which type of Th cell plays the dominant role in SLE development remains unclear. Levels of the proinflammatory cytokine IL-17 and Th17 cells are increased in SLE patients and have in some studies been shown to correlate with disease activity [75, 76]. In patients with SLE, IL-17 can also be secreted from double negative (CD4-CD8-) T cells, a population of cells that are rare under normal conditions but whose numbers are increased in SLE [76]. Furthermore, it has been shown that SLE patients have a higher Th17/Th1 ratio compared to healthy control subjects but a higher proportion of Th1 compared to Th2 cells [77, 78]. In atherosclerosis, Th1 cells are proatherogenic whereas the roles of Th2 and Th17 cells remain incompletely understood. Some studies have demonstrated increased circulating IL-17 and Th17 cells in patients with CVD; however, several groups have reported no differences in IL-17 and Th17 cells [79]. Furthermore, it was recently reported that low circulating IL-17 levels in myocardial infarction patients were associated with an increased risk of a new cardiovascular event. This finding suggests a protective role of IL-17 in vascular inflammation [80]. Blocking IL-17 and/or Th17 cells might be beneficial in SLE but the effects in atherosclerosis and CVD are more uncertain and need to be carefully investigated.

Treg cells have the ability to dampen immune responses and are thereby believed to be protective in autoimmune diseases. It has been shown that Treg cells are reduced in number and have reduced functional capacity in SLE patients [81]. However, it has also been reported that the percentage of Treg cells correlates positively with disease activity in SLE, and this discrepancy seems to depend on how the Treg cells are defined [82]. Treg cells have been associated with a protective role in atherosclerosis based on both human studies and mouse models [83–85]. Increasing the activity and/or the proportion of Treg cells might be a potential way to target both SLE disease and the rise in CVD that occurs in SLE.

Cytokines in SLE and atherosclerosis

Several cytokines play important roles both in atherosclerosis and SLE. Studies have shown that some of the most important of these cytokines are protective in CVD and disease promoting in SLE, and vice versa for others. The precise roles of these cytokines in accelerated atherosclerosis in SLE need to be fully elucidated [86].

Type I IFN

Overexpression of type I IFN-regulated genes, termed the IFN signature, has been demonstrated in leukocytes and tissues from SLE patients, and the level of expression of these genes correlated with disease activity [87]. The type I IFN cytokine family is represented primarily by IFN-α and IFN-β, the former being mainly produced by plasmacytoid dendritic cells and the latter by many cell subsets in response to viral infections leading to activation of a wide range of both innate and adaptive immune cell functions [88]. Several studies have shown that type I IFNs can be involved in the accelerated CVD observed in SLE, as these IFNs enhance macrophage migration into the vessel wall leading to increased foam cell formation [20]. Type I IFNs also activate platelets and change their transcriptional profile resulting in increased thrombus formation [89, 90]. Endothelial progenitor cells (EPCs) are crucial for vascular repair as they can replace damaged endothelial cells. It has been shown that the reparative capacity of EPCs in SLE patients is disturbed, presumably because of the chronic inflammatory processes [15]. Type I IFNs influence vascular repair by impairing the function of EPCs as well as decreasing the numbers of these cells, leading to endothelial dysfunction and reduced angiogenesis [91]. The possibility of using type I IFNs as a target for future SLE therapies is currently under investigation. An anti-IFN-α monoclonal antibody was found to be safe, well tolerated, and effective and will be further investigated in clinical trials. Vaccination strategies leading to induction of anti-IFN-α antibodies are also under development [88]. As type I IFNs also have a disease-promoting role in atherosclerosis, blocking of these cytokines may be beneficial in regard to CVD, both in SLE patients and in subjects without SLE. Additionally, type I IFNs may promote atherosclerosis development via their actions on lipoprotein function. HDL normally protects against atherosclerosis development because of its ability to take up and clear lipids from plaques. HDL also has anti-oxidative functions but under chronic inflammatory conditions, such as persistent exposure to type I IFNs, the anti-oxidative capacity can be lost and it is considered that the HDL becomes proinflammatory. This can, at least partly, be a result of decreased amounts of apoA-1 in HDL due to the ongoing inflammation [92]. Antimalarial agents, particularly hydroxychloroquine and chloroquine, are widely used as treatments for mild–moderate SLE. Previous observations indicate that antimalarial medications may have a vasculoprotective role [93]. Part of the mechanism of action of these drugs in SLE is related to their ability to block both TLR-induced synthesis of type I IFNs and NET formation. As such, it is possible that the vasculoprotective effect of antimalarial agents is mediated in part by their role in blocking type-I IFN pathways in SLE [55, 94].

IL-6

IL-6 is an inflammatory cytokine and both murine and human studies have shown that it has an important role in SLE pathogenesis. Renal damage is reduced in IL-6-deficient MRL/lpr mice. This finding has been supported by results from studies in which mice were treated with recombinant IL-6 or blocking IL-6 antibodies resulting in increased and decreased lupus nephritis, respectively. IL-6 has an important role in B cell maturation into plasma cells and it has been shown that blockade of this cytokine reduces the production of autoantibodies. Furthermore, increased levels of IL-6 in serum and IL-6 mRNA in freshly isolated peripheral blood mononuclear cells have been reported in SLE patients compared to healthy control subjects [95]. Mouse studies of atherosclerosis and IL-6 have shown both protective and disease-promoting functions; administration of IL-6 was found to exacerbate atherosclerosis but hypercholesterolemic mice lacking IL-6 had an increased plaque area. As the role of IL-6 in atherosclerosis is not completely understood, the impact of the increased IL-6 in SLE on atherosclerosis development is unclear. Blockade of the IL-6 receptor with tocilizumab is currently being investigated as a potential SLE therapy. Tocilizumab has shown good tolerability in Phase I trials and it restores B and T cell homeostasis [96]. As the role of IL-6 in atherosclerosis and CVD is unclear, the impact on these conditions of blocking IL-6 signaling needs to be thoroughly monitored during clinical testing.

IL-10

IL-10 seems to have dual roles in SLE. It is a cytokine with anti-inflammatory properties through inhibition of the production of proinflammatory cytokines such as IFN-γ. Moreover, IL-10 is important in B cell activity leading to proliferation and differentiation of B cells, antibody class switch, and decreased apoptosis of B cells in germinal centers supporting autoantibody production. Experimental studies in mice with SLE-like disease have shown that anti-IL-10 antibodies can have a protective role, but it has also been reported that disease severity is increased in MRL/lpr mice deficient in IL-10 [97]. It has been shown in several studies that IL-10 is increased in SLE patients and also correlates with disease activity [98]. Therefore blocking IL-10 might provide a potential therapy for SLE. Preliminary data from clinical trials of monoclonal anti-IL-10 antibodies have shown protective effects in SLE indicating that the disease-promoting functions of IL-10 predominate over the protective properties. In atherosclerosis, IL-10 has been shown to have a protective role likely via its ability to downregulate both innate and adaptive immune responses. Macrophages are the main cytokine-producing cell type in atherosclerotic plaques and the key source of IL-10 [99]. In contrast to the situation in SLE, increased serum levels of IL-10 seem to be protective in CVD as evidenced by the fact that IL-10 is an important prognostic determinant in patients with acute coronary syndromes [100]. Furthermore, increased expression of IL-10 on macrophages in plaques leads to reduced inflammation and stimulates plaque healing [101]. The effect of anti-IL-10 antibodies as SLE treatment on atherosclerosis is unknown and needs to be thoroughly investigated as potentially undesirable effects on atherosclerosis and CVD may be observed. Fig. 2 shows a summary of the potential therapeutic strategies in SLE that target the immune system, and their impact on atherosclerosis and CVD.

Figure 2.

Potential future therapies targeting the immune system in systemic lupus erythematous (SLE) and cardiovascular disease (CVD).

Conclusion

Cardiovascular disease is an important complication of SLE and effective preventive measures remain to be identified. The pathogenic immune responses in SLE and development of atherosclerotic plaques have some similar characteristics, suggesting novel targets for intervention. From a cardiovascular perspective, SLE poses many challenges as it is a heterogenous and relatively rare disease and, in order to demonstrate significant effects of intervention on clinical endpoints such as myocardial infarction and stroke, study cohorts of many thousands of subjects are usually required. Therefore, even if the relative increase in CVD risk in SLE is high, the absolute number of events is still low. Accordingly, it is likely that clinical testing of novel therapies for prevention of CVD in SLE will have to rely on surrogate markers for CVD risk such as vascular imaging and function. As novel immune-based therapies for CVD are being developed and tested in clinical trials [102] it is likely that some of these may also show efficacy for the treatment of SLE. Cardiovascular research may also benefit from studies of pathogenic immunity in SLE to achieve a better understanding of how local tolerance in atherosclerotic plaques is lost and how this is associated with increased plaque inflammation and risk for clinical events.

Future perspectives

The fact that SLE is a rare and complex disease has seriously hampered the development of novel therapies targeting key disease mechanisms. It has also been difficult to determine whether different organ complications in SLE involve separate pathogenic processes. However, with the rapid advances in DNA, proteomic, and immune-based multiplex technologies, new opportunities are now becoming available that will change this situation dramatically. These technologies are also likely to provide a more personalized diagnosis of the disease with new opportunities for individualized treatment. Because of this and the increasing availability of a wide variety of biological agents, we believe it is likely that the clinical consequences of SLE will be significantly reduced within the coming decades.