Immunity in Atherosclerosis: Focusing On T And B Cells Part 1

Abstract:

Atherosclerosis is the major cause of the development of cardiovascular disease, which, in turn, is one of the leading causes of mortality worldwide. From the point of view of pathogenesis, atherosclerosis is an extremely complex disease. A huge variety of processes, such as violation of mitophagy, oxidative stress, damage to the endothelium, and others, are involved in atherogenesis; however, the main components of atherogenesis are considered to be inflammation and alterations of lipid metabolism. 

In this review, we want to focus on inflammation, and more specifically on the cellular elements of adaptive immunity, T and B cells. It is known that various T cells are widely represented directly in atherosclerotic plaques, while B cells can be found, for example, in the adventitia layer. Of course, such widespread and well-studied cells have attracted attention as potential therapeutic targets for the treatment of atherosclerosis. Various approaches have been developed and tested for their efficacy.

The relationship between atherosclerotic plaque and immunity is mainly manifested in the following two aspects:

1. Effect of immune response on plaque formation: The formation of atherosclerotic plaque is a complex biological process in which the immune response plays an important role. When the vascular endothelium is damaged, immune cells (such as monocytes and macrophages) in the peripheral blood will gather to the damaged area, and mediate the inflammatory response and plaque formation through phagocytosis and secretion of cytokines. The immunity level of the body's immune system is closely related to the functional state of immune cells. Individuals with low immunity are prone to inflammatory reactions and plaque formation, while individuals with strong immunity are less prone to this situation.

2. The impact of the immune response after plaque rupture: When the plaque ruptures, the internal substances will be released, triggering the body's immune response, causing inflammation and thrombus formation. Individuals with stronger immunity have better cellular immunity and humoral immunity, can clear the released inflammatory factors and thrombus faster, and reduce the occurrence of vascular restenosis and cardiovascular events.

Therefore, maintaining good immunity can prevent and treat atherosclerotic plaque and related cardiovascular diseases. Good living habits, such as a reasonable diet, moderate exercise, not smoking, reducing stress, etc., can improve immunity. In addition, depending on the individual's immune status, doctors may also prescribe corresponding immunomodulatory drugs to reduce inflammation and plaque formation. Therefore, in our daily life, we need to improve our immunity. Cistanche can significantly improve immunity. Cistanche is rich in a variety of antioxidant substances, such as vitamin C, carotenoids, etc. These ingredients can scavenge free radicals and reduce oxidative stress Stimulate and improve the resistance of the immune system.

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Keywords:

atherosclerosis; CVD; immunity; T cells; B cells.

1. Introduction

Cardiovascular disease (CVD) is the most widespread cause of death. In 2013, 7.3 million people died because of CVD, which, according to world statistics, is 31.5% of total deaths [1]. To maintain cardiovascular system health, it is recommended to stop smoking, increase physical activity, control body mass by adopting a healthy diet, monitor blood pressure, and conserve normal levels of blood lipids and glycemia [2]. 

Thus, the most important thing is the diet, which can provide a good cardiovascular health status. This type of diet is related to a balanced energy intake. This involves product consumption of whole-grain foods, legumes, seafood, fish, and an increased amount of vegetables and fruits; it also involves a lower consumption of processed foods, red meat, sugar-containing foods and drinks, and refined grains [3].

Atherosclerosis is a chronic systemic inflammatory disease that attacks artery walls because of an altered inflammatory response. The development of atherosclerosis is often caused by lipid metabolism impairments [4]. Cholesterol-rich lipoproteins with apolipoprotein B are receptive to absorption and merging into the subendothelial matrix of the arteries. Due to oxidation, enzymatic and non-enzymatic cleavage, as well as aggregation, the lipoproteins contained in this matrix create pro-inflammatory particles and trigger the overlying endothelium. 

Then, the monocyte-derived cells internalize the subendothelium and trigger the immune response. These cells turn into mononuclear phagocytes, which absorb normal cells and altered lipoproteins, then convert into cholesterol foam cells. By remaining in the plaque, the cholesterol foam cells absorb lipids and stimulate the progression of the disease, developing a chronic inflammatory response [5].

Foam cells are considered a hallmark of atherosclerosis. At the same stage, when they are formed, a series of complex inflammatory cascades are induced. This stimulates the development of atherosclerotic lesions and leads to plaque rupture and related cardiovascular events.

Macrophages and monocytes are part of the innate immune system, which plays an essential role in the preservation of immune homeostasis by eliminating infectious agents and stimulating tissue damage repair. In atherosclerosis, these cells participate in the chronic inflammatory process, which typically occurs within the arterial wall [6].

Adaptive immunity is a very exact lifelong immune response. It is essential for distinguishing foreign- from self-antigens. The main cellular elements of adaptive immunity are T and B cells, which recognize antigens via a specific T-cell receptor (TCR) and B-cell receptor (BCR).

The set of membrane and intracellular markers underlies the classification of T cells. They express the αβ or γδ TCR, CD3, and one of the coreceptors CD4 or CD8. The TCR-CD3 complex recognizes antigens presented in the context of major histocompatibility complex molecules (MHC or human leukocyte antigen (HLA) in humans) by an antigen-presenting cell.

B cells are classified by the expression of the cell-lineage marker CD19, a range of surface and intracellular proteins, their distinct B cell receptors, and their production of antibodies. B cells can also produce cytokines and act as antigen-presenting cells. Antigen-presenting cells can present antigens to cognate naïve CD4+ and CD8+ T cells. 

Among such antigens, there are self- and non-self-antigens, for example, HSP60 (heat shock protein 60) and modified LDL particles. Being activated, CD8+ T cells proliferate and differentiate into CD8+ cytotoxic T lymphocytes (CTL), and CD4+ T cells proliferate and differentiate into specialized effector T helper (Th) cells. Naïve CD4+ T cells have the potential to differentiate into various cell subsets, such as effector T cells (T helper 1 (Th1), Th2, and Th17) and regulatory T cells (Treg). The type of antigen, T-cell receptor signal intensity, and the local cytokine environment define the Th subsets into which T-cells can differentiate. These factors mediate Th polarization in atherosclerotic lesions [7]. The implication of immune cells in atherogenesis is briefly summarized in Figure 1.

Figure 1. Various types of T cells are attracted to the atherosclerotic lesion site by the chemokines released by the activated endothelial cells. IFNγ (interferon-gamma) is produced by Th1 cells and has proatherogenic features. It inhibits the proliferation of smooth muscle cells, decreases collagen production, and activates macrophages. IL-4 (interleukin-4) is produced by Th2 cells and has atheroprotective effects mediated by the ability to inhibit Th1 cells. Granzyme B and perforin, which are released by CD4+CD28nullT-cells can damage vascular wall cells. CD8+ T-cells produce proatherogenic IFNγ or cause an atheroprotective effect via decreasing macrophage content in the plaque. Treg cells release TGF-β (transforming growth factor β), contributing to Th1 and Th17 response inhibition, as well as enhancing smooth muscle cell proliferation. NK-T cells are potentially involved in the destabilization of atherosclerotic plaques. No exact roles for Th17 and γδ T-cells, which are present in plaque, have yet been established.

2. T-Cells

Studies conducted in the 1980s gave rise to the assumption that adaptive immunity plays an important role in human atherosclerosis. These studies demonstrated broad expression of the MHC-II molecule linked with human leukocyte antigen D (HLA-DR) in human atheroma, alongside a multiplicity of CD3+ T cells [8]. The majority of the T cells found in human atherosclerotic plaques show an effector memory phenotype. Most of them display an activation token and approximately 2/3 are CD4+ T helper cells (Th) carrying the αβ T cell receptor (TCR) [9].

Human atherosclerotic plaques also contain a multitude of CD8+ cytotoxic T cells. Among others, the first cells accumulating in atheroma are T cells, which are fortified with unstable plaques. Since atherosclerotic plaques tend to rupture, this might lead to blood clotting, blood vessel blockage, and acute cardiovascular events [10]. Using monoclonal TCR, such as HLA-DR+ and CD28null T cells, it was found that atherosclerotic lesions in patients, who suffer from acute coronary syndrome (ACS), are not only subjected to macrophage infiltration, but are also infiltrated by oligoclonal T cells, displaying a constant, antigen-driven immune response, and specific activated subsets of T cells [11].

It has already been noted that the identification of the corresponding antigens that are recognized by these cells remains the primary unanswered question. While the plaque inflammatory environment can recruit a normal heterogeneous polyclonal cell population, most of the T cells that are insulated and cloned from human plaques react to oxidized low-density lipoprotein (ox-LDL) or other antigens (i.e., antigenic determinant of the bacterial wall, in an HLA-DR-restricted manner) [12]. In 78% of patients with acute myocardial infarction, the DNA of oral viridian streptococci was found in their blood clots. This indicates that in acute coronary syndrome, the activation of inflammatory pathways is not limited to coronary vessel damage and may also be contained in a thrombus [13].

A fairly large number of antigens can be detected systematically. Therefore, effector T-cell reactions, in most cases, appear in secondary lymphoid organs such as the lymph nodes and spleen. It is generally assumed that activated T cells circulate in atherosclerotic lesions, where the putative antigens are settled. This hypothesis is confirmed by the identification of an elevated number of chemokine receptors participating in the mobilization of T-cell plaques. One such example is the presence of CCR5 and CXCR3 on the surface of CD4+ T cells in patients with CAD [14]. It is noteworthy that the suppression of chemokine receptors (CCR5 and CXCR3) participating in the recruitment of T cells, circulating into the human plaque, weakens the development of atherosclerotic lesions in animal models [15]. Thus, atherogenic T-cell responses are possibly characterized as systemic. This is an argument for studying T-cells both inside the plaque and systemically, by analyzing the profile of T-cells in peripheral blood [11].

2.1. T Cells within Plaque

Atherosclerotic plaques store plenty of CD4+ T cells. In reaction to comprehensive stimulation with antigen, co-stimulators, and peculiar cytokines, T cells separate distinct effectors or Th subsets which are differentiated by the cytokines that they secrete [16]. The main characteristic subsets of Th are (1) Th1, which secretes interferon (IFN)-γ; (2) Th2, which secretes IL-4, IL-5, and IL-13; and (3) Th17, which secretes IL-17 and IL-22. Chronic or secondary exposure to the antigen that presents during atherosclerosis usually occurs in a predominant subset of Treg. Significant arguments point to the importance of Th1 and IFN-γ in atherosclerosis development and inflammation [17].

In human atherosclerotic lesions, the greatest signs of activity are shown by Th1, which is the most common subtype of T cells [18]. For example, they secrete IFN-γ, TNF-α, and IL-2 [19]. It is also important to note that these cells secrete IFN-γ when stimulated by oxidized LDL and LDL. It has been detected that IFN-γ generates the progression and enhances atherosclerotic lesion resistance in various ways, entailing changes in endothelial function, recruitment of inflammatory cells in the lesion, and intervention in the export of cholesterol from cells in the lesion [20]. One of the key cytokines of the Th2 subset, IL-4, significantly suppresses Th1 differentiation and follows IFN-γ secretion, which indicates a potential protective role against atherosclerosis. However, definitive pathological evidence in humans is currently lacking [21]

An interaction between variants near the IL-5 gene locus and coronary artery disease has been shown [22]. This allows us to guess the role of the Th2 subset in modulating CAD development and promotion. A possible neuroprotective effect has been proposed for IL-5, due to its negative correlation with the density of the carotid intima medium (IMT), a marker of subclinical atherosclerosis [23]. It is believed that subsets of Th17 are linked with atherosclerosis [24]. However, their role is unconfirmed. Studies have also shown that the development of IL-17A caused by damaged T cells is linked with inflammation and plaque destabilization [25]. In humans, a subset of CD28null CD4+ T cells is enlarged against a background of inflammatory disease, cytomegalovirus infection, and old age. By producing anti-inflammatory cytokines, which include IFN-γ, these cells demonstrate cytotoxicity [26].

Clonally expanded CD28null CD4 T-cells, which can cause and enhance inflammation, were found in unstable coronary plaques [27]. Most of these cells uniquely identify HSP60 and express members of the TNF receptor family. Such an example is OX40 (CD 131), which can act as an alternative co-stimulating receptor [28]. Moreover, the cells are shown to be regulatory T cells which are stable in the context of in vitro suppression [29]. They also include several CD4+ T cell subsets that can suppress immunity and are essential in self-tolerance and patronage, despite autoimmunity.

About 1–5% of all T cells in atherosclerotic lesions are Tregs, which is less than 25% of their presence in other chronically inflamed tissues [30]. The results of some studies have shown a decrease in the amount of Tregs in unstable plaques [31], implying an atheroprotective role that utilizes their anti-inflammatory function as an immune regulator. Other studies offer a different point of view, indicating Treg content elevation in lesions [32]. This may be due to both an adjustment of the functional state of Tregs and its compensatory elevation to balance the level of T-cell activity in the plaque. 

According to Klingenberg and colleagues’ recent report, an elevation of the amount of Tregs in coronary artery clot aspirate was found in 16 patients with ACS, in contrast to circulating Treg in the same patients or healthy control groups [33]. Remarkably, the T cells demonstrated limited TCN expression; thus, these data prove differential, antigenic trapping of Tregs in the thrombus as a result of ACS [34].

As a rule, in human atherosclerotic plaques, CD8+ cytotoxic T cells are not as common as CD4+. However, in severe lesions, they may comprise no more than 50% of the cells, which indicates a possible role in plaque inflammation and instability [35].

NK-T—Natural Killer T cells—is a precise subset of T cells expressing both the natural killer and T cell markers. Stimulation by lipid antigens, which is mediated via the MHC-I-like CD1d molecule, activates NK-T; this is of additional interest in the study of atherosclerosis [36]. The cells that are contained in the human atheroma exhibit CD1 and NK-T cells, which indicates the proatherogenic role of this subtype of T cells [11].

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