Immune Mechanisms in Atherosclerosis, Especially in Diabetes Type 2

Abstract

Atherosclerosis and ensuing cardiovascular disease (CVD) are major complications of diabetes type 2. Atherosclerosis is a chronic inflammatory condition involving immunocompetent cells of different types present in the lesions. Even though inflammation and immune activation may be more pronounced in atherosclerosis in diabetes type 2, there does not appear to be any major differences between diabetics and non-diabetics. Similar factors are thus implicated in atherosclerosis-associated immune activation in both groups. The cause of immune activation is not known and different mutually non-exclusive possibilities exist. Oxidized and/or enzymatically modified forms of low-density lipoprotein (OxLDL) and dead cells are present in atherosclerotic plaques. OxLDL could play a role, being pro-inflammatory and immunostimulatory as it activates T-cells and is cytotoxic at higher concentrations. Inflammatory phospholipids in OxLDL are implicated, with phosphorylcholine (PC) as one of the exposed antigens. Antibodies against PC (anti-PC) are anti-atherogenic in mouse studies, and anti-PC is negatively associated with development of atherosclerosis and CVD in humans. Bacteria and virus have been discussed as potential causes of immune activation, but it has been difficult to find direct evidence supporting this hypothesis, and antibiotic trials in humans have been negative or inconclusive. Heat shock proteins (HSP) could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include cytokines such as interleukin 1β (IL-1β), tumor necrosis factor (TNF), and also lipid mediators as leukotrienes. In addition, in diabetes, hyperglycemia and oxidative stress appear to accelerate the development of atherosclerosis, one mechanism could be via promotion of immune reactions. To prove that immune reactions are causative of atherosclerosis and CVD, further studies with immune-modulatory treatments are needed.

Inflammatory markers and cardiometabolic diseases

“…8,29 Even though inflammation and immune activation may be more pronounced in atherosclerosis in T2DM, no major differences could be detected between diabetic and nondiabetic individuals. 29 The cause of immune activation is not known and different mutually non-exclusive possibilities exist.…”

Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice

“…Immune dysfunction-induced pancreatic β-cell apoptosis is crucially involved in the pathogenesis of this disease (2). A variety of immune cells and cytokines are involved in this process (3). Among them, T helper (Th) cell subpopulations imbalance has attracted significant attention (4).…”

The role of the immune system in the pathogenesis of diabetic complications

“…The pathogenesis of these complications is multifactorial, but there is strong evidence implicating chronic, smoldering, and inflammation as a main pathogenic event in the development of diabetic complications (1). Although the mechanisms responsible for vascular inflammation in diabetes are similar to those involved in vascular disease in non-diabetics (2), chronic hyperglycemia and dysregulated immune responses in diabetes are responsible for the activation of inflammatory circuits, inducing oxidative stress and promoting insulin resistance (1, 3), thus creating conditions that lead to the development of diabetes and diabetic complications. Changes in gene expression associated with diabetes like increased ICAM-1 expression (4) may also play a role in inducing inflammation and the development of diabetic complications.…”

“…Advanced glycation end-products (AGE)-modified LDL plays an important pathogenic role through its interactions with RAGE and angiotensin receptors (3). Oxidized LDL activates T cells, leading to enhanced inflammation through the release of macrophage-activating mediators (2). The adaptive humoral autoimmune response to modified forms of LDL is well characterized and strong evidence exists linking the formation of immune complexes (IC) involving modified forms of LDL and the corresponding autoantibodies with the development of diabetic complications.…”

“…The most immunogenic and better characterized are modified lysine epitopes, but oxidized phospholipids are also exposed to the immune system (2). Phosphorylcholine is a particularly interesting epitope because the resulting antibodies appear to protect against the development of atherosclerosis (2). Because phospholipid autoantibodies are usually of the IgM isotype, their protective effect could be a result of the reduced inflammatory potential of IgM IC, which cannot activate phagocytic cells through Fc receptors.…”