Role of Immune System in Atherogenesis
Atherosclerosis is a complex, chronic inflammatory disease of the arterial wall. Its underlying pathophysiologic mechanisms involve endothelial dysfunction, infiltration of atherogenic lipoproteins into the subendothelial layer with subsequent retention and oxidation, and activation of an immunoinflammatory gene program resulting in recruitment, retention, and activation of immunoinflammatory cells. The components of the immune system in the plaques include activated immune cells of both innate and adaptive immunity, immune-modulating cytokines, complement, and immunoglobulins. ,
According to the classic paradigm, the immune system consists of innate and adaptive immunity. Innate immunity is the first response to injury and offending organisms, does not require prior antigen exposure, and lacks immunologic memory. It is rapidly activated and relatively nonspecific. One of the important components of the innate immune response uses a small number of germline-encoded receptors, Toll-like receptors (TLRs), recognizing common molecular patterns shared by various infectious and noninfectious pathogens (pathogen-associated molecular patterns [PAMPs]). These PAMPs include lipopolysaccharides (LPSs) in gram-negative bacteria and unmethylated CpG DNA motif and lack immune memory. The innate immune response involves effector cells such as the macrophages, natural killer cells, mast cells, and natural antibodies produced by B-1 cells, which are a specific subset of B cells. In contrast to innate immunity, adaptive immunity involves specific antigen exposure and recognition of highly specific epitopes, is slower to respond, and includes effector mechanisms such as T and B cells, antibodies, antibody-dependent cell-mediated cytotoxicity, cytokines, and chemokines. Although each type of immunity has its distinctive properties, such distinction is somewhat artificial because emerging experimental evidence indicates that innate and adaptive immunity are intricately linked and should be viewed as a continuum.
Immune Responses
Both innate and adaptive immune responses have been shown to promote or inhibit atherosclerosis in experimental models, with likely parallel implications in human atherosclerosis.
Atheropromoting Immune Response
Most of our knowledge of atherogenesis has been gained from observations in experimental animal studies. CD4+ T cells have been shown to play a pivotal role in atherogenesis. Activated CD4+ T cells and major histocompatibility complex (MHC)-II antigens are abundantly present in atherosclerotic plaques, suggesting their potential role in atherogenesis. Adoptive transfer of naïve CD4+ T cells or CD4+ T cells from malondialdehyde (MDA)–low-density lipoprotein (LDL) immunized donors into hypercholesterolemic immunodeficient mice results in an increase in atherosclerosis, further strengthening the notion that CD4+ T-cell–mediated adaptive immunity is proatherogenic. , In contrast, the role of CD8+ T cells in atherogenesis is currently unclear. Natural killer (NK) T cells, a subset of T cells bearing markers of NK cells, also participate in atherogenesis. NK T cells recognize lipid antigens presented by the class I–like molecule CD1d. Deficiency of CD1d molecule results in a reduction of atherogenesis, whereas activation of NK T cells via CD1d by α-galactosylceramide worsens atherosclerosis in experimental animals. Adoptive transfer of NK T-cell–enriched splenocytes into immunodeficient, atherosclerosis-prone RAG1 (−/−)/LDL (−/−) mice resulted in increased atherogenesis when compared with the recipients transferred with NK T-cell–deficient splenocytes.
TLRs are a group of pattern recognition receptors that orchestrate an innate proinflammatory immune response. Macrophages and endothelial cells in murine and human atherosclerotic lesions express TLR4 and TLR2. , Genetic deletion of TLR4 or its downstream signaling adaptor molecule (myeloid differentiation factor 88, Myd-88) reduces atherosclerosis, plaque inflammation, and circulating inflammatory proteins in mice, , indicating the proatherogenic role of the TLR4- and Myd-88-mediated innate immune signaling pathway.
NK cells, another key component of innate immunity, are also present in atherosclerotic lesions. Deficiency of functional NK cells significantly reduces atherosclerotic lesion size in experimental animals, further implicating innate immunity in proatherogenic effects.
Atheroprotective Immune Response
There is abundant experimental evidence to support that certain aspects of the immune response have atheroprotective effects. Splenectomy has been shown to aggravate atherosclerotic lesions in apolipoprotein E (apo E) (−/−) mice; adoptive transfer of B cells from donor mice to splenectomized recipient ameliorates such increases in atherosclerosis. This establishes the atheroprotective role of splenic B cells in atherogenesis. Such a role of B cells was confirmed by data showing that B-cell deficiency in LDL receptor (LDLR) (−/−) mice was associated with a reduced level of antioxidized LDL antibody and a concomitant increase in the aortic atherosclerotic lesion area. A subset of CD4+ T cells that constitutively express CD25 is called regulatory T cells (Treg cells). These endogenous Treg cells are mostly produced by the normal thymus and are not induced from naïve T cells after antigen exposure in the periphery. Their major function is to maintain immunologic self-tolerance actively by blocking T-cell activation in response to an antigen. In experimental animals, deficiency of Treg cells has been shown to increase atherosclerosis, whereas promoting Treg cell function in vivo attenuates atherosclerosis. , It has been observed that the number of Treg cells and their ability to inhibit the proliferation of responder T cells were significantly hampered, respectively, in patients with acute coronary syndrome.
Activation of a humoral innate B-1 cell–mediated response to a phosphorylcholine head group exposed during LDL oxidation has been shown to reduce atherosclerosis in experimental models further demonstrating the atheroprotective aspects of the immune system. A series of experimental studies has also shown that immunization with various LDL-related antigens (e.g., MDA-modified LDL, copper oxidized LDL, and apo B–related peptide epitopes) consistently reduces atherosclerosis in rabbits and mice.
Taken these together, it is apparent that an individual immune component could be atherogenic or atheroprotective ( Box 8-1 and Fig. 8-1 ). The overall atherogenic process is likely to be the result of complex interplay and balance among these individual components and other atherogenic risk factors, such as hyperlipidemia, hypertension, diabetes mellitus, age, and cigarette smoking. Although information about the role of individual immune components in atherogenesis is increasing, their exact pathophysiologic role in acute coronary syndrome remains to be defined fully.
BOX 8-1 
Evidence of Immune System Activation During Acute Coronary Syndrome
The hallmark of acute coronary syndrome is the disruption of an unstable atherosclerotic plaque leading to thrombosis superimposed on the plaque leading to critical coronary luminal obstruction ( Fig. 8-2 ). Rupture-prone vulnerable plaques contain a large lipid core with a thin fibrous cap, increased matrix-degrading metalloproteinases (MMPs), increased neovascularity, and inflammatory cell infiltration localized at the shoulder regions of the plaques in the thin collagen–depleted fibrous cap and in the adventitia. Depletion of collagen from the fibrous cap, a prerequisite for plaque disruption, can result from excessive MMP-mediated collagen breakdown and/or depletion of collagen-synthesizing smooth muscle cells. Although the exact trigger for plaque rupture is not known, numerous observations have demonstrated that activated immune components exist in the unstable plaques. T cells, predominantly CD4+ T cells, and related cytokines, such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are present more abundantly in unstable plaques when compared with stable plaques. Such inflamed plaques contain higher amount of activated dendritic cells to produce T-cell recruiting chemokines (CCL19 and CCL21) and these dendritic cells colocalize with activated T cells.
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