Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E-deficient (apoE-/-) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE-/- mice crossed with CD1d-/- (CD1d-/-apoE-/-) mice exhibited a 25% decrease in lesion size compared with apoE-/- mice. Administration of alpha-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE-/- mice, whereas it did not affect lesion size in apoE-/-CD1d-/- mice. Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.
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PMID:CD1d-dependent activation of NKT cells aggravates atherosclerosis. 1474 94

We have investigated the potential role of CD1d-restricted natural killer T (NKT) cells in the development of atherosclerosis in mice. When fed an atherogenic diet (AD), NKT cell-deficient CD1d(-/-) mice had significantly smaller atherosclerotic lesions than AD-fed C57BL/6 (wild-type [WT]) mice. A significant reduction in atherosclerotic lesions was also demonstrated in AD-fed, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice reconstituted with CD1d(-/-) bone marrow cells compared with the lesions observed in Ldlr(-/-)mice reconstituted with WT marrow cells. In addition, repeated injections of alpha-GalCer or the related glycolipid OCH to apolipoprotein E knockout (apoE(-/-)) mice during the early phase of atherosclerosis significantly enlarged the lesion areas compared with mice injected with vehicle control. However, administering alpha-GalCer to apoE(-/-) mice with established lesions did not significantly increase the lesion area but considerably decreased the collagen content. Atherosclerosis development in either AD-fed WT or apoE(-/-) mice was associated with the presence of Valpha14Jalpha18 transcripts in the atherosclerotic arterial walls, indicating that NKT cells were recruited to these lesions. Thioglycolate-elicited macrophages pulsed with oxidized low-density lipoproteins expressed enhanced CD1d levels and induced NKT cells to produce interferon-gamma, a potentially proatherogenic T-helper 1 (TH1) cytokine. Collectively, we conclude that NKT cells are proatherogenic in mice.
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PMID:Natural killer T cells accelerate atherogenesis in mice. 1511 55

CD1d-restricted natural killer T (NKT) cells are innate lymphocytes that play a regulatory role during an immune response. The identification of alpha-galactosylceramide (alpha-GalCer), a marine sponge-derived glycosphingolipid, as a potent stimulator of NKT cells led many laboratories to investigate the effects of NKT cell activation on the regulation of immune responses. These studies revealed that alpha-GalCer induces rapid and robust cytokine production by NKT cells, secondary activation of a variety of innate and adaptive immune cells, and modulation of Th cell responses. Further, alpha-GalCer influences disease progression in a variety of experimental models of autoimmunity and inflammation in mice, including models for type 1 diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and atherosclerosis. While these studies have raised significant enthusiasm for manipulation of NKT cells as a means of preventing autoimmunity in the clinical setting, there are significant concerns regarding the safety of repeated alpha-GalCer injections in human subjects.
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PMID:Natural killer T cells as targets for immunotherapy of autoimmune diseases. 1518 63

Natural killer T (NKT) cells are a subset of T cells that share properties of natural killer cells and conventional T cells. They are involved in immediate immune responses, tumor rejection, immune surveillance and control of autoimmune diseases. Most NKT cells express both an invariant T cell antigen receptor and the NK cell receptor NK1.1, and are referred to as invariant NKT cells. This invariant T cell receptor is restricted to interactions with glycolipids presented by the non-classical MHC, CD1d. These NKT cells rapidly produce high levels of interleukin (IL)-2, IFN-gamma, TNF-alpha, and IL-4 upon stimulation through their TCR. Most also have cytotoxic activity similar to NK cells. NKT cells are involved in a number of pathological conditions, and have been shown to regulate viral infections in vivo, and control tumor growth. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma.
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PMID:Natural killer T cells: rapid responders controlling immunity and disease. 1583 65

iNKT cells are a unique subset of CD1-restricted T lymphocytes that express T cell receptor (TCR) and some NK receptors. iNKT cells express an invariant TCRalpha chain composed of Valpha14-Jalpha18 segments in mice and Valpha24-Jalpha18 segments in humans associated with TCRbeta chains using a restricted set of Vbeta. iNKT cells recognize glycolipid antigens such as alpha-galactosylceramide (alpha-GC) presented by CD1d, non-pormorphic MHC class I-like molecule, and rapidly secrete large amounts of cytokines including IL-4 and IFN-gamma upon activation. Due to its potent ability to produce a variety of cytokines, iNKT cells are involved in a various kinds of immunoregulation. iNKT cells play a regulatory role in some disease models such as type I diabetes in NOD mice. In contrast, iNKT cells exaggerate the pathogenesis such as arthritis, allergic airway inflammation and atherosclerosis. In addition, iNKT cells are an attractive target for immunotherapy because several different synthetic glycolipid antigens to modify the function of iNKT cells are available. In this review, we examine the potential roles of NKT cells in the pathogenesis of a variety of diseases including autoimmunity , allergy, infection and cancer. Additionally, we discuss on the recent advances in glycolipid therapy for these disease models.
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PMID:[iNKT cells, a friend or a foe for autoimmune disease and allergy?]. 1650

CD1 molecules are a family of major histocompatibility complex (MHC)-related glycoproteins that present lipid and glycolipid antigens to T cells. Interestingly, it has been demonstrated that CD1d-restricted T cells have a pathogenic role in atherosclerosis. Recent studies suggest an association between the cellular machinery that loads CD1 molecules with glycolipids and several key proteins in lipid metabolism. These proteins include the sphingolipid activator proteins (SAPs), microsomal triglyceride transfer protein (MTP) and apolipoprotein E (apoE). MTP and SAPs seem to be crucial for loading CD1d with lipids in the endoplasmic reticulum and endosomal compartments, respectively, whereas apoE facilitates efficient uptake and delivery of exogenous lipid antigens to CD1d in endosomal compartments. These studies reveal new and unexpected relationships between lipid metabolism and antigen presentation by CD1 molecules. Targeting this pathway of immune activation might have therapeutic potential for the treatment of chronic inflammatory diseases.
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PMID:Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. 1665 Oct 26

Natural killer T (NKT) cells have recently been implicated in atherogenesis, primarily for their ability to recognize and respond to lipid antigens. Because the atherosclerotic lesion is characterized by the retention and modification of lipids in the vascular wall, NKT cells may be involved in promoting the local vascular inflammatory response. Here, we investigate the proatherogenic role of NKT cells in an adoptive transfer model of atherosclerosis, using as recipients immune-deficient, atherosclerosis-susceptible RAG1(-/-)LDLR(-/-) mice. The adoptive transfer of an NKT cell-enriched splenocyte population from Valpha14Jalpha18 T-cell receptor transgenic mice resulted in a 73% increase in aortic root lesion area compared with recipients of NKT cell-deficient splenocytes derived from CD1d(-/-) mice after 12 weeks of Western-type diet feeding. The total serum from hypercholesterolemic mice leads to a small but significant activation of Valpha14Jalpha18 T-cell receptor-expressing hybridoma line by dendritic cells that is CD1d-dependent. Therefore, these studies demonstrate that NKT cells are proatherogenic in the absence of exogenous stimulation, and this activity is likely associated with endogenous lipid antigens carried by lipoproteins in the circulation and perhaps also in the atherosclerotic plaque.
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PMID:Characterization of the natural killer T-cell response in an adoptive transfer model of atherosclerosis. 1732 92

Natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens in the context of the MHC class I-related glycoprotein CD1d. Recent studies have identified multiple ways in which NKT cells can become activated during microbial infection. Mechanisms of CD1d-restricted antigen presentation are being unraveled, and a surprising connection has been made to proteins that control lipid metabolism and atherosclerosis. It appears that several microorganisms have developed strategies to interfere with the CD1d antigen-presentation pathway. New studies have also provided important insight into the mechanisms that control effector cell differentiation of NKT cells and have revealed specialized functions of distinct NKT cell subsets. Finally, there is continued enthusiasm for the development of NKT cell-based therapies of human diseases.
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PMID:NKT cells: T lymphocytes with innate effector functions. 1742 48

Recent studies have established that the immune system plays an important role in the development of atherosclerosis. However, its role in regulating the arterial response to mechanical injury is less well studied. Arterial injury is associated with local accumulation of antibodies, and mice lacking functional T and B cells exhibit increased neointima formation, indicating that adaptive immune responses to neoantigens in the damaged tissue modulate the vascular repair process. To study the role of lipid antigen presentation in the arterial response to injury, we analyzed neointima formation in mice deficient in the lipid antigen-presenting molecule CD1d using a carotid collar model. As compared with control mice, neointima formation was reduced by >60% (P<0.01) in CD1d-/- mice. Moreover, carotid injury of wild-type C57BL/6 mice was associated with expansion of CD1d-restricted natural killer T cells in the spleen and accumulation of natural killer T cells in the periadventitial space of injured arteries. The results suggest that presentation of lipid antigens through the CD1d-natural killer T cell pathway modulates vascular repair responses.
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PMID:Involvement of the CD1d-natural killer T cell pathway in neointima formation after vascular injury. 1788 16

Dendtritic cells (DCs) are potent antigen-presenting cells and have an important role in the pathogenesis of atherosclerosis. Recent data suggests oxidized low-density lipoprotein (oxLDL) promotes the transition of a differentiating monocyte to a mature dendritic cell. In this study, we examined whether oxLDL could induce the differentiation of mature macrophages into DCs. After 48 h treatment with oxLDL, RAW264.7 cells increased in cell size and exhibited dendritic morphology. At the optimal oxLDL dose (10 microg/ml), approximately 74% of RAW264.7 cells differentiated into dendritic-like cells. Flow cytometric analysis detected dendritic cell surface markers (CD83, CD40, CD86, MHC Class II, and CD1d), and their expression increased in a dose- and time-dependent manner. Moreover, oxLDL-treated RAW264.7 cells showed functional changes including reduced endocytic activity, increased allostimulatory activity, and IL-12 production. The findings of the present work demonstrate that RAW264.7 cells, incubated with oxLDL, acquire some dendritic cell features.
Atherosclerosis 2008 Aug
PMID:Oxidized low-density lipoprotein induces differentiation of RAW264.7 murine macrophage cell line into dendritic-like cells. 1819 61


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