T-cell activation is characteristic during the development of atherosclerosis. While overall T-cell responses have been implicated in disease acceleration, regulatory T cells (Tregs) exhibit ...atheroprotective effects. The expression of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which catalyzes the degradation of tryptophan (Trp) along the kynurenine pathway, has been implicated in the induction and expansion of Treg populations. Hence, Tregs can reciprocally promote IDO1 expression in dendritic cells (DCs)
reverse signaling mechanisms during antigen presentation. In this study, we hypothesize that triggering the "Treg/IDO axis" in the artery wall is atheroprotective. We show that apolipoprotein B100-pulsed tumor growth factor beta 2-treated tolerogenic DCs promote
FoxP3
Treg expansion
. This local increase in Treg numbers is associated with increased vascular IDO1 expression and a robust reduction in the atherosclerotic burden. Using human primary cell cultures, we show for the first time that IDO1 expression and activity can be regulated by cytotoxic T-lymphocyte associated protein-4, which is a constitutive molecule expressed and secreted by Tregs, in smooth muscle cells, endothelial cells, and macrophages. Altogether, our data suggest that Tregs and IDO1-mediated Trp metabolism can mutually regulate one another in the vessel wall to promote vascular tolerance mechanisms that limit inflammation and atherosclerosis.
Atherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic vascular inflammation with an autoimmune response to ...low-density lipoprotein components.
To dampen the inflammatory component of atherosclerosis, we injected hypercholesterolemic huB100(tg) × Ldlr(-/-) mice (mice transgenic for human apolipoprotein B100 ApoB100 and deficient for the low-density lipoprotein receptor) intravenously with dendritic cells (DCs) that had been pulsed with the low-density lipoprotein protein ApoB100 in combination with the immunosuppressive cytokine interleukin-10. DCs treated with ApoB100 and interleukin-10 reduced proliferation of effector T cells, inhibited production of interferon-γ, and increased de novo generation of regulatory T cells in vitro. Spleen cells from mice treated with DCs plus ApoB100 plus interleukin-10 showed diminished proliferative responses to ApoB100 and significantly dampened T-helper 1 and 2 immunity to ApoB100. Spleen CD4(+) T cells from these mice suppressed activation of ApoB100-reactive T cells in a manner characteristic of regulatory T cells, and mRNA analysis of lymphoid organs showed induction of transcripts characteristic of these cells. Treatment of huB100(tg) × Ldlr(-/-) mice with ApoB100-pulsed tolerogenic DCs led to a significant (70%) reduction of atherosclerotic lesions in the aorta, with decreased CD4(+) T-cell infiltration and signs of reduced systemic inflammation.
Tolerogenic DCs pulsed with ApoB100 reduced the autoimmune response against low-density lipoprotein and may represent a novel possibility for treatment or prevention of atherosclerosis.
T cell-based therapies for atherosclerosis Ketelhuth, Daniel F J; Gisterå, Anton; Johansson, Daniel K ...
Current pharmaceutical design,
10/2013, Volume:
19, Issue:
33
Journal Article
Peer reviewed
Cardiovascular diseases (CVDs), largely due to atherosclerosis, are the major causes of death in today's world. Atherosclerosis is a chronic inflammatory condition initiated by retention and ...accumulation of cholesterol-containing lipoproteins, in particular low-density lipoprotein (LDL), in the artery wall. This initiates pathological responses of immune cells that lead to atherosclerotic plaque formation. T cells are present during all stages of the disease, and play an essential role in the initiation and progression of plaques. Whereas most T effector cell responses have been suggested to aggravate atherosclerosis, regulatory T cells (Tregs) have been shown to limit inflammation and inhibit the formation of lesions. In addition to their effects on the local pathological process, T cells and their released mediators modulate systemic lipid metabolism and can increase risk of CVDs. Such knowledge on the pathological and protective function of these cells has led to significant advances in the field. This review examines experimental and pre-clinical studies approaching the manipulation of cellular immunity in atherosclerosis. Modulation of T cells responses by vaccination, antibody therapies, dendritic cell based-therapies, and using amino acid-derived metabolites have shown benefits against atherosclerotic plaque progression in animal models. The clinical benefit of T cell-based therapies in humans still requires further investigation.
Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic ...inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe
mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.
The V1 (VHS107.1.42) immunoglobulin heavy chain gene is thought to be critical in producing IgM natural antibodies of the T15-idiotype that protect against both atherosclerosis and infection from ...Streptococcus pneumoniae. Our aim was to determine whether genetic loss of the V1 gene increased atherosclerotic plaque burden in vivo because of a reduction in the T15-idiotype or other atheroprotective antibodies.
We crossed VHS107.1.42-deficient mice with the atherosclerosis-prone Apoe(-/-) and Ldlr(-/-) strains. Although these double knockout strains manifested no defects in B-cell development, we did observe a substantial reduction in early immune responses against phosphocholine after immunization. However, the titers of plasma antibodies reacting against defined atherosclerotic antigens such as oxidized low-density lipoprotein, as well as the T15-idiotype, were unaffected by loss of the VHS107.1.42 gene in hypercholesterolemic mice. Furthermore, we observed no increase in atherosclerotic lesion formation, either within the aortic arch or aortic root. Robust deposition of IgM within atherosclerotic plaques could also be readily observed in both control and experimental mice.
Our data indicate that IgM-dependent protection against atherosclerosis is unlikely to be dependent on antibodies that use the VHS107.1.42 gene, in contrast to the acute immune response conferred by this heavy chain in the response to phosphocholine and in providing resistance against lethal S pneumoniae infection.
Abstract
Objectives
Although personality change is typically considered a symptom of dementia, some studies suggest that personality change may be an early indication of dementia. One prospective ...study found increases in neuroticism preceding dementia diagnosis (Yoneda, T., Rush, J., Berg, A. I., Johansson, B., & Piccinin, A. M. (2017). Trajectories of personality traits preceding dementia diagnosis. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 72, 922–931. doi:10.1093/geronb/gbw006). This study extends this research by examining trajectories of personality traits in additional longitudinal studies of aging.
Methods
Three independent series of latent growth curve models were fitted to data from the Longitudinal Aging Study Amsterdam and Einstein Aging Study to estimate trajectories of personality traits in individuals with incident dementia diagnosis (total N = 210), in individuals with incident Mild Cognitive Impairment (N = 135), and in individuals who did not receive a diagnosis during follow-up periods (total N = 1740).
Results
Controlling for sex, age, education, depressive symptoms, and the interaction between age and education, growth curve analyses consistently revealed significant linear increases in neuroticism preceding dementia diagnosis in both datasets and in individuals with mild cognitive impairment. Analyses examining individuals without a diagnosis revealed nonsignificant change in neuroticism overtime.
Discussion
Replication of our previous work in 2 additional datasets provides compelling evidence that increases in neuroticism may be early indication of dementia, which can facilitate development of screening assessments.
In this study we conceptualise how a capability approach could be used for analysing the conditions for preserving security of energy supply. We derive a concept, ‘energy system capability’, to ...describe how well the system is designed for this purpose. Based on a socio-technical systems perspective, we suggest that this capability is composed of five categories of ‘building blocks’: technical structures, natural resources, economic resources, institutions and actors. The configurations of these building blocks and the interactions between them provide the system with a certain level of reliability, robustness, flexibility, adaptivity and capacity for swift recovery and handling. These building blocks and system characteristics form various capabilities along the event chain (prevent, withstand, recover, handle, prepare, detect etc.) that together build the energy system capability.
•We conceptualise a capability approach for analysing the risks of energy systems.•We suggest that Energy systems capability is built by five types of building blocks.•They are technologies, natural and economic resources, institutions and actors.•The blocks build the primary capabilities to prevent, withstand, recover and handle.
Energy security has gained increasing prominence on the EU political agenda, but is often framed narrowly, in terms of import dependency or security of supply. In this paper we screen and scope out a ...more comprehensive suite of energy security aspects to be considered when assessing low-carbon energy scenarios and apply it using the EU Energy Roadmap as an example. Availability and affordability issues as well as security of demand matters and geopolitical security aspects are identified and discussed. External factors, e.g., future international climate treaties and international relations, are important for some energy security outcomes. A broader framing of energy security together with structured assessments on the security implications of energy transitions would benefit future EU energy policy.
•Framing the energy security concept narrowly increases the risk of incoherent policy.•External factors are often decisive for future energy security outcomes.•A framework for nuanced security assessment of low-carbon scenarios is suggested.•The EU Energy Roadmap is used as assessment example.•More diverse energy scenarios might facilitate relevant and integrated assessments.
The ~31-km-wide Hiawatha structure, located beneath Hiawatha Glacier in northwestern Greenland, has been proposed as an impact structure that may have formed after the Pleistocene inception of the ...Greenland Ice Sheet. To date the structure, we conducted Ar-40/Ar-39 analyses on glaciofluvial sand and U–Pb analyses on zircon separated from glaciofluvial pebbles of impact melt rock, all sampled immediately downstream of Hiawatha Glacier. Unshocked zircon in the impact melt rocks dates to ~1915 Ma, consistent with felsic intrusions found in local bedrock. The Ar-40/Ar-39 data indicate Late Paleocene resetting and shocked zircon dates to 57.99 ± 0.54 Ma, which we interpret as the impact age. Consequently, the Hiawatha impact structure significantly predates Pleistocene glaciation and is unrelated to either the Paleocene-Eocene Thermal Maximum or flood basalt volcanism in east Greenland. However, it was contemporaneous with the Paleocene Carbon Isotope Maximum, although the impact’s exact paleoenvironmental and climatic significance await further investigation.
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