Effects of fatty acids on T cell function: role in atherosclerosis

Fatty acids affect the pathogenesis of atherosclerosis, and accumulating evidence shows that fatty acids also modulate T cell functions and processes. This Review summarizes the effects of circulating fatty acids on the metabolism, activation, proliferation and polarization of T cells and how these changes influence the subsequent functions of T cells in the pathogenesis of atherosclerosis.T cells are among the most common cell types present in atherosclerotic plaques and are increasingly being recognized as a central mediator in atherosclerosis development and progression. At the same time, triglycerides and fatty acids have re-emerged as crucial risk factors for atherosclerosis. Triglycerides and fatty acids are important components of the milieu to which the T cell is exposed from the circulation to the plaque, and increasing evidence shows that fatty acids influence T cell function. In this Review, we discuss the effects of fatty acids on four components of the T cell response - metabolism, activation, proliferation and polarization - and the influence of these changes on the pathogenesis of atherosclerosis. We also discuss how quiescent T cells can undergo a type of metabolic reprogramming induced by exposure to fatty acids in the circulation that influences the subsequent functions of T cells after activation, such as in atherosclerotic plaques.Cardiolog

An infinite genus mapping class group and stable cohomology

We exhibit a finitely generated group \M whose rational homology is isomorphic to the rational stable homology of the mapping class group. It is defined as a mapping class group associated to a surface \su of infinite genus, and contains all the pure mapping class groups of compact surfaces of genus $g$ with $n$ boundary components, for any $g\geq 0$ and $n>0$. We construct a representation of \M into the restricted symplectic group ${\rm Sp_{res}}({\cal H}_r)$ of the real Hilbert space generated by the homology classes of non-separating circles on \su, which generalizes the classical symplectic representation of the mapping class groups. Moreover, we show that the first universal Chern class in H^2(\M,\Z) is the pull-back of the Pressley-Segal class on the restricted linear group ${\rm GL_{res}}({\cal H})$ via the inclusion ${\rm Sp_{res}}({\cal H}_r)\subset {\rm GL_{res}}({\cal H})$.Comment: 14p., 8 figures, to appear in Commun.Math.Phy

Toll-Like Receptor induced CD11b and L-selectin response in patients with coronary artery disease

Toll-Like Receptor (TLR) -2 and -4 expression and TLR-induced cytokine response of inflammatory cells are related to atherogenesis and atherosclerotic plaque progression. We examined whether immediate TLR induced changes in CD11b and L-selectin (CD62L) expression are able to discriminate the presence and severity of atherosclerotic disease by exploring single dose whole blood TLR stimulation and detailed dose-response curves. Blood samples were obtained from 125 coronary artery disease (CAD) patients and 28 controls. CD11b and L-selectin expression on CD14+ monocytes was measured after whole blood stimulation with multiple concentrations of the TLR4 ligand LPS (0.01-10 ng/ml) and the TLR2 ligand P3C (0.5-500 ng/ml). Subsequently, dose-response curves were created and the following parameters were calculated: hillslope, EC50, area under the curve (AUC) and delta. These parameters provide information about the maximum response following activation, as well as the minimum trigger required to induce activation and the intensity of the response. CAD patients showed a significantly higher L-selectin, but not CD11b response to TLR ligation than controls after single dose stimulations as well as significant differences in the hillslope and EC50 of the dose-response curves. Within the CAD patient group, dose-response curves of L-selectin showed significant differences in the presence of hypertension, dyslipidemia, coronary occlusion and degree of stenosis, whereas CD11b expression had the strongest discriminating power after single dose stimulation. In conclusion, single dose stimulations and dose-response curves of CD11b and L-selectin expression after TLR stimulation provide diverse but limited information about atherosclerotic disease severity in stable angina patients. However, both single dose stimulation and dose-response curves of LPS-induced L-selectin expression can discriminate between controls and CAD patients.Biopharmaceutic

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U−), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U− versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U− and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+

Retina-arrestin specific CD8+ T cells are not implicated in HLA-A29-positive birdshot chorioretinitis

Background: HLA-A29-positive birdshot chorioretinitis (BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified. Objectives: The identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls. Methods: We performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to determine expansion of antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls. Results: We report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmed in vitro by the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no enhanced antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients. Conclusions: Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG

On the geometrization of matter by exotic smoothness

In this paper we discuss the question how matter may emerge from space. For that purpose we consider the smoothness structure of spacetime as underlying structure for a geometrical model of matter. For a large class of compact 4-manifolds, the elliptic surfaces, one is able to apply the knot surgery of Fintushel and Stern to change the smoothness structure. The influence of this surgery to the Einstein-Hilbert action is discussed. Using the Weierstrass representation, we are able to show that the knotted torus used in knot surgery is represented by a spinor fulfilling the Dirac equation and leading to a mass-less Dirac term in the Einstein-Hilbert action. For sufficient complicated links and knots, there are "connecting tubes" (graph manifolds, torus bundles) which introduce an action term of a gauge field. Both terms are genuinely geometrical and characterized by the mean curvature of the components. We also discuss the gauge group of the theory to be U(1)xSU(2)xSU(3).Comment: 30 pages, 3 figures, svjour style, complete reworking now using Fintushel-Stern knot surgery of elliptic surfaces, discussion of Lorentz metric and global hyperbolicity for exotic 4-manifolds added, final version for publication in Gen. Rel. Grav, small typos errors fixe

Noncommutative Topological Theories of Gravity

The possibility of noncommutative topological gravity arising in the same manner as Yang-Mills theory is explored. We use the Seiberg-Witten map to construct such a theory based on a SL(2,C) complex connection, from which the Euler characteristic and the signature invariant are obtained. This gives us a way towards the description of noncommutative gravitational instantons as well as noncommutative local gravitational anomalies.Comment: 17+1 pages, LaTeX, no figures, some clarifications, comments and references added, style improve

Transcriptome network analysis implicates CX3CR1-positive type 3 dendritic cells in non-infectious uveitis

BACKGROUND: Type I interferons (IFNs) promote the expansion of subsets of CD1c+ conventional dendritic cells (CD1c+ DCs), but the molecular basis of CD1c+ DCs involvement in conditions not associated without elevated type I IFNs remains unclear. METHODS: We analyzed CD1c+ DCs from two cohorts of non-infectious uveitis patients and healthy donors using RNA-sequencing followed by high-dimensional flow cytometry to characterize the CD1c+ DC populations. RESULTS: We report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed toward a gene module with the chemokine receptor CX3CR1 as the key hub gene. We confirmed these results in an independent case-control cohort and show that the disease-associated gene module is not mediated by type I IFNs. An analysis of peripheral blood using flow cytometry revealed that CX3CR1+ DC3s were diminished, whereas CX3CR1- DC3s were not. Stimulated CX3CR1+ DC3s secrete high levels of inflammatory cytokines, including TNF-alpha, and CX3CR1+ DC3 like cells can be detected in inflamed eyes of patients. CONCLUSIONS: These results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. FUNDING: The presented work is supported by UitZicht (project number #2014-4, #2019-10, and #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study

Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases

Background Phosphorylcholine (PC) is an important pro-inflammatory damage-associated molecular pattern. Previous data have shown that natural IgM anti-PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti-inflammatory and anti-atherosclerotic properties.Methods Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys.Results A chimeric anti-PC (PC-mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC-mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti-PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti-PC (PC-mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC-mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC-mAb antibodies resulted in selection of PC-mAb X19-A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys.Conclusions Chimeric anti-PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC-mAb represents a novel strategy for cardiovascular disease prevention.Cardiolog