N-3 polyunsaturated fatty acids differentially enhance B-cell mediated immunity in lean and obese mice

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are bioactive n-3 polyunsaturated fatty acids (PUFAs) in fish oil that exert immunomodulatory effects. The general paradigm suggests n-3 PUFAs exert immunosuppressive effects, however, the role of n-3 PUFAs on B-cell mediated immunity is understudied. We first tested the hypothesis that n-3 PUFAs would suppress B-cell activation and antigen presentation. The functional changes n-3 PUFAs exert on B cells were determined and compared to dendritic cells (DC). Initially, we established n-3 PUFAs increased cytokine production from lipopolysaccharide (LPS) stimulated B cells ex vivo relative to the control. In contrast, n-3 PUFAs decreased DC activation with LPS by reducing cytokine secretion and decreasing surface expression of costimulatory molecules. The antigen presentation assays revealed n-3 PUFAs decreased IL-2 secretion from CD4 p+ T cells when B cells presented antigen compared to the control. In comparison, only CD69 surface expression on CD4 p+ T cells decreased when n-3 PUFA treated DCs presented the antigen compared to the control. Mechanistically, we investigated changes in lipid microdomain clustering on B cells and DCs induced by n-3 PUFAs to determine if the observed functional changes correlated with membrane changes. N-3 PUFAs diminished lipid microdomain clustering on the B-cell surface, but had no effect on DCs. We then relied on a lean and obese murine model to determine if the functional enhancement of B cells observed ex vivo were recapitulated in vivo. N-3 PUFAs increased serum IgM levels compared to controls when stimulated by a T-independent antigen. Additionally, n-3 PUFAs supplemented to an obesogenic diet rescued the decrement in serum IgM levels observed with the obesogenic diet compared to the lean control. Considering the limitations of fish oil, we investigated the effects of the clinically relevant EPA and DHA ethyl esters on antibody production in an obese murine model. EPA and DHA differentially increased ex vivo B-cell activation, in vivo natural serum IgM and cecal IgA compared to controls. Altogether, the data show n-3 PUFAs boost immune responses from B cells, which challenges the current notion about n-3 PUFAs, and has clinical implications for immunocompromised populations, such as the obese.Ph.D

Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects

Acknowledgments We thank Myron Waclawiw of the NHLBI Biostatistics Branch for assistance with the clinical protocol design, Chromadex for supplying NR and matching placebo capsules for the in vivo study and NR powder for the cell culture studies, and an NIH Bench-to-Bedside award for supplemental funding. We additionally thank Dr. Nina Klimova, formerly of the NHLBI, and Dr. Yun-Wei A. Hsu for their support of the metabolomics analysis at the Northwest Metabolomics Research Center of the University of Washington (NIH grant 1S10OD021562-01). We thank and acknowledge the assistance of the NHLBI DNA Sequencing and Genomics Core in performing the RNA library sequencing and Dr. Pradeep Dagur in the NHLBI Flow Cytometry Core for performing the immunophenotyping. Trial registration was as follows: ClinicalTrials.gov: NCT01934660, NCT02812238, and NCT01143454 and NIH Clinical Center blood bank (ClinicalTrials.gov: NCT00001846). This work was supported by the NHLBI Division of Intramural Research (ZIA-HL005102 to M.N.S.), NIH Bench-to-Bedside award (HL-129510-04S1 to M.N.S. and R.T.) and the NIH Office of Dietary Supplements (J.T.), the Spanish Ministry of Science and Innovation (RYC2018-026050-I and PID2019-105665RA-I00 to J.T.), and the UK MRC (MR/P011705/2 and UKDRI-5002 to J.L.G.; MAP UK).Peer reviewedPublisher PD

Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

N-3 polyunsaturated fatty acids differentially enhance B-cell\r\nmediated immunity in lean and obese mice

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are\r\nbioactive n-3 polyunsaturated fatty acids (PUFAs) in fish oil that\r\nexert immunomodulatory effects. The general paradigm suggests n-3\r\nPUFAs exert immunosuppressive effects, however, the role of n-3 PUFAs on B-cell mediated immunity is understudied. We first tested the hypothesis that n-3 PUFAs would suppress B-cell activation and\r\nantigen presentation. The functional changes n-3 PUFAs exert on B\r\ncells were determined and compared to dendritic cells (DC).\r\nInitially, we established n-3 PUFAs increased cytokine production\r\nfrom lipopolysaccharide (LPS) stimulated B cells ex vivo relative to\r\nthe control. In contrast, n-3 PUFAs decreased DC activation with LPS\r\nby reducing cytokine secretion and decreasing surface expression of\r\ncostimulatory molecules. The antigen presentation assays revealed n-3 PUFAs decreased IL-2 secretion from CD4 p+ T cells when B cells\r\npresented antigen compared to the control. In comparison, only CD69\r\nsurface expression on CD4 p+ T cells decreased when n-3 PUFA\r\ntreated DCs presented the antigen compared to the control.\r\nMechanistically, we investigated changes in lipid microdomain\r\nclustering on B cells and DCs induced by n-3 PUFAs to determine if\r\nthe observed functional changes correlated with membrane changes. N-3 PUFAs diminished lipid microdomain clustering on the B-cell surface, but had no effect on DCs. We then relied on a lean and obese murine model to determine if the functional enhancement of B cells observed ex vivo were recapitulated in vivo. N-3 PUFAs increased serum IgM levels compared to controls when stimulated by a T-independent antigen. Additionally, n-3 PUFAs supplemented to an obesogenic diet rescued the decrement in serum IgM levels observed with the obesogenic diet compared to the lean control. Considering the limitations of fish oil, we investigated the effects of the\r\nclinically relevant EPA and DHA ethyl esters on antibody production\r\nin an obese murine model. EPA and DHA differentially increased ex\r\nvivo B-cell activation, in vivo natural serum IgM and cecal IgA\r\ncompared to controls. Altogether, the data show n-3 PUFAs boost\r\nimmune responses from B cells, which challenges the current notion\r\nabout n-3 PUFAs, and has clinical implications for immunocompromised populations, such as the obese

Potential Immunological Links Between Psoriasis and Cardiovascular Disease

Preclinical and clinical research provide strong evidence that chronic, systemic inflammation plays a key role in development and progression of atherosclerosis. Indeed, chronic inflammatory diseases, such as psoriasis, are associated with accelerated atherosclerosis and increased risk of cardiovascular events. Contemporary research has demonstrated plausible mechanistic links between immune cell dysfunction and cardiometabolic disease in psoriasis. In this review, we describe the role of potential common immunological mechanisms underlying both psoriasis and atherogenesis. We primarily discuss innate and adaptive immune cell subsets and their contributions to psoriatic disease and cardiovascular morbidity. Emerging efforts should focus on understanding the interplay among immune cells, adipose tissue, and various biomarkers of immune dysfunction to provide direction for future targeted therapy

Estimated sdLDL-C for predicting high-risk coronary plaque features in psoriasis: a prospective observational study

Abstract Background Psoriasis (PSO) is a skin disorder with systemic inflammation and high coronary artery disease risk. A distinct lipid phenotype occurs in psoriasis, which is characterized by high plasma triglycerides (TGs) with typically normal or even low LDL-C. The extent to which cholesterol on LDL subfractions, such as small dense LDL-C (sdLDL-C), are associated with vulnerable coronary plaque characteristics in PSO remains elusive. Methods A recently developed equation for estimating sdLDL-C from the standard lipid panel was utilized in a PSO cohort (n = 200) with 4-year follow-up of 75 subjects. Coronary plaque burden was assessed by quantitative coronary computed tomography angiography (CCTA). Multivariate regression analyses were used for establishing associations and prognostic value of estimated sdLDL-C. Results Estimated sdLDL-C was positively associated with non-calcified burden (NCB) and fibro-fatty burden (FFB), which remained significant after multivariate adjustment for NCB (β = 0.37; P = 0.050) and LDL-C adjustment for FFB (β = 0.29; P < 0.0001). Of note, total LDL-C calculated by the Friedewald equation was not able to capture these associations in the study cohort. Moreover, in the regression modelling estimated sdLDL-C was significantly predicting necrotic burden progression over 4 years follow-up (P = 0.015), whereas LDL-C did not. Finally, small LDL particles (S-LDLP) and small HDL particles (S-HDLP), along with large and medium TG-rich lipoproteins (TRLPs) had the most significant positive correlation with estimated sdLDL-C. Conclusions Estimated sdLDL-C has a stronger association than LDL-C with high-risk features of coronary atherosclerotic plaques in psoriasis patients. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifiers: NCT0177856

Skin-specific expression of PCSK9 may provide novel link for increased cardiovascular disease risk in psoriasis

Cardiovascular disease (CVD) remains the most common cause of death worldwide and is more prevalent in chronic inflammatory states such as psoriasis. Recently, pro-protein convertase subtilisin/kexin type 9 (PCSK9) has gained attention as a novel therapeutic target in CVD due to its LDL cholesterol lowering capabilities. Therefore, we sought to investigate the relationship between PCSK9 and psoriasis. In patients with psoriasis (n=88), circulating PCSK9 levels are elevated compared to those of healthy volunteers (HV) (n=52) (Psoriasis: 253 ng/mL vs HV: 189 ng/mL, p\u3c0.001) and are positively associated with coronary artery calcium (CAC) scores, beyond traditional cardiovascular risk factors (β =0.38, p\u3c0.004). Similarly, in our mouse model of psoriasis, we observe a 1.7-fold increase (p\u3c0.0001) in circulating PCSK9 compared to that of littermate controls. Moreover, there is a robust relationship between circulating PCSK9 levels and psoriasis skin severity (β =0.92, p\u3c0.001). We also find that although hepatic PCSK9 protein levels are unchanged in the psoriatic mice, low-density lipoprotein receptor (LDLR), the direct target of PCSK9, is significantly decreased at the protein level. Furthermore, we determine that both PCSK9 mRNA and protein levels are elevated in the lesional skin of psoriatic mice compared to those of littermate controls, a finding we confirmed in our psoriatic human skins. Taken together, we postulate that psoriatic lesional skin, specifically the epidermis, is the source for elevated plasma PCSK9, thereby decreasing hepatic LDLR, and suggesting a potential link between psoriasis and cardiovascular disease