Cross-Presentation of Cell-Associated Antigens by Mouse Splenic Dendritic Cell Populations

Cross-presentation of cell-associated antigens (Ag) plays an important role in the induction of anti-tumor responses, autoimmune diseases, and transplant rejection. While several dendritic cell (DC) populations can induce pro-inflammatory CD8+ T cell responses to cell-associated Ag during infection, in the absence of infection, cross-priming of naïve CD8+ T cells is highly restricted. Comparison of the main splenic DC populations in mice – including the classic, cross-presenting CD8α DC and the recently described merocytic DC (mcDC) – reveals that cross-priming DCs display a distinct phenotype in cell-associated Ag uptake, endosomal/lysosomal trafficking, lysosomal acidification, and Ag persistence compared to non-cross-priming DC populations. Although the CD8α DC and mcDC subsets utilize similar processing pathways to cross-present cell-associated Ag, cross-priming by CD8α DCs is associated with IL-12 production, while the superior priming of the mcDC is critically dependent on type I IFN production. This discussion illustrates how subtle differences in internal processing pathways and their signaling sequelae significantly affect the duration of Ag cross-presentation and cytokine production by DCs, thereby shaping the ensuing CD8+ T cell response

Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans

Increased prevalence of advanced liver fibrosis in patients with psoriasis: A cross-sectional analysis from the rotterdam study

Prevalence of non-alcoholic fatty liver disease is increased in patients with psoriasis. However, it is not known how liver fibrosis correlates with psoriasis. This study investigated the association between psoriasis and liver fibrosis compared with participants without psoriasis within the population-based Rotterdam Study. All participants were screened for liver fibrosis using transient elastography. Liver stiffness > 9.5 kPa suggested advanced liver fibrosis. Psoriasis was identified using a validated algorithm. A total of 1,535 participants were included (mean age ± standard deviation 70.5 ± 7.9 years; 50.8% female; median body mass index 26.4 kg/ m2 (interquartile range 24.2–28.9)) of whom 74 (4.7%) had psoriasis. Prevalence of advanced liver fibrosis was 8.1% in psoriasis patients compared with 3.6% in the reference group (p = 0.05). The risk of advanced liver fibrosis in psoriasis patients remained comparable after adjustment for demographics, lifestyle characteristics and laboratory findings (odds ratio 2.57 (95% confidence interval 1.00–6.63). This study suggests that elderly people with psoriasis are twice as likely to have advanced liver fibrosis irrespective of common risk factors

Применение оксидно-рутениевых титановых анодов, модифицированных сурьмой для очистки воды

Rationale: Unlike conventional dendritic cells, plasmacytoid DCs (PDC) are poor in antigen presentation and critical for type 1 interferon response. Though proposed to be present in human atherosclerotic lesions, their role in atherosclerosis remains elusive. Objective: To investigate the role of PDC in atherosclerosis. Methods and Results: We show that PDC are scarcely present in human atherosclerotic lesions and almost absent in mouse plaques. Surprisingly, PDC depletion by 120G8 mAb administration was seen to promote plaque T-cell accumulation and exacerbate lesion development and progression in LDLr(-/-) mice. PDC depletion was accompanied by increased CD4(+) T-cell proliferation, interferon-gamma expression by splenic T cells, and plasma interferon-gamma levels. Lymphoid tissue PDC from atherosclerotic mice showed increased indoleamine 2,3-dioxygenase (IDO) expression and IDO blockage abrogated the PDC suppressive effect on T-cell proliferation. Conclusions: Our data reveal a protective role for PDC in atherosclerosis, possibly by dampening T-cell proliferation and activity in peripheral lymphoid tissue, rendering PDC an interesting target for future therapeutic interventions. (Circ Res. 2011;109:1387-1395.

Combining MRI and clinical data to detect high relapse risk after the first episode of psychosis.

Detecting patients at high relapse risk after the first episode of psychosis (HRR-FEP) could help the clinician adjust the preventive treatment. To develop a tool to detect patients at HRR using their baseline clinical and structural MRI, we followed 227 patients with FEP for 18-24 months and applied MRIPredict. We previously optimized the MRI-based machine-learning parameters (combining unmodulated and modulated gray and white matter and using voxel-based ensemble) in two independent datasets. Patients estimated to be at HRR-FEP showed a substantially increased risk of relapse (hazard ratio=4.58, P<0.05). Accuracy was poorer when we only used clinical or MRI data. We thus show the potential of combining clinical and MRI data to detect which individuals are more likely to relapse, who may benefit from increased frequency of visits, and which are unlikely, who may be currently receiving unnecessary prophylactic treatments. We also provide an updated version of the MRIPredict software.We would also like to thank the Instituto de Salud Carlos III, the Spanish Ministry of Science, Innovation, and Universities, the European Regional Development Fund (ERDF/FEDER), European Social Fund, “Investing in your future”, “A way of making Europe” (projects: PI08/0208, PI11/00325, PI14/00292, PI14/00612, PI14/01148, PI14/01151, PI17/00481, PI17/01997, PI18/01055, PI19/00394, PI19/00766, PI20/00721, PI20/01342, and PI21/00713; contracts: CP14/00041, JR19/00024, CPII19/00009, and CD20/00177); CERCA Program; Catalan Government, the Secretariat of Universities and Research of the Department of Enterprise and Knowledge (2017SGR01271, 2017SGR1355, and 2017SGR1365); Institut de Neurociències, Universitat de Barcelona; Madrid Regional Government (B2017/BMD-3740 AGES-CM-2); the University of the Basque Country (2019 321218ELCY GIC18/107); the Basque Government (2017111104); European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. The funding organizations played no role in the study design, data collection, analysis, or manuscript approval

Ablation of CD8 alpha(+) dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice

Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr(-/-) mice were transplanted with batf3(-/-) or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8 alpha(+) DC numbers in spleen and lymph nodes (>80%;P < 0, 001). Concordantly, batf3(-/-) chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3(-/-) chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3(-/-) chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3(-/-) chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8 alpha(+) DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8 alpha(+) DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability

The quality of service and the satisfaction of the users of the Local Educational Management Unit 01 - San Juan de Miraflores

La investigación tuvo como objetivo principal calcular el nivel de relación entre la calidad de servicio y la satisfacción de los usuarios de la UGEL 01 de San Juan de Miraflores. Ha sido una tesis de enfoque cuantitativo y diseño descriptivo correlacional. Se aplicó a los docentes de la UGEL que estaban haciendo algún trámite y que en forma voluntaria participaron contestando los cuestionarios. Se utilizaron dos encuestas tipo Likert. El trabajo concluyó que existe una correlación alta entre las variables, siendo r de Pearson igual a 0,7145. Además, el nivel de la calidad de servicio era buena y la mayoría de los usuarios se sentían muy satisfechos con el servicio.The research had as the principal objective to calculate the level of relationship between the service quality and user satisfaction for the UGEL 01 from San Juan de Miraflores. The thesis focus has been the quantitative and correlational descriptive design. Two questionnaires were applied to UGEL teachers who were doing any document procedure and they voluntarily answered the questionnaires. Two surveys Likert type were used. The conclusion was that exists a high correlation between the variables, being r of Pearson equals to 0,7145. Besides, the level of service quality was good and the most of the teachers were very satisfied by the service

Residential traffic exposure and pregnancy-related outcomes: a prospective birth cohort study

Background. The effects of ambient air pollution on pregnancy outcomes are under debate. Previous studies have used different air pollution exposure assessment methods. The considerable traffic-related intra-urban spatial variation needs to be considered in exposure assessment. Residential proximity to traffic is a proxy for traffic-related exposures that takes into account within-city contrasts. Methods. We investigated the association between residential proximity to traffic and various birth and pregnancy outcomes in 7,339 pregnant women and their children participating in a population-based cohort study. Residential proximity to traffic was defined as 1) distance-weighted traffic density in a 150 meter radius, and 2) proximity to a major road. We estimated associations of these exposures with birth weight, and with the risks of preterm birth and small size for gestational age at birth. Additionally, we examined associations with pregnancy-induced hypertension, (pre)eclampsia, and gestational diabetes. Results. There was considerable variation in distance-weighted traffic density. Almost fifteen percent of the participants lived within 50 m of a major road. Residential proximity to traffic was not associated with birth and pregnancy outcomes in the main analysis and in various sensitivity analyses. Conclusions. Mothers exposed to residential traffic had no higher risk of adverse birth outcomes or pregnancy complications in this study. Future studies may be refined by taking both temporal and spatial variation in air pollution exposure into account