Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by ...single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed ...tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.
In mice, time of day strongly influences lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here we show that feeding, rather than light, ...controls time-of-day dependent LPS sensitivity. Mortality following LPS administration is independent of cytokine production and the clock regulator BMAL1 expressed in myeloid cells. In contrast, deletion of BMAL1 in hepatocytes globally disrupts the transcriptional response to the feeding cycle in the liver and results in constitutively high LPS sensitivity. Using RNAseq and functional validation studies we identify hepatic farnesoid X receptor (FXR) signalling as a BMAL1 and feeding-dependent regulator of LPS susceptibility. These results show that hepatocyte-intrinsic BMAL1 and FXR signalling integrate nutritional cues to regulate survival in response to innate immune stimuli. Understanding hepatic molecular programmes operational in response to these cues could identify novel pathways for targeting to enhance endotoxemia resistance.
To compare the 12-month postoperative quality of vision and visual performance of 2 different refractive rotationally asymmetric multifocal intraocular lenses (IOLs).
Cathedral Eye Clinic, Belfast, ...Northern Ireland, United Kingdom.
Retrospective case series.
Refractive lens exchange (RLE) patients were divided into 2 groups. Group A comprised eyes receiving a Lentis Mplus LS-312 MF30 IOL and Group B, eyes receiving a Lenstec SBL-3 IOL. Refraction, uncorrected (UDVA) and corrected distance visual acuities, uncorrected intermediate (UIVA) and near (UNVA) visual acuities, distance-corrected intermediate and near (DCNVA) visual acuities, and quality of vision were evaluated preoperatively and up to 12 months postoperatively.
Each group comprised 90 eyes. Both groups had a high level of quality of vision 12 months postoperatively with no significant difference between the 2 groups (P = .919). There was no significant between-group difference in mean monocular and binocular UDVA, monocular UIVA, or monocular UNVA. Group B had statistically significantly better mean monocular DCNVA (P = .049), binocular UNVA (P = .011), and binocular DCNVA (P = .035). Group B had a higher percentage of complete spectacle independence.
Both refractive rotationally asymmetric multifocal IOLs provided an excellent level of quality of vision 12 months postoperatively. Both IOL models restored distance, intermediate, and near visual function; however the IOLs in Group B provided better near visual performance.
Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA ...sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
Mutations affecting the apoptosis-inducing function of the Fas/CD95 TNF-family receptor result in autoimmune and lymphoproliferative disease. However, Fas can also costimulate T-cell activation and ...promote tumour cell growth and metastasis. Palmitoylation at a membrane proximal cysteine residue enables Fas to localize to lipid raft microdomains and induce apoptosis in cell lines. Here, we show that a palmitoylation-defective Fas C194V mutant is defective in inducing apoptosis in primary mouse T cells, B cells and dendritic cells, while retaining the ability to enhance naive T-cell differentiation. Despite inability to efficiently induce cell death, the Fas C194V receptor prevents the lymphoaccumulation and autoimmunity that develops in Fas-deficient mice. These findings indicate that induction of apoptosis through Fas is dependent on receptor palmitoylation in primary immune cells, and Fas may prevent autoimmunity by mechanisms other than inducing apoptosis.
Malgré les travaux, aujourd'hui nombreux et pluridisciplinaires, portant sur la santé et l'alimentation de l'enfant dans l'Antiquité, sa consommation d'un lait autre que celui de sa mère ou d'une ...nourrice apparaît souvent comme une évidence qui repose davantage sur les pratiques modernes que sur les témoignages des Anciens (textes, artefacts, images). L'arrivée des laits en poudre, pasteurisés et concentrés, mis au point depuis la seconde moitié du xix e siècle, serait à l'origine de cette erreur. En effet, l'administration de lait à des enfants est très rarement mentionnée dans les traités médicaux anciens et, lorsque c'est le cas, la dose semble plutôt homéopathique et ponctuelle. Les différents spécialistes de l'enfant dans l'Antiquité s'appuient sur le mythe et proposent de voir l'allaitement de Zeus par la chèvre Amalthée comme un modèle aux allaitements de substitutions. Comment dès lors considérer les allaitements mythiques par une biche, la louve romaine ou encore des colombes ? Il était donc urgent de reprendre ce dossier en considérant l'ensemble des sources écrites anciennes et en les confrontant aux résultats des analyses isotopiques - capables aujourd'hui de mettre en évidence l'alimentation et le sevrage des enfants - et des analyses biochimiques révélatrices du contenu des vases biberons antiques.
The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to ...discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system
. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG
and IgA
plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.
Purpose To assess the 3-month and 12-month postoperative visual performance and subjective patient satisfaction after refractive lens exchange (RLE) with implantation of a rotationally asymmetric ...multifocal intraocular lens (IOL). Setting Cathedral Eye Clinic, Belfast, United Kingdom. Design Prospective case series. Methods The refraction, uncorrected (UDVA) and corrected distance visual acuities, uncorrected intermediate (UIVA) and near (UNVA) visual acuities, distance-corrected intermediate and near visual acuities, and a quality of vision (QoV) questionnaire were evaluated 3 months and 12 months after implantation of an SBL-3 IOL. Results The study enrolled 100 eyes of 50 patients. The mean monocular UDVA was −0.02 logarithm of minimum angle of resolution (logMAR) ± 0.12 (SD) 3 months postoperatively and −0.01 ± 0.10 logMAR at 12 months ( P = .393). The mean monocular UIVA was 0.39 ± 0.11 logMAR and 0.41 ± 0.12 logMAR, respectively ( P = .06). The mean monocular UNVA was 0.12 ± 0.13 logMAR and 0.14 ± 0.12 logMAR, respectively ( P = .077). The mean QoV score was 8.26 ± 1.16 at 3 months with a significant improvement at 12 months, at which time the mean QoV score was 8.84 ± 1.08 ( P ≤ .001). Conclusions This asymmetric multifocal IOL provided excellent unaided vision with no significant difference in near, intermediate, and distance vision 3 months and 12 months postoperatively. However, there was a significant improvement in subjective outcomes at the second postoperative assessment, during which patients reported a significantly better QoV score and less blurred vision.
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