Using single-cell technologies to map the human immune system - implications for nephrology.

Advances in single-cell technologies are transforming our understanding of cellular identity. For instance, the application of single-cell RNA sequencing and mass cytometry technologies to the study of immune cell populations in blood, secondary lymphoid organs and the renal tract is helping researchers to map the complex immune landscape within the kidney, define cell ontogeny and understand the relationship of kidney-resident immune cells with their circulating counterparts. These studies also provide insights into the interactions of immune cell populations with neighbouring epithelial and endothelial cells in health, and across a range of kidney diseases and cancer. These data have translational potential and will aid the identification of drug targets and enable better prediction of off-target effects. The application of single-cell technologies to clinical renal biopsy samples, or even cells within urine, will improve diagnostic accuracy and assist with personalized prognostication for patients with various kidney diseases. A comparison of immune cell types in peripheral blood and secondary lymphoid organs in healthy individuals and in patients with systemic autoimmune diseases that affect the kidney will also help to unravel the mechanisms that underpin the breakdown in self-tolerance and propagation of autoimmune responses. Together, these immune cell atlases have the potential to transform nephrology

Disparities in hypertension and cardiovascular disease in blacks: The critical role of medication adherence

Blacks are two to three times as likely as whites to die of preventable heart disease and stroke. Declines in mortality from heart disease have not eliminated racial disparities. Control and effective treatment of hypertension, a leading cause of cardiovascular disease, among blacks is less than in whites and remains a challenge. One of the driving forces behind this racial/ethnic disparity is medication nonadherence whose cause is embedded in social determinants. Eight practical approaches to addressing medication adherence with the potential to attenuate disparities were identified and include: (1) patient engagement strategies, (2) consumer-directed health care, (3) patient portals, (4) smart apps and text messages, (5) digital pillboxes, (6) pharmacist-led engagement, (7) cardiac rehabilitation, and (8) cognitive-based behavior. However, while data suggest that these strategies may improve medication adherence, the effect on ameliorating racial/ethnic disparities is not certain. This review describes the relationship between disparities and medication adherence, which likely plays a role in persistent disparities in cardiovascular morbidity and mortality

Abrupt closure: The CAVEAT I experience

Objectives.This study sought to assess the incidence and consequences of abrupt closure in a series of patients undergoing directional coronary atherectomy versus percutaneous coronary angioplasty.Background.Abrupt closure with coronary angioplasty has been associated with adverse outcome. The results from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) I, a randomized trial of coronary angioplasty versus directional coronary atherectomy, were analyzed.Method.This multicenter trial enrolled 1,012 patients from 1991 to 1992. All records from patients with abrupt closure, which was coded as a discrete complication, were reviewed.Results.Abrupt closure occurred in 60 patients (5.9%) and was associated with a significantly longer hospital stay (median 8 vs. 3 days). Severe proximal target vessel tortuosity was more common in patients with abrupt closure (20.3% vs. 11.6%, p = 0.046), as was preexistent coronary artery thrombus (30.5% vs. 18.3%, p = 0.02). Abrupt closure was associated with a marked increase in subsequent complications (myocardial infarction 46.7% vs. 2.1%, emergency bypass surgery 383% vs. 0.32%, death 33% vs. 0%) and occurred more frequently in the directional coronary atherectomy group (8.0% vs. 3.8%, p = 0.005). In the coronary angioplasty group, the occlusion usually occurred at the target lesion (91%), presumably related to the effects of barotrauma. In the directional coronary atherectomy group, the site of the occlusion was the target lesion in only 58% (p = 0.045). The remaining occlusions related to problems with the technique (guide catheter or nose cone trauma), reflecting the fact that directional coronary atherectomy is a more complex procedure.Conclusions.Abrupt closure remains the principal determinant of adverse outcome after percutaneous procedures for the treatment of coronary artery disease. Although abrupt closure is more common with directional atherectomy than angioplasty, the sequelae are similar

Bostonia: The Boston University Alumni Magazine. Volume 10

Founded in 1900, Bostonia magazine is Boston University's main alumni publication, which covers alumni and student life, as well as university activities, events, and programs

Identification of sex hormone-binding globulin in the human hypothalamus

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin ( SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin. Copyright (c) 2005 S. Karger AG, Base

A model of impaired Langerhans cell maturation associated with HPV induced epithelial hyperplasia.

Funder: National Health and Medical Research CouncilLangerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers

Cytokine absorption during human kidney perfusion reduces delayed graft function–associated inflammatory gene signature

Funder: NIHR Cambridge Biomedical research CentreTransplantation is the optimal treatment for most patients with end‐stage kidney disease but organ shortage is a major challenge. Normothermic machine perfusion (NMP) has been used to recondition marginal organs; however, mechanisms by which NMP might benefit organs are not well understood. Using pairs of human kidneys obtained from the same donor, we compared the effect of NMP with that of cold storage on the global kidney transcriptome. We found that cold storage led to a global reduction in gene expression, including inflammatory pathway genes and those required for energy generation processes, such as oxidative phosphorylation (OXPHOS). In contrast, during NMP, there was marked upregulation OXPHOS genes, but also of a number of immune and inflammatory pathway genes. Using biopsies from kidneys undergoing NMP that were subsequently transplanted, we found that higher inflammatory gene expression occurred in organs with prolonged delayed graft function (DGF). Therefore, we used a hemoadsorber (HA) to remove pro‐inflammatory cytokines. This attenuated inflammatory gene expression increased OXPHOS pathway genes and had potentially clinically important effects in reducing the expression of a DGF‐associated gene signature. Together, our data suggest that adsorption of pro‐inflammatory mediators from the perfusate represents a potential intervention which may improve organ viability

Cytokine absorption during human kidney perfusion reduces delayed graft function–associated inflammatory gene signature

Funder: NIHR Cambridge Biomedical research CentreTransplantation is the optimal treatment for most patients with end‐stage kidney disease but organ shortage is a major challenge. Normothermic machine perfusion (NMP) has been used to recondition marginal organs; however, mechanisms by which NMP might benefit organs are not well understood. Using pairs of human kidneys obtained from the same donor, we compared the effect of NMP with that of cold storage on the global kidney transcriptome. We found that cold storage led to a global reduction in gene expression, including inflammatory pathway genes and those required for energy generation processes, such as oxidative phosphorylation (OXPHOS). In contrast, during NMP, there was marked upregulation OXPHOS genes, but also of a number of immune and inflammatory pathway genes. Using biopsies from kidneys undergoing NMP that were subsequently transplanted, we found that higher inflammatory gene expression occurred in organs with prolonged delayed graft function (DGF). Therefore, we used a hemoadsorber (HA) to remove pro‐inflammatory cytokines. This attenuated inflammatory gene expression increased OXPHOS pathway genes and had potentially clinically important effects in reducing the expression of a DGF‐associated gene signature. Together, our data suggest that adsorption of pro‐inflammatory mediators from the perfusate represents a potential intervention which may improve organ viability

Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis.

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

Reversal of graft-versus-host disease with infusion of autologous bone marrow

Graft-versus-host disease (GVHD) remains a major complication of bone marrow transplantation. This report describes reversal of GVHD by infusion of stored recipient bone marrow following combined liver-bone marrow allotransplantation. Graft-versus-host disease developed at the end of the first postoperative week. The skin involvement progressively spread to approximately 80% of the body surface and was not affected by modification of the immunosuppressive treatment. On the 42nd and 43rd postoperative day 1.23 × 108 and 1.6 × 108 autologous bone marrow cells per kg of recipient body weight were infused. The skin rush began to dramatically improve and resolved within 2 wk from the autologous marrow infusion. Autologous bone marrow storage previous to allogeneic bone marrow transplantation for tolerance induction could constitute a safety net in case of occurrence of GVHD. © 1994