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Wednesday, February 28, 2018
This Months Highlights
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The Era of Human Developmental Nephrology
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Evolution and Kidney Development: A Rosetta Stone for Nephrology
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The Benefits of Tubular Proteinuria: An Evolutionary Perspective
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The UMOD Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease
The identification of genetic factors associated with kidney disease has the potential to provide critical insights into disease mechanisms. Genome-wide association studies have uncovered genomic regions associated with renal function metrics and risk of CKD. UMOD is among the most outstanding loci associated with CKD in the general population, because it has a large effect on eGFR and CKD risk that is consistent across different ethnic groups. The relevance of UMOD for CKD is clear, because the encoded protein, uromodulin (Tamm–Horsfall protein), is exclusively produced by the kidney tubule and has specific biochemical properties that mediate important functions in the kidney and urine. Rare mutations in UMOD are the major cause of autosomal dominant tubulointerstitial kidney disease, a condition that leads to CKD and ESRD. In this brief review, we use the UMOD paradigm to describe how population genetic studies can yield insight into the pathogenesis and prognosis of kidney diseases.
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Salt-Losing Tubulopathies in Children: Whats New, Whats Controversial?
Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle’s loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.
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Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives
The unique contributions of memory B cells and plasma cells in kidney diseases remain unclear. In this review, we evaluate the clinical experience with treatments directed at B cells, such as rituximab, and at plasma cells, such as proteasome inhibition, to shed light on the role of these two B lineage compartments in glomerular diseases. Specifically, analysis of these targeted interventions in diseases such as ANCA-associated vasculitis, SLE, and antibody-mediated transplant rejection permits insight into the pathogenetic effect of these cells. Notwithstanding the limitations of preclinical models and clinical studies (heterogeneous populations, among others), the data suggest that memory B and plasma cells represent two engines of autoimmunity, with variable involvement in these diseases. Whereas memory B cells and plasma cells appear to be key in ANCA-associated vasculitis and antibody-mediated transplant rejection, respectively, SLE seems likely to be driven by both autoimmune compartments. These conclusions have implications for the future development of targeted therapeutics in immune-mediated renal disease.
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Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach
FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.
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Reciprocal Spatiotemporally Controlled Apoptosis Regulates Wolffian Duct Cloaca Fusion
The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLC docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo. Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT.
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Conserved and Divergent Features of Human and Mouse Kidney Organogenesis
Human kidney function is underpinned by approximately 1,000,000 nephrons, although the number varies substantially, and low nephron number is linked to disease. Human kidney development initiates around 4 weeks of gestation and ends around 34–37 weeks of gestation. Over this period, a reiterative inductive process establishes the nephron complement. Studies have provided insightful anatomic descriptions of human kidney development, but the limited histologic views are not readily accessible to a broad audience. In this first paper in a series providing comprehensive insight into human kidney formation, we examined human kidney development in 135 anonymously donated human kidney specimens. We documented kidney development at a macroscopic and cellular level through histologic analysis, RNA in situ hybridization, immunofluorescence studies, and transcriptional profiling, contrasting human development (4–23 weeks) with mouse development at selected stages (embryonic day 15.5 and postnatal day 2). The high-resolution histologic interactive atlas of human kidney organogenesis generated can be viewed at the GUDMAP database (www.gudmap.org) together with three-dimensional reconstructions of key components of the data herein. At the anatomic level, human and mouse kidney development differ in timing, scale, and global features such as lobe formation and progenitor niche organization. The data also highlight differences in molecular and cellular features, including the expression and cellular distribution of anchor gene markers used to identify key cell types in mouse kidney studies. These data will facilitate and inform in vitro efforts to generate human kidney structures and comparative functional analyses across mammalian species.
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Conserved and Divergent Features of Mesenchymal Progenitor Cell Types within the Cortical Nephrogenic Niche of the Human and Mouse Kidney
Cellular interactions among nephron, interstitial, and collecting duct progenitors drive mammalian kidney development. In mice, Six2+ nephron progenitor cells (NPCs) and Foxd1+ interstitial progenitor cells (IPCs) form largely distinct lineage compartments at the onset of metanephric kidney development. Here, we used the method for analyzing RNA following intracellular sorting (MARIS) approach, single-cell transcriptional profiling, in situ hybridization, and immunolabeling to characterize the presumptive NPC and IPC compartments of the developing human kidney. As in mice, each progenitor population adopts a stereotypical arrangement in the human nephron-forming niche: NPCs capped outgrowing ureteric branch tips, whereas IPCs were sandwiched between the NPCs and the renal capsule. Unlike mouse NPCs, human NPCs displayed a transcriptional profile that overlapped substantially with the IPC transcriptional profile, and key IPC determinants, including FOXD1, were readily detected within SIX2+ NPCs. Comparative gene expression profiling in human and mouse Six2/SIX2+ NPCs showed broad agreement between the species but also identified species-biased expression of some genes. Notably, some human NPC-enriched genes, including DAPL1 and COL9A2, are linked to human renal disease. We further explored the cellular diversity of mesenchymal cell types in the human nephrogenic niche through single-cell transcriptional profiling. Data analysis stratified NPCs into two main subpopulations and identified a third group of differentiating cells. These findings were confirmed by section in situ hybridization with novel human NPC markers predicted through the single-cell studies. This study provides a benchmark for the mesenchymal progenitors in the human nephrogenic niche and highlights species-variability in kidney developmental programs.
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Conserved and Divergent Molecular and Anatomic Features of Human and Mouse Nephron Patterning
The nephron is the functional unit of the kidney, but the mechanism of nephron formation during human development is unclear. We conducted a detailed analysis of nephron development in humans and mice by immunolabeling, and we compared human and mouse nephron patterning to describe conserved and divergent features. We created protein localization maps that highlight the emerging patterns along the proximal–distal axis of the developing nephron and benchmark expectations for localization of functionally important transcription factors, which revealed unanticipated cellular diversity. Moreover, we identified a novel nephron subdomain marked by Wnt4 expression that we fate-mapped to the proximal mature nephron. Significant conservation was observed between human and mouse patterning. We also determined the time at which markers for mature nephron cell types first emerge—critical data for the renal organoid field. These findings have conceptual implications for the evolutionary processes driving the diversity of mammalian organ systems. Furthermore, these findings provide practical insights beyond those gained with mouse and rat models that will guide in vitro efforts to harness the developmental programs necessary to build human kidney structures.
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Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney
Tamm–Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP–/– mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP–/– mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP–/– mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP–/– mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI.
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GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation
Collecting ducts make up the distal-most tubular segments of the kidney, extending from the cortex, where they connect to the nephron proper, into the medulla, where they release urine into the renal pelvis. During water deprivation, body water preservation is ensured by the selective transepithelial reabsorption of water into the hypertonic medullary interstitium mediated by collecting ducts. The collecting duct epithelium forms tight junctions composed of barrier-enforcing claudins and exhibits a higher transepithelial resistance than other segments of the renal tubule exhibit. However, the functional relevance of this strong collecting duct epithelial barrier is unresolved. Here, we report that collecting duct–specific deletion of an epithelial transcription factor, grainyhead-like 2 (GRHL2), in mice led to reduced expression of tight junction–associated barrier components, reduced collecting duct transepithelial resistance, and defective renal medullary accumulation of sodium and other osmolytes. In vitro, Grhl2-deficient collecting duct cells displayed increased paracellular flux of sodium, chloride, and urea. Consistent with these effects, Grhl2-deficient mice had diabetes insipidus, produced dilute urine, and failed to adequately concentrate their urine after water restriction, resulting in susceptibility to prerenal azotemia. These data indicate a direct functional link between collecting duct epithelial barrier characteristics, which appear to prevent leakage of interstitial osmolytes into urine, and body water homeostasis.
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ApoL1 Overexpression Drives Variant-Independent Cytotoxicity
Coding variants in the APOL1 gene are associated with kidney diseases in African ancestral populations; yet, the underlying biologic mechanisms remain uncertain. Variant-dependent autophagic and cytotoxic cell death have been proposed as pathogenic pathways mediating kidney injury. To examine this possibility, we conditionally expressed APOL1-G0 (reference), -G1, and -G2 (variants) using a tetracycline-regulated system in HEK293 cells. Autophagy was monitored biochemically and cell death was measured using multiple assays. We measured intracellular Na+ and K+ content with atomic absorption spectroscopy and APOL1-dependent currents with whole-cell patch clamping. Neither reference nor variant APOL1s induced autophagy. At high expression levels, APOL1-G0, -G1, and -G2 inserted into the plasma membrane and formed pH-sensitive cation channels, causing collapse of cellular Na+ and K+ gradients, phosphorylation of p38 mitogen-activated protein kinase, and cell death, without variant-dependent differences. APOL1-G0 and -G2 exhibited similar channel properties in whole-cell patch clamp experiments. At low expression levels, neither reference nor variant APOL1s localized on the plasma membrane, Na+ and K+ gradients were maintained, and cells remained viable. Our results indicate that APOL1-mediated pore formation is critical for the trypanolytic activity of APOL1 and drives APOL1-mediated cytotoxicity in overexpression systems. The absence of cytotoxicity at physiologic expression levels suggests variant-dependent intracellular K+ loss and cytotoxicity does not drive kidney disease progression.
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Proteomic Profiling Reveals the Transglutaminase-2 Externalization Pathway in Kidneys after Unilateral Ureteric Obstruction
Increased export of transglutaminase-2 (TG2) by tubular epithelial cells (TECs) into the surrounding interstitium modifies the extracellular homeostatic balance, leading to fibrotic membrane expansion. Although silencing of extracellular TG2 ameliorates progressive kidney scarring in animal models of CKD, the pathway through which TG2 is secreted from TECs and contributes to disease progression has not been elucidated. In this study, we developed a global proteomic approach to identify binding partners of TG2 responsible for TG2 externalization in kidneys subjected to unilateral ureteric obstruction (UUO) using TG2 knockout kidneys as negative controls. We report a robust and unbiased analysis of the membrane interactome of TG2 in fibrotic kidneys relative to the entire proteome after UUO, detected by SWATH mass spectrometry. The data have been deposited to the ProteomeXchange with identifier PXD008173. Clusters of exosomal proteins in the TG2 interactome supported the hypothesis that TG2 is secreted by extracellular membrane vesicles during fibrosis progression. In established TEC lines, we found TG2 in vesicles of both endosomal (exosomes) and plasma membrane origin (microvesicles/ectosomes), and TGF-β1 stimulated TG2 secretion. Knockout of syndecan-4 (SDC4) greatly impaired TG2 exosomal secretion. TG2 coprecipitated with SDC4 from exosome lysate but not ectosome lysate. Ex vivo, EGFP-tagged TG2 accumulated in globular elements (blebs) protruding/retracting from the plasma membrane of primary cortical TECs, and SDC4 knockout impaired bleb formation, affecting TG2 release. Through this combined in vivo and in vitro approach, we have dissected the pathway through which TG2 is secreted from TECs in CKD.
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Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling
In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2. We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD.
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Exosomal CCL2 from Tubular Epithelial Cells Is Critical for Albumin-Induced Tubulointerstitial Inflammation
Albuminuria is a key instigator of tubulointerstitial inflammation associated with CKD, but the mechanism through which filtered albumin propagates renal injury remains unclear. In this study, we explored the role in this process of exosome mRNA released from tubular epithelial cells (TECs). Compared with control mice, acute and chronic kidney injury models had more exosomes containing inflammatory cytokine mRNA, particularly the chemokine CCL2, in kidneys and urine. In vitro stimulation of TECs with BSA recapitulated this finding. Notably, the internalization of purified TEC exosomes by cultured macrophages increased if TECs were exposed to BSA. Macrophage internalization of exosomes from BSA-treated TECs led to an enhanced inflammatory response and macrophage migration, but CCL2 silencing in TECs prevented these effects. Using a GFP-CCL2 fusion mRNA construct, we observed direct transfer of CCL2 mRNA from TEC exosomes to macrophages. Mice subjected to tail vein injection of purified BSA-treated TEC exosomes developed tubular injury with renal inflammatory cell infiltration. However, injection of exosomes from BSA-treated CCL2-deficient TECs induced less severe kidney inflammation. Finally, in patients with IgA nephropathy, the increase of proteinuria correlated with augmented urinary excretion of exosomes with exaggerated expression of CCL2 mRNA. Moreover, the level of CCL2 mRNA in urinary exosomes correlated closely with levels of renal interstitial macrophage infiltration in these patients. Our studies demonstrate that the increasing release of exosomes that transfer CCL2 mRNA from TECs to macrophages constitutes a critical mechanism of albumin-induced tubulointerstitial inflammation.
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CHIP Regulates Aquaporin-2 Quality Control and Body Water Homeostasis
The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins have a regulatory role in these cells and how these cells can be regulated by individual physiologic stimuli. By combining proteomics, bioinformatics, and cell biology approaches, we found that the E3 ubiquitin ligase CHIP is highly expressed throughout the collecting duct; is modulated in abundance by vasopressin; interacts with aquaporin-2 (AQP2), Hsp70, and Hsc70; and can directly ubiquitylate the water channel AQP2 in vitro. shRNA knockdown of CHIP in CCD cells increased AQP2 protein t1/2 and reduced AQP2 ubiquitylation, resulting in greater levels of AQP2 and phosphorylated AQP2. CHIP knockdown increased the plasma membrane abundance of AQP2 in these cells. Compared with wild-type controls, CHIP knockout mice or novel CRISPR/Cas9 mice without CHIP E3 ligase activity had greater AQP2 abundance and altered renal water handling, with decreased water intake and urine volume, alongside higher urine osmolality. We did not observe significant changes in other water- or sodium-transporting proteins in the gene-modified mice. In summary, these results suggest that CHIP regulates AQP2 and subsequently, renal water handling.
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Pathogenicity of a Human Laminin {beta}2 Mutation Revealed in Models of Alport Syndrome
Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin β2 (LAMB2), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient’s nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a Col4a3–/– mouse model of autosomal recessive Alport syndrome and increased proteinuria in Col4a5+/– females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen α3α4α5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same COL4 mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.
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Potentiating Tissue-Resident Type 2 Innate Lymphoid Cells by IL-33 to Prevent Renal Ischemia-Reperfusion Injury
The IL-33-type 2 innate lymphoid cell (ILC2) axis has an important role in tissue homeostasis, inflammation, and wound healing. However, the relative importance of this innate immune pathway for immunotherapy against inflammation and tissue damage remains unclear. Here, we show that treatment with recombinant mouse IL-33 prevented renal structural and functional injury and reduced mortality in mice subjected to ischemia-reperfusion injury (IRI). Compared with control-treated IRI mice, IL-33–treated IRI mice had increased levels of IL-4 and IL-13 in serum and kidney and more ILC2, regulatory T cells (Tregs), and anti-inflammatory (M2) macrophages. Depletion of ILC2, but not Tregs, substantially abolished the protective effect of IL-33 on renal IRI. Adoptive transfer of ex vivo–expanded ILC2 prevented renal injury in mice subjected to IRI. This protective effect associated with induction of M2 macrophages in kidney and required ILC2 production of amphiregulin. Treatment of mice with IL-33 or ILC2 after IRI was also renoprotective. Furthermore, in a humanized mouse model of renal IRI, treatment with human IL-33 or transfer of ex vivo–expanded human ILC2 ameliorated renal IRI. This study has uncovered a major protective role of the IL-33–ILC2 axis in renal IRI that could be potentiated as a therapeutic strategy.
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Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific {gamma}ENaC Knockout
The amiloride-sensitive epithelial sodium channel (ENaC) and the thiazide-sensitive sodium chloride cotransporter (NCC) are key regulators of sodium and potassium and colocalize in the late distal convoluted tubule of the kidney. Loss of the αENaC subunit leads to a perinatal lethal phenotype characterized by sodium loss and hyperkalemia resembling the human syndrome pseudohypoaldosteronism type 1 (PHA-I). In adulthood, inducible nephron-specific deletion of αENaC in mice mimics the lethal phenotype observed in neonates, and as in humans, this phenotype is prevented by a high sodium (HNa+)/low potassium (LK+) rescue diet. Rescue reflects activation of NCC, which is suppressed at baseline by elevated plasma potassium concentration. In this study, we investigated the role of the ENaC subunit in the PHA-I phenotype. Nephron-specific ENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking αENaC or βENaC, an HNa+/LK+ diet did not normalize plasma potassium (K+) concentration or increase NCC activation. However, when K+ was eliminated from the diet at the time that ENaC was deleted, plasma K+ concentration and NCC activity remained normal, and progressive weight loss was prevented. Loss of the late distal convoluted tubule, as well as overall reduced βENaC subunit expression, may be responsible for the more severe hyperkalemia. We conclude that plasma K+ concentration becomes the determining and limiting factor in regulating NCC activity, regardless of Na+ balance in ENaC-deficient mice.
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Magnesium and Risk of Hip Fracture among Patients Undergoing Hemodialysis
Magnesium is an essential mineral for bone metabolism. However, little is known about the relationship between magnesium and the risk of fractures. In this cohort study, we elucidated the association between serum magnesium level and the risk of incident hip fracture among patients undergoing hemodialysis. We identified 113,683 patients undergoing hemodialysis with no history of hip fracture from a nation-wide database of patients undergoing dialysis in Japan. During a 2-year follow-up, a total of 2305 (2%) new hip fractures occurred. The crude incidence rate was significantly higher among patients in the lower quartiles of serum magnesium levels (2.63%, 2.08%, 1.76%, and 1.49% in Q1–Q4, respectively; P<0.001 for trend). The range of serum magnesium levels (in milligrams per deciliter) in each quartile was as follows: Q1, <2.3; Q2, 2.4–2.6; Q3, 2.7–2.8, and Q4, >2.9. After adjustment for demographic and clinical factors, patients in Q1 had a 1.23-fold higher risk for hip fracture than those in Q4 (95% confidence interval, 1.06 to 1.44; P<0.01). Similarly, an inverse probability weighting analysis showed an increased risk of hip fracture among patients in the lower magnesium quartiles. We did not observe significant effect modifications in subgroup analyses. The population-attributable fraction of serum magnesium level for incident hip fractures was 13.7% (95% confidence interval, 3.7% to 22.7%), which was much higher than that of serum calcium, serum phosphate, and parathyroid hormone levels. Thus, mild hypermagnesemia is associated with a lower risk of hip fracture among patients undergoing hemodialysis.
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Causes of Death after a Hospitalization with AKI
Mortality after AKI is high, but the causes of death are not well described. To better understand causes of death in patients after a hospitalization with AKI and to determine patient and hospital factors associated with mortality, we conducted a population-based study of residents in Ontario, Canada, who survived a hospitalization with AKI from 2003 to 2013. Using linked administrative databases, we categorized cause of death in the year after hospital discharge as cardiovascular, cancer, infection-related, or other. We calculated standardized mortality ratios to compare the causes of death in survivors of AKI with those in the general adult population and used Cox proportional hazards modeling to estimate determinants of death. Of the 156,690 patients included, 43,422 (28%) died in the subsequent year. The most common causes of death were cardiovascular disease (28%) and cancer (28%), with respective standardized mortality ratios nearly six-fold (5.81; 95% confidence interval [95% CI], 5.70 to 5.92) and eight-fold (7.87; 95% CI, 7.72 to 8.02) higher than those in the general population. The highest standardized mortality ratios were for bladder cancer (18.24; 95% CI, 17.10 to 19.41), gynecologic cancer (16.83; 95% CI, 15.63 to 18.07), and leukemia (14.99; 95% CI, 14.16 to 15.85). Along with older age and nursing home residence, cancer and chemotherapy strongly associated with 1-year mortality. In conclusion, cancer-related death was as common as cardiovascular death in these patients; moreover, cancer-related deaths occurred at substantially higher rates than in the general population. Strategies are needed to care for and counsel patients with cancer who experience AKI.
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Long-Term Clinical Outcomes after Early Initiation of RRT in Critically Ill Patients with AKI
Whether earlier initiation of RRT in critically ill patients with AKI can improve outcomes remains debated. We examined follow-up data from a large clinical trial to prospectively investigate the long-term outcomes associated with the timing of RRT initiation in such patients. We extended the follow-up of patients in the Early Versus Delayed Initiation of RRT in Critically Ill Patients with AKI (ELAIN) Trial from 90 days to 1 year after randomization for 230 (99.6%) patients. The primary outcome was a composite of major adverse kidney events (persistent renal dysfunction, dialysis dependence, and mortality) at 1 year. Secondary outcomes included inflammatory markers. Overall, 72 of 111 (64.9%) and 106 of 119 (89.1%) patients met the primary outcome in the early (stage 2 AKI) and delayed (stage 3 AKI) initiation groups, respectively (odds ratio [OR] with early initiation, 0.23; 95% confidence interval [95% CI], 0.11 to 0.45; P< 0.001). The early initiation group had a 1-year all-cause mortality rate (56 of 111 [50.2%]) significantly lower than that of the delayed initiation group (83 of 119 [69.8%]; absolute difference, –19.6%; 95% CI, –32.0% to –7.2%; P<0.01). After 1 year, 16 of 55 (29.1%) and 23 of 36 (63.9%) surviving patients in the early and delayed groups, respectively, failed to recover renal function (absolute difference, –34.8%; 95% CI, –54.6% to –15.0%; P=0.001). In conclusion, early initiation of RRT in these critically ill patients with AKI significantly reduced the occurrence of major adverse kidney events, reduced mortality, and enhanced renal recovery at 1 year.
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Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome
Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1–4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear.
from Journal of the American Society of Nephrology current issue http://ift.tt/2oEkJf7
Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas
The frequency of primary failure in arteriovenous fistulas (AVFs) remains unacceptably high. This lack of improvement is due in part to a poor understanding of the pathobiology underlying AVF nonmaturation. This observational study quantified the progression of three vascular features, medial fibrosis, intimal hyperplasia (IH), and collagen fiber organization, during early AVF remodeling and evaluated the associations thereof with AVF nonmaturation. We obtained venous samples from patients undergoing two-stage upper-arm AVF surgeries at a single center, including intraoperative veins at the first-stage access creation surgery and AVFs at the second-stage transposition procedure. Paired venous samples from both stages were used to evaluate change in these vascular features after anastomosis. Anatomic nonmaturation (AVF diameter never ≥6 mm) occurred in 39 of 161 (24%) patients. Neither preexisting fibrosis nor IH predicted AVF outcomes. Postoperative medial fibrosis associated with nonmaturation (odds ratio [OR], 1.55; 95% confidence interval [95% CI], 1.05 to 2.30; P=0.03, per 10% absolute increase in fibrosis), whereas postoperative IH only associated with failure in those individuals with medial fibrosis over the population’s median value (OR, 2.63; 95% CI, 1.07 to 6.46; P=0.04, per increase of 1 in the intima/media ratio). Analysis of postoperative medial collagen organization revealed that circumferential alignment of fibers around the lumen associated with AVF nonmaturation (OR, 1.38; 95% CI, 1.03 to 1.84; P=0.03, per 10° increase in angle). This study demonstrates that excessive fibrotic remodeling of the vein after AVF creation is an important risk factor for nonmaturation and that high medial fibrosis determines the stenotic potential of IH.
from Journal of the American Society of Nephrology current issue http://ift.tt/2FFbraW
Acidosis and Deafness in Patients with Recessive Mutations in FOXI1
Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.
from Journal of the American Society of Nephrology current issue http://ift.tt/2HVKfWc
Control of Humoral Response in Renal Transplantation by Belatacept Depends on a Direct Effect on B Cells and Impaired T Follicular Helper-B Cell Crosstalk
Generation of de novo donor-specific antibodies (dnDSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dnDSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dnDSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated. Here, we analyzed the effect of Belatacept on different steps of the B cell–mediated response in humans. In vitro, Belatacept reduced plasmablast differentiation, Ig production, and the expression of the major transcription factor involved in plasma cell function, Blimp-1, in a T cell–independent manner. Moreover, Belatacept induced activation of the STAT3 transcription factor in stimulated B cells and reduced the expression of CD86. Additionally, Belatacept blocked CD28-mediated activation of T follicular helper cells (Tfhs) in an autologous Tfh-memory B cells model. We then validated these observations in KTRs treated with Belatacept, who had a reduced proportion of blood effector B cells and activated Tfh (PD1+ICOS+) compared with control-treated KTRs. Our in vitro and in vivo results suggest that Belatacept modulates B cell function directly and at the level of B cell-Tfh interaction. These mechanisms likely account for the optimal control of humoral responses observed in KTRs treated with Belatacept.
from Journal of the American Society of Nephrology current issue http://ift.tt/2FCYFcM
Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans
Individuals with CKD are particularly predisposed to thrombosis after vascular injury. Using mouse models, we recently described indoxyl sulfate, a tryptophan metabolite retained in CKD and an activator of tissue factor (TF) through aryl hydrocarbon receptor (AHR) signaling, as an inducer of thrombosis across the CKD spectrum. However, the translation of findings from animal models to humans is often challenging. Here, we investigated the uremic solute–AHR–TF thrombosis axis in two human cohorts, using a targeted metabolomics approach to probe a set of tryptophan products and high-throughput assays to measure AHR and TF activity. Analysis of baseline serum samples was performed from 473 participants with advanced CKD from the Dialysis Access Consortium Clopidogrel Prevention of Early AV Fistula Thrombosis trial. Participants with subsequent arteriovenous thrombosis had significantly higher levels of indoxyl sulfate and kynurenine, another uremic solute, and greater activity of AHR and TF, than those without thrombosis. Pattern recognition analysis using the components of the thrombosis axis facilitated clustering of the thrombotic and nonthrombotic groups. We further validated these findings using 377 baseline samples from participants in the Thrombolysis in Myocardial Infarction II trial, many of whom had CKD stage 2–3. Mechanistic probing revealed that kynurenine enhances thrombosis after vascular injury in an animal model and regulates thrombosis in an AHR-dependent manner. This human validation of the solute-AHR-TF axis supports further studies probing its utility in risk stratification of patients with CKD and exploring its role in other diseases with heightened risk of thrombosis.
from Journal of the American Society of Nephrology current issue http://ift.tt/2oFuOs6
FOX NEWS: Another reason to worry about overcrowded emergency rooms
Another reason to worry about overcrowded emergency rooms
Patients are more likely to be misdiagnosed or experience treatment delays when emergency rooms are so crowded that they receive care in a hallway, a survey of physicians suggests.
FOX NEWS: Teen who was told he had the flu, really had stage 4 cancer
Teen who was told he had the flu, really had stage 4 cancer
A teenager from Tampa, Florida who was told her had the flu discovers he is battling stage 4 cancer.
FOX NEWS: Obese high school student who attempted suicide drops 157 pounds
Obese high school student who attempted suicide drops 157 pounds
An obese high school student makes a turnaround after attempting suicide, and decides to have weight-loss surgery and loses 157 pounds.
FOX NEWS: Popular Alaska peak weighs new rules for climbers' poop
Popular Alaska peak weighs new rules for climbers' poop
Climbers on North America's tallest mountain may have to start packing out more of their poop after a researcher determined a glacier in which much of it has been dumped over the past decade probably is not decomposing the human waste.
FOX NEWS: What's in the IV bag? Studies show safer option than saline
What's in the IV bag? Studies show safer option than saline
Two large studies found that using a different intravenous fluid instead of the usual saline significantly reduced the risk of death or kidney damage.
FOX NEWS: The Spice Diet: A diet that explodes with flavor ... and happens to be healthy
The Spice Diet: A diet that explodes with flavor ... and happens to be healthy
The Spice Diet breaks down what spices to pair with specific ingredients to yield a dish that explodes with flavor and that just so happens to be very healthy for you.
FOX NEWS: Former Yankees GM refuses kidney donation offers from his children
Former Yankees GM refuses kidney donation offers from his children
A former New York Yankees general manager turned his children’s offers to donate a new kidney as he battles kidney failure.
Tuesday, February 27, 2018
FOX NEWS: U.S. to file 'statement of interest' in lawsuits against opioid makers, distributors
U.S. to file 'statement of interest' in lawsuits against opioid makers, distributors
The United States will file a "statement of interest" in an action involving hundreds of lawsuits against drug manufacturers and distributors, U.S. Attorney General Jeff Sessions said on Tuesday.
FOX NEWS: Aerobic exercise slows cognitive decline in Alzheimer's disease
Aerobic exercise slows cognitive decline in Alzheimer's disease
Cardiovascular exercise training may help slow the decline in brain function seen in Alzheimer's patients, a new review of past research suggests.
FOX NEWS: Standing desks may be harmful to your health, according to new study
Standing desks may be harmful to your health, according to new study
New research suggests that using standing desks for a prolonged period of time will create "discomfort and deteriorating mental reactiveness."
FOX NEWS: Too much tech: Today's kids struggle to hold pencils, study says
Too much tech: Today's kids struggle to hold pencils, study says
Overuse of touchscreen phones and tablets is preventing children's finger muscles from developing so they can properly hold a pencil says a new report.
FOX NEWS: Teen sexting may be more common than you think
Teen sexting may be more common than you think
At least one in four teens are receiving sexually explicit texts and emails, and at least one in seven are sending sexts, a new study suggests.
FOX NEWS: Woman's hand that was chopped off in machine was saved by co-workers
Woman's hand that was chopped off in machine was saved by co-workers
A woman has miraculously regained the use of her hand after it was completely severed by a coconut chopping machine.
Sneeze Into Your Elbow, Not Your Hand. Please.
By DANIEL VICTOR from NYT Health http://ift.tt/2HMKvXk
Monday, February 26, 2018
FOX NEWS: Mom 'fighting for her life' in ICU after contracting rare, rodent-carried Hantavirus
Mom 'fighting for her life' in ICU after contracting rare, rodent-carried Hantavirus
In early January, Kiley Lane went to the hospital for what she thought was the flu.
FOX NEWS: Pediatricians issue new guidelines for depression screening for teens
Pediatricians issue new guidelines for depression screening for teens
The American Academy of Pediatrics has issued updated guidelines that call for universal screening for depression.
F.D.A. to Expand Medication-Assisted Therapy for Opioid Addicts
By SHEILA KAPLAN from NYT Health http://ift.tt/2HLBePt
FOX NEWS: Childhood obesity is worse among 2-5 year olds
Childhood obesity is worse among 2-5 year olds
New data published in the journal Pediatrics reports that childhood obesity is not improving, and actually rose from 9-14% since 1999.
FOX NEWS: Supermodel Niki Taylor opens up about the heart disease that killed her sister
Supermodel Niki Taylor opens up about the heart disease that killed her sister
In a rare interview, supermodel Niki Taylor opens up about losing her younger sister, Krissy Taylor, to heart disease and why she’s raising awareness 23 years after her tragic death.
FOX NEWS: Fertility doctor's secret reveals discovery of at least 23 half-siblings
Fertility doctor's secret reveals discovery of at least 23 half-siblings
After Dr. Donald Cline received a one-year suspended sentence for lying when denied being a sperm donor to unwitting patients, a special bond has formed between half-siblings decades later.
Sunday, February 25, 2018
FOX NEWS: Tourist infected with measles went to New York art museum, area hotels, health officials say
Tourist infected with measles went to New York art museum, area hotels, health officials say
An Australian tourist infected with measles visited several locations in New York City, included the famed The Metropolitan Museum of Art, health officials warned Saturday.
Friday, February 23, 2018
FOX NEWS: Fake urine: Mississippi in legislative push to flush it away
Fake urine: Mississippi in legislative push to flush it away
Political and business leaders in Mississippi are working to pass a law that would flush fake urine down the toilet. The Mississippi Urine Trouble Act would ban the sale or use of synthetic human urine for the purposes of defrauding a drug test.
FOX NEWS: Fake Urine: Mississippi lawmakers say flush it away
Fake Urine: Mississippi lawmakers say flush it away
Political and business leaders in Mississippi are working to pass a law that would flush fake urine down the toilet The Mississippi Urine Trouble Act would ban the sale or use of synthetic human urine for the purposes of defrauding a drug test.
FOX NEWS: Martin Shkreli controversies: A timeline of events
Martin Shkreli controversies: A timeline of events
Martin Shkreli, the former biotech CEO known for hiking up the price of a life-saving drug, was convicted on federal charges he deceived investors in a pair of failed hedge funds.
FOX NEWS: Potentially toxic chemicals were found in e-cigarette vaper
Potentially toxic chemicals were found in e-cigarette vaper
A significant number of e-cigarette devices produced aerosols with potentially dangerous levels of lead, as well as other metals like chromium, manganese, and nickel which could cause cancer.
Patients Eagerly Awaited a Generic Drug. Then They Saw the Price.
By KATIE THOMAS from NYT Health http://ift.tt/2sOiwTA
FOX NEWS: Young men's drinking tied to later liver disease risk
Young men's drinking tied to later liver disease risk
Researchers found that a percentage of men who drank heavily in their younger years developed severe liver disease later in life.
FOX NEWS: Nasty flu season showing signs of winding down
Nasty flu season showing signs of winding down
U.S. health officials say fewer visits to the doctor last week — 1 out of 16 — were for fever, cough and other flu symptoms than during the previous two weeks. The number of states reporting high patient traffic for the flu also dropped, to 39 from 43.
FOX NEWS: One-third of millennials brush teeth just once a day, study shows
One-third of millennials brush teeth just once a day, study shows
A new survey of 2000 people shows that 30% of millennials only brush their teeth once a day.
Measles Cases in Europe Quadrupled in 2017
By DONALD G. McNEIL Jr. from NYT Health http://ift.tt/2oo2on6
Thursday, February 22, 2018
Opening Mental Hospitals Unlikely to Prevent Mass Shootings, Experts Say
By BENEDICT CAREY from NYT Health http://ift.tt/2HEhLjF
FOX NEWS: Bubble parade for boy who survives bone marrow transplant
Bubble parade for boy who survives bone marrow transplant
Hospital staff at Boston Children's Hospital throw a "bubble parade" for a boy who was discharged after a grueling bone marrow transplant.
FOX NEWS: YouTube star who claims veganism healed her breast cancer dies from disease
YouTube star who claims veganism healed her breast cancer dies from disease
Mari Lopez, who hosted a YouTube channel, died from breast cancer after claiming her vegan and spiritual lifestyle cured her of the disease.
FOX NEWS: Doctors successfully remove 4-pound brain tumor, bigger than head itself
Doctors successfully remove 4-pound brain tumor, bigger than head itself
Surgeons in India successfully removed a 4 pound tumor from a 31 year old man.
Wednesday, February 21, 2018
FOX NEWS: Florida House declares porn a public health risk
Florida House declares porn a public health risk
Florida lawmakers on Tuesday declared pornography a health risk, and called for more research on its affects.
FOX NEWS: Healthy food blogger almost died from dieting obsession
Healthy food blogger almost died from dieting obsession
A woman was so obsessed with posting pictures of superfoods, she ended up with an eating disorder.
FOX NEWS: Parents say amazing ultrasound shows unborn baby giving V-sign
Parents say amazing ultrasound shows unborn baby giving V-sign
An amazing 4D scan shows an unborn baby giving the V-sign to his parents when they suggested a name.
FOX NEWS: Herbal drug kratom is linked to salmonella illnesses, CDC says
Herbal drug kratom is linked to salmonella illnesses, CDC says
The popular botanical drug kratom is being linked to salmonella according to the Centers for Disease Control and Prevention.
FOX NEWS: Parents say amazing scan shows unborn baby giving V-sign
Parents say amazing scan shows unborn baby giving V-sign
An amazing 4D scan shows an unborn baby giving the V-sign to his parents when they suggested a name.
FOX NEWS: Heart alert: Pacemakers can be hacked, new research shows
Heart alert: Pacemakers can be hacked, new research shows
There is a possibility that pacemakers and other electrical devices could be targeted by hackers, according to a paper published in the Journal of American College of Cardiology.
FOX NEWS: Florida House declares pornography a public health risk
Florida House declares pornography a public health risk
Florida lawmakers on Tuesday declared pornography a health risk, and called for more research on its affects.
Tuesday, February 20, 2018
FOX NEWS: Florida House declares pornography a public health risk
Florida House declares pornography a public health risk
Florida lawmakers on Tuesday declared pornography a health risk, and called for more research on its affects.
Comment on "{gamma}{delta} T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations" [LETTERS TO THE EDITOR]
from The Journal of Immunology current issue http://ift.tt/2BJ145I
Response to Comment on "{gamma}{delta} T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations" [LETTERS TO THE EDITOR]
from The Journal of Immunology current issue http://ift.tt/2C9n2js
The Chemical Elucidation of Slow-Reacting Substance: Bronchospasm and Beyond [PILLARS OF IMMUNOLOGY]
from The Journal of Immunology current issue http://ift.tt/2olYjiu
Pillars Article: Leukotriene C: A Slow-Reacting Substance from Murine Mastocytoma Cells. Proc. Natl. Acad. Sci. USA. 1979. 76: 4275-4279 [PILLARS OF IMMUNOLOGY]
from The Journal of Immunology current issue http://ift.tt/2C7xc4l
Sepsis-Induced T Cell Immunoparalysis: The Ins and Outs of Impaired T Cell Immunity [BRIEF REVIEWS]
Sepsis results in a deluge of pro- and anti-inflammatory cytokines, leading to lymphopenia and chronic immunoparalysis. Sepsis-induced long-lasting immunoparalysis is defined, in part, by impaired CD4 and CD8 αβ T cell responses in the postseptic environment. The dysfunction in T cell immunity affects naive, effector, and memory T cells and is not restricted to classical αβ T cells. Although sepsis-induced severe and transient lymphopenia is a contributory factor to diminished T cell immunity, T cell–intrinsic and -extrinsic factors/mechanisms also contribute to impaired T cell function. In this review, we summarize the current knowledge of how sepsis quantitatively and qualitatively impairs CD4 and CD8 T cell immunity of classical and nonclassical T cell subsets and discuss current therapeutic approaches being developed to boost the recovery of T cell immunity postsepsis induction.
from The Journal of Immunology current issue http://ift.tt/2okRXQx
Cutting Edge: Nqo1 Regulates Irritant Contact Hypersensitivity against Croton Oil through Maintenance of Dendritic Epidermal T Cells [CUTTING EDGE]
Irritant contact dermatitis (ICD) is associated with local release of inflammatory mediators such as reactive oxygen species and regulated by various antioxidative enzymes and antioxidants. Although Nqo1 is involved in antioxidative reactions and detoxification, its role in ICD remains unknown. Nqo1-deficient mice exhibited augmented ear swelling accompanied by neutrophil infiltration in the croton oil–induced mouse ICD model. In the skin of Nqo1-deficient mice, V5V1+ dendritic epidermal T cells (DETCs), which are known to suppress ICD, were severely reduced. As the transfer of DETCs into Nqo1-deficient mice reversed an increased ICD response, loss of DETCs could account for the increased ICD. DETCs from Nqo1-deficient mice were sensitive to oxidative stress–induced cell death in vitro, and antioxidant NAC treatment in the ears of these mice rescued the number of DETCs and produced a normal ICD response. Taken together, the current results demonstrate that antioxidative enzyme Nqo1 regulates ICD through DETC maintenance.
from The Journal of Immunology current issue http://ift.tt/2ERR5NE
Biased Generation and In Situ Activation of Lung Tissue-Resident Memory CD4 T Cells in the Pathogenesis of Allergic Asthma [ALLERGY AND OTHER HYPERSENSITIVITIES]
Asthma is a chronic inflammatory disease mediated by allergen-specific CD4 T cells that promote lung inflammation through recruitment of cellular effectors into the lung. A subset of lung T cells can persist as tissue-resident memory T cells (TRMs) following infection and allergen induction, although the generation and role of TRM in asthma persistence and pathogenesis remain unclear. In this study, we used a mouse model of chronic exposure to intranasal house dust mite (HDM) extract to dissect how lung TRMs are generated and function in the persistence and pathogenesis of allergic airway disease. We demonstrate that both CD4+ and CD8+ T cells infiltrate into the lung tissue during acute HDM exposure; however, only CD4+ TRMs, and not CD8+ TRMs, persist long term following cessation of HDM administration. Lung CD4+ TRMs are localized around airways and are rapidly reactivated upon allergen re-exposure accompanied by the rapid induction of airway hyperresponsiveness independent of circulating T cells. Lung CD4+ TRM activation to HDM challenge is also accompanied by increased recruitment and activation of dendritic cells in the lungs. Our results indicate that lung CD4+ TRMs can perpetuate allergen-specific sensitization and direct early inflammatory signals that promote rapid lung pathology, suggesting that targeting lung CD4+ TRMs could have therapeutic benefit in alleviating recurrent asthma episodes.
from The Journal of Immunology current issue http://ift.tt/2olVnT2
Therapeutic Application of an Extract of Helicobacter pylori Ameliorates the Development of Allergic Airway Disease [ALLERGY AND OTHER HYPERSENSITIVITIES]
Epidemiological and experimental studies have shown that exposure to the gastric bacterium Helicobacter pylori, especially in early life, prevents the development of asthma. Recent mouse studies have shown that this protective effect does not require live bacteria and that treatment with an extract of H. pylori in neonates prevents the development of airway inflammation and goblet cell metaplasia. In the current study, the effect of administration of an extract of H. pylori was assessed in a therapeutic study design with application of the extract just prior to allergen challenge. C57BL/6 mice were sensitized and challenged with OVA or house dust mite. Treatment with H. pylori extract just prior to the challenge significantly reduced airway inflammation, as assessed in bronchoalveolar lavage fluid and lung tissue, and reduced airway remodeling, as assessed by goblet cell quantification. These effects were apparent in the OVA model and in the house dust mite model. Injection of H. pylori extract reduced the processing of allergen by dendritic cells in the lungs and mediastinal lymph node. Bone marrow–derived dendritic cells exposed to H. pylori extract were affected with regard to their ability to process Ag. These data show that application of H. pylori extract after sensitization effectively inhibits allergic airway disease.
from The Journal of Immunology current issue http://ift.tt/2C7x8l7
IL-10 Paradoxically Promotes Autoimmune Neuropathy through S1PR1-Dependent CD4+ T Cell Migration [AUTOIMMUNITY]
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a debilitating condition caused by autoimmune demyelination of peripheral nerves. CIDP is associated with increased IL-10, a cytokine with well-described anti-inflammatory effects. However, the role of IL-10 in CIDP is unclear. In this study, we demonstrate that IL-10 paradoxically exacerbates autoimmunity against peripheral nerves. In IL-10–deficient mice, protection from neuropathy was associated with an accrual of highly activated CD4+ T cells in draining lymph nodes and absence of infiltrating immune cells in peripheral nerves. Accumulated CD4+ T cells in draining lymph nodes of IL-10–deficient mice expressed lower sphingosine-1-phosphate receptor 1 (S1pr1), a protein important in lymphocyte egress. Additionally, IL-10 stimulation in vitro induced S1pr1 expression in lymph node cells in a STAT3-dependent manner. Together, these results delineate a novel mechanism in which IL-10–induced STAT3 increases S1pr1 expression and CD4+ T cell migration to accelerate T cell–mediated destruction of peripheral nerves.
from The Journal of Immunology current issue http://ift.tt/2BEQgFW
cIAP1/2-TRAF2-SHP-1-Src-MyD88 Complex Regulates Lipopolysaccharide-Induced IL-27 Production through NF-{kappa}B Activation in Human Macrophages [CLINICAL AND HUMAN IMMUNOLOGY]
The inhibitors of apoptosis (IAP) proteins, initially described in the context of apoptosis regulation as promoting cell survival, have recently emerged as key regulators of innate immune signaling. As a result, downregulation of IAP via Smac mimetics (SMM) has both survival and immunoregulatory effects. IAPs modulate cytokine production in murine models either as a single agent or in response to LPS. However, the role of SMM and the involvement of IAPs in primary human cells and in particular macrophages with respect to cytokine production and innate immune responses remain largely unknown. IL-27, a member of the IL-12 cytokine family produced by APCs such as macrophages, has broad immunoregulatory properties in both innate and adaptive immune responses. Herein, we show that cellular IAPs (cIAPs) positively regulate LPS-induced IL-27 production in both primary human monocytes and macrophages. Investigations for the signaling mechanism of cIAPs involvement in IL-27 production in human macrophages revealed that LPS-induced IL-27 production is regulated by a novel signaling complex comprising cIAP1/2, TNFR-associated factor 2 (TRAF2), SHP-1, Src, and MyD88 leading to p38, c-Jun N-terminal kinases (JNK) and Akt activation and NF-B signaling. In cancer cells, SMM induce the production of cytokines by activating the noncanonical alternate NF-B pathway. However, in human macrophages, SMM do not induce the production of TNF-α and other cytokines while inhibiting LPS-induced IL-27 production by inhibiting the classical NF-B pathway. These signaling pathways may constitute novel therapeutic avenues for immune modulation of IL-27 and provide insight into the modulatory immune effects of SMM.
from The Journal of Immunology current issue http://ift.tt/2C7x7h3
Copper Regulates the Canonical NLRP3 Inflammasome [CLINICAL AND HUMAN IMMUNOLOGY]
Inflammasomes are multimeric protein complexes that are activated through a NOD-like receptor and regulate the proteolytic activation of caspase-1 and cytokines, like IL-1β. The NLRP3 inflammasome is implicated in many human pathologies including infections, autoinflammatory syndromes, chronic inflammation, and metabolic diseases; however, the molecular mechanisms of activation are not fully understood. In this study we show that NLRP3 inflammasome activation requires intracellular copper. A clinically approved copper chelator, tetrathiomolybdate, inhibited the canonical NLRP3 but not the AIM2, NLRC4, and NLRP1 inflammasomes or NF-B–dependent priming. We demonstrate that NLRP3 inflammasome activation is blocked by removing copper from the active site of superoxide dismutase 1, recapitulating impaired inflammasome function in superoxide dismutase 1–deficient mice. This regulation is specific to macrophages, but not monocytes, both in mice and humans. In vivo, depletion of bioavailable copper resulted in attenuated caspase-1–dependent inflammation and reduced susceptibility to LPS-induced endotoxic shock. Our results indicate that targeting the intracellular copper homeostasis has potential for the treatment of NLRP3-dependent diseases.
from The Journal of Immunology current issue http://ift.tt/2BHlcVR
DDIT4 and Associated lncDDIT4 Modulate Th17 Differentiation through the DDIT4/TSC/mTOR Pathway [CLINICAL AND HUMAN IMMUNOLOGY]
Inflammation that complicates many autoimmune diseases, such as multiple sclerosis (MS), has been correlated to abnormal differentiation of Th17 cells. However, the reasons that promote Th17 cell–driven autoimmunity are yet to be discovered. In this study, we sought evidence that DNA-damage-inducible transcript 4 (DDIT4) and its associated long noncoding RNA DDIT4 (lncDDIT4) inhibit Th17 cell differentiation. We recruited 36 patients. Six MS patients and five healthy volunteers (controls) contributed PBMCs as material for microarray analysis. Microarray assays of lncDDIT4 and DDIT4 RNA expression identified outstanding differences between MS and control subjects, which were verified with real-time quantitative PCR. We then interrupted the expression of lncDDIT4 and DDIT4 mRNA in MS patients’ naive CD4+ T cells and observed the resulting changes in Th17 cells. The expression of lncDDIT4 and DDIT4 mRNA were higher both in PBMCs and CD4+ T cells of MS patients than in healthy controls. DDIT4 (2.79-fold upregulation) was then recognized as a candidate for the cis-regulated target of lncDDIT4 (4.32-fold upregulation). Isolation of naive CD4+ T cells revealed enhanced levels of lncDDIT4 and DDIT4 after stimulated with Th17-inducing cytokines, but not after Th1, Th2, or T regulatory cell induction. Overexpression of lncDDIT4 in naive CD4+ T cells inhibited IL-17 transcription through increased DDIT4 expression and decreased activation of the DDIT4/mTOR pathway. Consistently, silencing lncDDIT4 in naive CD4+ T cells enhanced Th17 differentiation through increased activation of the DDIT4/mTOR pathway. However, these results vanished when DDIT4 was silenced. This outcome suggests that lncDDIT4 regulates Th17 cell differentiation by directly targeting DDIT4.
from The Journal of Immunology current issue http://ift.tt/2Cbhjtt
Activation and Regulation of Blood V{delta}2 T Cells Are Amplified by TREM-1+ during Active Pulmonary Tuberculosis [IMMUNE REGULATION]
Triggering receptor expressed on myeloid cells 1 (TREM-1) is a receptor mainly expressed on myeloid cells, and it plays an important role in modulating immune response against infectious agents. The function of TREM-1 on nonmyeloid cells such as V2 T cells has not been characterized, and their role in pulmonary tuberculosis (TB) remains unclear. To assess the expression of TREM-1 on blood V2 T cells from pulmonary TB patients and investigate its mechanism of induction, we exploited flow cytometry analysis to study the expression of TREM-1 on V2 T cells from active pulmonary TB patients and control subjects. In this study we demonstrate that TREM-1 (TREM-1+) is highly expressed on V2 T cells of patients with active pulmonary TB. Unlike TREM-1––expressing V2 T cells, TREM-1+–producing V2 T cells display APC-like phenotypes. Surprisingly, TREM-1+ signaling promotes the Ag-presenting capability of V2 T cells to induce the CD4+ T cell response. TREM-1+V2 T cells induced the proliferation and differentiation of naive CD4+ T cells, as well as the elimination of intracellular mycobacteria. We identified TREM-1+ (but not TREM-1–) as an Ag-presentation amplifier on human blood V2 T cells, and data shed new light on the regulation of V2 T cells in the phase of innate and adaptive immune responses against Mycobacterium tuberculosis infection. Targeting TREM-1+V2 T cells may be a promising approach for TB therapy.
from The Journal of Immunology current issue http://ift.tt/2BJ13Pc
CCR8 Expression Defines Tissue-Resident Memory T Cells in Human Skin [IMMUNE REGULATION]
Human skin harbors two major T cell compartments of equal size that are distinguished by expression of the chemokine receptor CCR8. In vitro studies have demonstrated that CCR8 expression is regulated by TCR engagement and the skin tissue microenvironment. To extend these observations, we examined the relationship between CCR8+ and CCR8– skin T cells in vivo. Phenotypic, functional, and transcriptomic analyses revealed that CCR8+ skin T cells bear all the hallmarks of resident memory T cells, including homeostatic proliferation in response to IL-7 and IL-15, surface expression of tissue localization (CD103) and retention (CD69) markers, low levels of inhibitory receptors (programmed cell death protein 1, Tim-3, LAG-3), and a lack of senescence markers (CD57, killer cell lectin-like receptor subfamily G member 1). In contrast, CCR8– skin T cells are heterogeneous and comprise variable numbers of exhausted (programmed cell death protein 1+), senescent (CD57+, killer cell lectin-like receptor subfamily G member 1+), and effector (T-bethi, Eomeshi) T cells. Importantly, conventional and high-throughput sequencing of expressed TCR β-chain (TRB) gene rearrangements showed that these CCR8-defined populations are clonotypically distinct, suggesting unique ontogenies in response to separate antigenic challenges and/or stimulatory conditions. Moreover, CCR8+ and CCR8– skin T cells were phenotypically stable in vitro and displayed similar levels of telomere erosion, further supporting the likelihood of a nonlinear differentiation pathway. On the basis of these results, we propose that long-lived memory T cells in human skin can be defined by the expression of CCR8.
from The Journal of Immunology current issue http://ift.tt/2ES2Gfv
CD8{alpha}+CD11c+ Extracellular Vesicles in the Lungs Control Immune Homeostasis of the Respiratory Tract via TGF-{beta}1 and IL-10 [IMMUNE REGULATION]
The immune balance of the respiratory tract is strictly regulated. Extracellular vesicles (EVs) have been reported to participate in maintaining the immune balance in the intestinal tract, but whether they are involved in regulation of the immune balance in the respiratory tract has yet to be revealed. In this study, we found that physiological EVs from lungs of WT mice (L-EVs) could be isolated, which contained the immunosuppressive cytokines TGF-β1 and IL-10. Among L-EV subsets, only the CD8α+CD11c+ EV subset was positive for TGF-β1 and IL-10 and could inhibit CD4+ T cell proliferation via TGF-β1 in vitro and relieve murine asthmatic symptoms. Mechanistically, L-EVs were effective at inhibiting OVA peptide–specific CD4+ T cell proliferation in a TGF-β1– and IL-10–dependent manner. In addition, they could prevent CD4+ T cells from hilar lymph nodes from secreting IL-4, IL-9, and IL-17A via IL-10 ex vivo, suggesting inhibition of Th2, Th9, and Th17 cell responses. Altogether, our results indicate that EVs from the lungs are involved in control of the immune balance in the respiratory tract, which reveals a novel mechanism in the maintenance of respiratory tract immune homeostasis.
from The Journal of Immunology current issue http://ift.tt/2olYfiK
Endoplasmic Reticulum-Bound Transcription Factor CREBH Stimulates RANKL-Induced Osteoclastogenesis [IMMUNE REGULATION]
Endoplasmic reticulum (ER) stress is triggered by various metabolic factors, such as cholesterol and proinflammatory cytokines. Recent studies have revealed that ER stress is closely related to skeletal disorders, such as osteoporosis. However, the precise mechanism by which ER stress regulates osteoclast differentiation has not been elucidated. In this study, we identified an ER-bound transcription factor, cAMP response element-binding protein H (CREBH), as a downstream effector of ER stress during RANKL-induced osteoclast differentiation. RANKL induced mild ER stress and the simultaneous accumulation of active nuclear CREBH (CREBH-N) in the nucleus during osteoclastogenesis. Overexpression of CREBH-N in osteoclast precursors enhanced RANKL-induced osteoclast formation through NFATc1 upregulation. Inhibiting ER stress using a specific inhibitor attenuated the expression of osteoclast-related genes and CREBH activation. In addition, inhibition of reactive oxygen species using N-acetylcysteine attenuated ER stress, expression of osteoclast-specific marker genes, and RANKL-induced CREBH activation. Furthermore, inhibition of ER stress and CREBH signaling pathways using an ER stress–specific inhibitor or CREBH small interfering RNAs prevented RANKL-induced bone destruction in vivo. Taken together, our results suggest that reactive oxygen species/ER stress signaling-dependent CREBH activation plays an important role in RANKL-induced osteoclastogenesis. Therefore, inactivation of ER stress and CREBH signaling pathways may represent a new treatment strategy for osteoporosis.
from The Journal of Immunology current issue http://ift.tt/2EWdhGi
CD22 Promotes B-1b Cell Responses to T Cell-Independent Type 2 Antigens [IMMUNE REGULATION]
CD22 (Siglec-2) is a critical regulator of B cell activation and survival. CD22–/– mice generate significantly impaired Ab responses to T cell–independent type 2 (TI-2) Ags, including haptenated Ficoll and pneumococcal polysaccharides, Ags that elicit poor T cell help and activate BCR signaling via multivalent epitope crosslinking. This has been proposed to be due to impaired marginal zone (MZ) B cell development/maintenance in CD22–/– mice. However, mice expressing a mutant form of CD22 unable to bind sialic acid ligands generated normal TI-2 Ab responses, despite significantly reduced MZ B cells. Moreover, mice treated with CD22 ligand–binding blocking mAbs, which deplete MZ B cells, had little effect on TI-2 Ab responses. We therefore investigated the effects of CD22 deficiency on B-1b cells, an innate-like B cell population that plays a key role in TI-2 Ab responses. B-1b cells from CD22–/– mice had impaired BCR-induced proliferation and significantly increased intracellular Ca2+ concentration responses following BCR crosslinking. Ag-specific B-1b cell expansion and plasmablast differentiation following TI-2 Ag immunization was significantly impaired in CD22–/– mice, consistent with reduced TI-2 Ab responses. We generated CD22–/– mice with reduced CD19 levels (CD22–/–CD19+/–) to test the hypothesis that augmented B-1b cell BCR signaling in CD22–/– mice contributes to impaired TI-2 Ab responses. BCR-induced proliferation and intracellular Ca2+ concentration responses were normalized in CD22–/–CD19+/– B-1b cells. Consistent with this, TI-2 Ag-specific B-1b cell expansion, plasmablast differentiation, survival, and Ab responses were rescued in CD22–/–CD19+/– mice. Thus, CD22 plays a critical role in regulating TI-2 Ab responses through regulating B-1b cell signaling thresholds.
from The Journal of Immunology current issue http://ift.tt/2om6qfc
MLL1 Promotes IL-7 Responsiveness and Survival during B Cell Differentiation [IMMUNE SYSTEM DEVELOPMENT]
B lymphocyte differentiation is an exquisitely regulated homeostatic process resulting in continuous production of appropriately selected B cells. Relatively small changes in gene expression can result in deregulation of this process, leading to acute lymphocytic leukemia (ALL), immune deficiency, or autoimmunity. Translocation of MLL1 (KMT2A) often results in a pro-B cell ALL, but little is known about its role in normal B cell differentiation. Using a Rag1-cre mouse knock-in to selectively delete Mll1 in developing lymphocytes, we show that B cell, but not T cell, homeostasis depends on MLL1. Mll1–/– B progenitors fail to differentiate efficiently through the pro- to pre-B cell transition, resulting in a persistent reduction in B cell populations. Cells inefficiently transit the pre-BCR checkpoint, despite normal to higher levels of pre-BCR components, and rearranged IgH expression fails to rescue this differentiation block. Instead of IgH-rearrangement defects, we find that Mll1–/– pre-B cells exhibit attenuated RAS/MAPK signaling downstream of the pre-BCR, which results in reduced survival in physiologic levels of IL-7. Genome-wide expression data illustrate that MLL1 is connected to B cell differentiation and IL-7–dependent survival through a complex transcriptional network. Overall, our data demonstrate that wild-type MLL1 is a regulator of pre-BCR signaling and B cell differentiation and further suggest that targeting its function in pro-B cell ALL may be more broadly effective than previously anticipated.
from The Journal of Immunology current issue http://ift.tt/2CaPEZN
Human and Rhesus Macaque KIR Haplotypes Defined by Their Transcriptomes [IMMUNOGENETICS]
The killer-cell Ig-like receptors (KIRs) play a central role in the immune recognition in infection, pregnancy, and transplantation through their interactions with MHC class I molecules. KIR genes display abundant copy number variation as well as high levels of polymorphism. As a result, it is challenging to characterize this structurally dynamic region. KIR haplotypes have been analyzed in different species using conventional characterization methods, such as Sanger sequencing and Roche/454 pyrosequencing. However, these methods are time-consuming and often failed to define complete haplotypes, or do not reach allele-level resolution. In addition, most analyses were performed on genomic DNA, and thus were lacking substantial information about transcription and its corresponding modifications. In this paper, we present a single-molecule real-time sequencing approach, using Pacific Biosciences Sequel platform to characterize the KIR transcriptomes in human and rhesus macaque (Macaca mulatta) families. This high-resolution approach allowed the identification of novel Mamu-KIR alleles, the extension of reported allele sequences, and the determination of human and macaque KIR haplotypes. In addition, multiple recombinant KIR genes were discovered, all located on contracted haplotypes, which were likely the result of chromosomal rearrangements. The relatively high number of contracted haplotypes discovered might be indicative of selection on small KIR repertoires and/or novel fusion gene products. This next-generation method provides an improved high-resolution characterization of the KIR cluster in humans and macaques, which eventually may aid in a better understanding and interpretation of KIR allele–associated diseases, as well as the immune response in transplantation and reproduction.
from The Journal of Immunology current issue http://ift.tt/2olYdr8
Massively Parallel Sequencing of Peritoneal and Splenic B Cell Repertoires Highlights Unique Properties of B-1 Cell Antibodies [IMMUNOGENETICS]
B-1 cells are a unique subset of B cells that are positively selected for expressing autoreactive BCRs. We isolated RNA from peritoneal (B-1a, B-1b, B-2) and splenic (B-1a, marginal zone, follicular) B cells from C57BL/6 mice and used 5'-RACE to amplify the IgH V region using massively parallel sequencing. By analyzing 379,000 functional transcripts, we demonstrate that B-1a cells use a distinct and restricted repertoire. All B-1 cell subsets, especially peritoneal B-1a cells, had a high proportion of sequences without N additions, suggesting predominantly prenatal development. Their transcripts differed markedly and uniquely contained VH11 and VH12 genes, which were rearranged only with a restricted selection of D and J genes, unlike other V genes. Compared to peritoneal B-1a, the peritoneal B-1b repertoire was larger, had little overlap with B-1a, and most sequences contained N additions. Similarly, the splenic B-1a repertoire differed from peritoneal B-1a sequences, having more unique sequences and more frequent N additions, suggesting influx of B-1a cells into the spleen from nonperitoneal sites. Two CDR3s, previously described as Abs to bromelain-treated RBCs, comprised 43% of peritoneal B-1a sequences. We show that a single-chain variable fragment designed after the most prevalent B-1a sequence bound oxidation-specific epitopes such as the phosphocholine of oxidized phospholipids. In summary, we provide the IgH V region library of six murine B cell subsets, including, to our knowledge for the first time, a comparison between B-1a and B-1b cells, and we highlight qualities of B-1 cell Abs that indicate unique selection processes.
from The Journal of Immunology current issue http://ift.tt/2EWjL8i
Recombinant Human Vimentin Binds to P-Selectin and Blocks Neutrophil Capture and Rolling on Platelets and Endothelium [IMMUNOTHERAPY AND VACCINES]
Leukocyte adhesion to vascular endothelium and platelets is an early step in the acute inflammatory response. The initial process is mediated through P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes binding to platelets adhered to endothelium and the endothelium itself via P-selectin. Although these interactions are generally beneficial, pathologic inflammation may occur in undesirable circumstances, such as in acute lung injury (ALI) and ischemia and reperfusion injury. Therefore, the development of novel therapies to attenuate inflammation may be beneficial. In this article, we describe the potential benefit of using a recombinant human vimentin (rhVim) on reducing human leukocyte adhesion to vascular endothelium and platelets under shear stress. The addition of rhVim to whole blood and isolated neutrophils decreased leukocyte adhesion to endothelial and platelet monolayers. Furthermore, rhVim blocked neutrophil adhesion to P-selectin–coated surfaces. Binding assays showed that rhVim binds specifically to P-selectin and not to its counterreceptor, PSGL-1. Finally, in an endotoxin model of ALI in C57BL/6J mice, treatment with rhVim significantly decreased histologic findings of ALI. These data suggest a potential role for rhVim in attenuating inflammation through blocking P-selectin–PSGL-1 interactions.
from The Journal of Immunology current issue http://ift.tt/2olYbQ2
Intracellular BH3 Profiling Reveals Shifts in Antiapoptotic Dependency in Human B Cell Maturation and Mitogen-Stimulated Proliferation [INFECTIOUS DISEASE AND HOST RESPONSE]
Apoptosis is critical to B cell maturation, but studies of apoptotic regulation in primary human B cells is lacking. In this study, we sought to better understand the mechanisms of apoptotic regulation in normal and activated B cells. Using intracellular BH3 profiling, we defined the Bcl2 dependency of B cell subsets from human peripheral blood and tonsillar lymphoid tissue as well as mitogen-activated B cells. We found that naive and memory B cells were BCL-2–dependent, whereas germinal center B cells were MCL-1–dependent and plasma cells were BCL-XL–dependent. B cells stimulated to proliferate ex vivo by CpG or CD40L/IL-4 became more dependent on MCL-1 and BCL-XL. As B cell lymphomas often rely on survival mechanisms derived from normal and activated B cells, these findings offer new insight into potential therapeutic strategies for lymphomas.
from The Journal of Immunology current issue http://ift.tt/2C7x44R
CD8+ T Cells Lack Local Signals To Produce IFN-{gamma} in the Skin during Leishmania Infection [INFECTIOUS DISEASE AND HOST RESPONSE]
Resolution of leishmaniasis depends upon parasite control and limiting inflammation. CD4+ Th1 cells are required to control parasites, whereas CD8+ T cells play a dual role: they promote Th1 cell differentiation but can also increase inflammation at the site of infection as a consequence of cytolysis. Although CD8+ T cells taken from leishmanial lesions are cytolytic, in this study, we showed that only a few CD8+ T cells produced IFN-. Correspondingly, only low levels of IL-12 and/or IL-12 mRNA were present in lesions from infected mice, as well as patients. Addition of IL-12 increased IFN- production by CD8+ T cells isolated from leishmanial lesions, suggesting that a lack of IL-12 at the site of infection limits IFN- production by CD8+ T cells. To determine whether CD8+ T cells could promote resistance in vivo if IL-12 was present, we administered IL-12 to Leishmania-infected RAG mice reconstituted with CD8+ T cells. IL-12 treatment increased the ability of CD8+ T cells to make IFN-, but CD8+ T cells still failed to control the parasites. Furthermore, despite the ability of CD8+ T cells to promote immunity to secondary infections, we also found that CD8+ T cells from immune mice were unable to control Leishmania in RAG mice. Taken together, these results indicate that lesional CD8+ T cells fail to make IFN- because of a deficit in IL-12 but that, even with IL-12, CD8+ T cells are unable to control Leishmania in the absence of CD4+ T cells.
from The Journal of Immunology current issue http://ift.tt/2BDTFVw
CD11b+ Dendritic Cell-Mediated Anti-Mycobacterium tuberculosis Th1 Activation Is Counterregulated by CD103+ Dendritic Cells via IL-10 [INFECTIOUS DISEASE AND HOST RESPONSE]
Mycobacterium tuberculosis, the pathogen causing pulmonary tuberculosis (TB) in humans, has evolved to delay Th1 immunity in the lung. Although conventional dendritic cells (cDCs) are known to be critical to the initiation of T cell immunity, the differential roles and molecular mechanisms of migratory CD11b+ and CD103+ cDC subsets in anti–M. tuberculosis Th1 activation remain unclear. Using a murine model of pulmonary M. tuberculosis infection, we found that slow arrival of M. tuberculosis–bearing migratory CD11b+ and CD103+ cDCs at the draining lymph nodes preceded the much-delayed Th1 immunity and protection in the lung. Contrary to their previously described general roles in Th polarization, CD11b+ cDCs, but not CD103+ cDCs, were critically required for Th1 activation in draining lymph nodes following M. tuberculosis infection. CD103+ cDCs counterregulated CD11b+ cDC–mediated Th1 activation directly by producing the immune-suppressive cytokine IL-10. Thus, our study provides new mechanistic insights into differential Th immune regulation by migratory cDC subsets and helps to develop novel vaccines and therapies.
from The Journal of Immunology current issue http://ift.tt/2CaPGAT
Cytokine- and TCR-Mediated Regulation of T Cell Expression of Ly6C and Sca-1 [INFECTIOUS DISEASE AND HOST RESPONSE]
Ly6C and Sca-1 (Ly6A/E) are Ly6 family GPI-anchored surface molecules that are differentially expressed by multiple immune populations. Ly6C expression has been used to distinguish short-lived effector CD4+ T cells from memory precursor effector cells, whereas Sca-1 has been used in the identification of CD8+ memory stem cells. This study examines the expression patterns of these molecules and establishes that, in vitro, IL-27, type I IFN, and IFN- are potent inducers of Ly6C and Sca-1 in naive mouse CD4+ and CD8+ T cells, whereas TGF-β limits their expression. The induction of Ly6C and Sca-1 by IL-27 and IFN- is dependent on STAT1, but not STAT3 or T-bet. In mouse splenocytes, at homeostasis, Ly6C and Sca-1 expression was not restricted to effector cells, but was also found at various levels on naive and memory populations. However, in response to infection with Toxoplasma gondii, pathogen-specific T cells expressed high levels of these molecules and in this context, endogenous IL-27 and IFN- were required for the expression of Ly6C but not Sca-1. Together, these findings highlight the TCR-dependent and cytokine-mediated signals that modulate T cell expression of Ly6C and Sca-1 in vitro and in vivo during infection.
from The Journal of Immunology current issue http://ift.tt/2olY9ro
Antagonism of Integrin CD11b Affords Protection against Endotoxin Shock and Polymicrobial Sepsis via Attenuation of HMGB1 Nucleocytoplasmic Translocation and Extracellular Release [INNATE IMMUNITY AND INFLAMMATION]
High mobility group box 1 (HMGB1), a chromatin-binding nuclear protein, plays a critical role in sepsis by acting as a key "late-phase" inflammatory mediator. Integrin CD11b is essential for inflammatory cell activation and migration, thus mediating inflammatory responses. However, it is unclear whether CD11b participates in the development of sepsis. In this study, we report that CD11b contributes to LPS-induced endotoxin shock and microbial sepsis, as antagonism of CD11b with the CD11b blocking Ab or CD11b inhibitor Gu-4 protects mice against LPS- and microbial sepsis-related lethality, which is associated with significantly diminished serum HMGB1 levels. Consistent with this, CD11b-deficient mice were more resistant to microbial sepsis with a much lower serum HMGB1 level compared with wild-type mice. Pharmacological blockage and genetic knockdown/knockout of CD11b in murine macrophages hampered LPS-stimulated HMGB1 nucleocytoplasmic translocation and extracellular release. Furthermore, silencing CD11b interrupted the interaction of HMGB1 with either a nuclear export factor chromosome region maintenance 1 or classical protein kinase C and inhibited classical protein kinase C–induced HMGB1 phosphorylation, the potential underlying mechanism(s) responsible for CD11b blockage-induced suppression of HMGB1 nucleocytoplasmic translocation and subsequent extracellular release. Thus, our results highlight that CD11b contributes to the development of sepsis, predominantly by facilitating nucleocytoplasmic translocation and active release of HMGB1.
from The Journal of Immunology current issue http://ift.tt/2ES2AVb
GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis [INNATE IMMUNITY AND INFLAMMATION]
At mucosal sites such as the intestine, the immune system launches robust immunity against invading pathogens while maintaining a state of tolerance to commensal flora and ingested food Ags. The molecular mechanisms underlying this phenomenon remain poorly understood. In this study, we report that signaling by GPR81, a receptor for lactate, in colonic dendritic cells and macrophages plays an important role in suppressing colonic inflammation and restoring colonic homeostasis. Genetic deletion of GPR81 in mice led to increased Th1/Th17 cell differentiation and reduced regulatory T cell differentiation, resulting in enhanced susceptibility to colonic inflammation. This was due to increased production of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and decreased expression of immune regulatory factors (IL-10, retinoic acid, and IDO) by intestinal APCs lacking GPR81. Consistent with these findings, pharmacological activation of GPR81 decreased inflammatory cytokine expression and ameliorated colonic inflammation. Taken together, these findings identify a new and important role for the GPR81 signaling pathway in regulating immune tolerance and colonic inflammation. Thus, manipulation of the GPR81 pathway could provide novel opportunities for enhancing regulatory responses and treating colonic inflammation.
from The Journal of Immunology current issue http://ift.tt/2olY8nk
Inflammation-Sensitive Myosin-X Functionally Supports Leukocyte Extravasation by Cdc42-Mediated ICAM-1-Rich Endothelial Filopodia Formation [INNATE IMMUNITY AND INFLAMMATION]
Leukocyte transendothelial migration is key to inflammation. Leukocytes first start rolling over the inflamed endothelium, followed by firmly adhering to it. Under inflammatory conditions, endothelial cells express small finger-like protrusions that stick out into the lumen. The function and regulation of these structures are unclear. We present evidence that these ICAM-1– and F-actin–rich endothelial finger-like protrusions are filopodia and function as adhesive structures for leukocytes to transit from rolling to crawling but are dispensable for diapedesis. Mechanistically, these structures require the motor function of myosin-X, activity of the small GTPase Cdc42, and p21-activated kinase 4. Moreover, myosin-X expression is under control of TNF-α–mediated c-Jun N-terminal kinase activity and is upregulated in human atherosclerotic regions. To our knowledge, this is the first study to identify that regulation of endothelial filopodia is crucial for leukocyte extravasation, in particular for the initiation of leukocyte adhesion under flow conditions.
from The Journal of Immunology current issue http://ift.tt/2C8YPtG
Monosodium Urate Crystals Generate Nuclease-Resistant Neutrophil Extracellular Traps via a Distinct Molecular Pathway [INNATE IMMUNITY AND INFLAMMATION]
Neutrophil extracellular traps (NETs) and the cell death associated with it (NETosis) have been implicated in numerous diseases. Mechanistic studies of NETosis have typically relied on nonphysiological stimuli, such as PMA. The human disease of gout is caused by monosodium urate (MSU) crystals. We observed that DNA consistent with NETs is present in fluid from acutely inflamed joints of gout patients. NETs also coat the crystals found in uninflamed tophi of chronic gout patients. We developed a quantitative, live cell imaging assay, which measures the key features of NETosis, namely, cell death and chromatin decondensation. We show that MSU and other physiologically relevant crystals induce NETosis through a molecular pathway that is distinct from PMA and Candida hyphae. Crystals interact with lysosomes to induce NADPH oxidase-independent cell death, with postmortem chromatin decondensation mediated by neutrophil elastase. The resulting MSU-induced NETs are enriched for actin and are resistant to serum and DNase degradation. These findings demonstrate a distinct physiological NETosis pathway in response to MSU crystals, which coats MSU crystals in DNA that persists in tissues as gouty tophi.
from The Journal of Immunology current issue http://ift.tt/2BCFq3j
FOX NEWS: Woman says she was paralyzed after doing a sit-up at the gym
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A fitness fanatic was left paralyzed from the neck down after falling on her head while doing an 'inverted' sit-up at the gym.
FOX NEWS: Best medicine: Woman recovering in hospital receives visit from her beloved horse
Best medicine: Woman recovering in hospital receives visit from her beloved horse
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FOX NEWS: Make-a-Wish grants leukemia patient her dream of having a backyard pirate ship
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Monday, February 19, 2018
FOX NEWS: More U.S. babies dying of suffocation, often in bed
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FOX NEWS: Autistic boy gets birthday surprise from 'Army guys' he 'idolizes'
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As Some Got Free Health Care, Gwen Got Squeezed: An Obamacare Dilemma
By ABBY GOODNOUGH from NYT Health http://ift.tt/2GrGWV8
FOX NEWS: Tragic faces of the deadly US flu outbreak
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FOX NEWS: 2 children died from the flu over the weekend, adding to the 84 pediatric deaths this season
2 children died from the flu over the weekend, adding to the 84 pediatric deaths this season
A child from Connecticut, and New Jersey died over the weekend from flu-related illnesses.
