No abstract availablehttp://ift.tt/2fEapkm
Παρασκευή 18 Νοεμβρίου 2016
Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model
BACKGROUND: Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. METHODS: Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant. RESULTS: DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: −4.9; 95% confidence interval [CI]: −8.8 to −0.9) as well as a decreased Cl/F (MD: −4.0; 95% CI: −8.9 to −0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1–1330.6), CMAX (MD: 6.8; 95% CI: 2.7–10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5–35.6), as well as a decreased Cl/F (MD: −7.0; 95% CI: −11.6 to −2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4–1065.4), CMAX (MD: 5.3; 95% CI: 3.2–10.3), and T1/2 (MD: 18.3; 95% CI: 2.8–33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: −779.9; 95% CI: −1229.8 to −330), CMAX (MD: −6.1; 95% CI: −11.4 to −0.9), and T1/2 (MD: −19; 95% CI: −35.1 to −2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3–10.4). CONCLUSIONS: Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.http://ift.tt/2g6GMXC
Indigenous Continuous Positive Airway Pressure Device for Mitigation of Hypoxemia During One Lung Ventilation
No abstract availablehttp://ift.tt/2fEamVI
Incremental Value of Preoperative Copeptin for Predicting Myocardial Injury
BACKGROUND: Copeptin, a novel marker of endogenous stress, has shown diagnostic and prognostic value in nonsurgical patients with a suspected coronary event. We aimed to assess the incremental value of copeptin in addition to established preoperative risk indices to predict the occurrence of postoperative myocardial injury. METHODS: This secondary analysis of prospectively collected data included adults undergoing noncardiac surgery with risk factors for adverse perioperative cardiac events based on preoperative risk stratification. We examined preoperative copeptin in patients without elevated preoperative troponin and its association with myocardial injury by receiver operator characteristic curves, logistic regression, and net reassignment indices. RESULTS: Of the 190 patients included, 33 (17.4%) experienced myocardial injury within 48 hours, and 17 (8.9%) experienced cardiac death and/or major adverse cardiac events within the first postoperative year. Preoperative copeptin showed an area under the receiver operator characteristic curve of .66 (95% confidence interval, .55–.76) for myocardial injury and an optimal cutoff of 9.6 pmol/L. This cutoff was an independent predictor of myocardial injury, with an odds ratio of 4.67 (95% confidence interval, 2.06–11.19) when adjusted for age, sex, and the revised cardiac risk index. The net reassignment improvement for myocardial injury was between 39% and 50% for both events and nonevents when adding copeptin to established preoperative risk indices. No significant difference in major adverse cardiac event and/or cardiac death was observed. CONCLUSIONS: Copeptin (≥9.6 pmol/L) was associated with significantly higher rates of myocardial injury and improved risk stratification in patients scheduled for noncardiac surgery with nonelevated preoperative troponin.http://ift.tt/2ePeRO5
Diversity and Similarity of Anesthesia Procedures in the United States During and Among Regular Work Hours, Evenings, and Weekends
BACKGROUND: Anesthesiologists providing care during off hours (ie, weekends or holidays, or cases started during the evening or late afternoon) are more likely to care for patients at greater risk of sustaining major adverse events than when they work during regular hours (eg, Monday through Friday, from 7:00 AM to 2:59 PM). We consider the logical inconsistency of using subspecialty teams during regular hours but not during weekends or evenings. METHODS: We analyzed data from the Anesthesia Quality Institute's National Anesthesia Clinical Outcomes Registry (NACOR). Among the hospitals in the United States, we estimated the average number of common types of anesthesia procedures (ie, diversity measured as inverse of Herfindahl index), and the average difference in the number of common procedures between 2 off-hours periods (regular hours versus weekends, and regular hours versus evenings). We also used NACOR data to estimate the average similarity in the distributions of procedures between regular hours and weekends and between regular hours and evenings in US facilities. Results are reported as mean ± standard error of the mean among 399 facilities nationwide with weekend cases. RESULTS: The distributions of common procedures were moderately similar (ie, not large, <.8 between regular hours and evenings index .59 .01 weekends .55 .02 for most facilities the number of common procedures differed by p .0001 average was .12 .13 weekends. pairwise differences facility were .07 .090 in contrast respectively when calculated using nationally pooled data. this because numbers .05 .11>2x the number of common procedures calculated by facility). CONCLUSIONS: The numbers of procedures commonly performed at most facilities are fewer in number than those that are commonly performed nationally. Thus, decisions on anesthesia specialization should be based on quantitative analysis of local data rather than national recommendations using pooled data. By facility, the number of different procedures that take place during regular hours and off hours (diversity) is essentially the same, but there is only moderate similarity in the procedures performed. Thus, at many facilities, anesthesiologists who work principally within a single specialty during regular work hours will likely not have substantial contemporary experience with many procedures performed during off hours.http://ift.tt/2ePfFm7
A Novel Device for the Evaluation of Hemostatic Function in Critical Care Settings
Major surgical procedures often result in significant intra- and postoperative bleeding. The ability to identify the cause of the bleeding has the potential to reduce the transfusion of blood products and improve patient care. We present a novel device, the Quantra Hemostasis Analyzer, which has been designed for automated, rapid, near-patient monitoring of hemostasis. The Quantra is based on Sonic Estimation of Elasticity via Resonance Sonorheometry, a proprietary technology that uses ultrasound to measure clot time and clot stiffness from changes in viscoelastic properties of whole blood during coagulation. We present results of internal validation and analytical performance testing of the technology and demonstrate the ability to characterize the key functional components of hemostasis.http://ift.tt/2ePk7kL
Epidural Local Anesthetics Versus Opioid-Based Analgesic Regimens for Postoperative Gastrointestinal Paralysis, Vomiting, and Pain After Abdominal Surgery: A Cochrane Review
BACKGROUND: The aim of this review was to compare the effects of postoperative epidural analgesia with local anesthetics to postoperative systemic or epidural opioids in terms of return of gastrointestinal transit, postoperative pain control, postoperative vomiting, incidence of gastrointestinal anastomotic leak, hospital length of stay, and cost after abdominal surgery. METHODS: Trials were identified by computerized searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 12), Medical Literature Analysis and Retrieval System Online (MEDLINE) (from 1950 to December, 2014) and Excerpta Medica dataBASE (EMBASE) (from 1974 to December 2014) and by checking the reference lists of trials retained. We included parallel randomized controlled trials comparing the effects of postoperative epidural local anesthetic with regimens based on systemic or epidural opioids. The quality of the studies was rated according to the Cochrane tool. Two authors independently extracted data. We judged the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) working group scale. RESULTS: Based on 22 trials including 1138 participants, an epidural containing a local anesthetic will decrease the time required for return of gastrointestinal transit as measured by time required to observe the first flatus after an abdominal surgery standardized mean difference (SMD) −1.28 (95% confidence interval [CI], −1.71 to −0.86; high quality of evidence; equivalent to 17.5 hours). The effect is proportional to the concentration of local anesthetic used. Based on 28 trials including 1559 participants, we also found a decrease in time to first feces (stool): SMD −0.67 (95% CI, −0.86 to −0.47; low quality of evidence; equivalent to 22 hours). Based on 35 trials including 2731 participants, pain on movement at 24 hours after surgery is also reduced: SMD −0.89 (95% CI, −1.08 to −0.70; moderate quality of evidence; equivalent to 2.5 on a scale from 0 to 10). Based on 22 trials including 1154 participants, we did not find a difference in the incidence of vomiting within 24 hours: risk ratio 0.84 (95% CI, 0.57–1.23); low quality of evidence. Based on 17 trials including 848 participants we did not find a difference in the incidence of gastrointestinal anastomotic leak: risk ratio 0.74 (95% CI, 0.41–1.32; low quality of evidence). Based on 30 trials including 2598 participants, epidural analgesia reduces length of hospital stay for an open surgery: SMD −0.20 (95% CI, −0.35 to −0.04; very low quality of evidence; equivalent to 1 day). Data on cost were very limited. CONCLUSIONS: An epidural containing a local anesthetic, with or without the addition of an opioid, accelerates the return of the gastrointestinal transit (high quality of evidence). An epidural containing a local anesthetic with an opioid decreases pain after an abdominal surgery (moderate quality of evidence). An epidural containing a local anesthetic does not affect the incidence of vomiting or anastomotic leak (low quality of evidence). For an open surgery, an epidural containing a local anesthetic would reduce the length of hospital stay (very low quality of evidence).http://ift.tt/2ePjCqP
SEER Sonorheometry Versus Rotational Thromboelastometry in Large Volume Blood Loss Spine Surgery
BACKGROUND: Sonic estimation of elasticity via resonance (SEER) sonorheometry is a novel technology that uses acoustic deformation of the developing clot to measure its viscoelastic properties and extract functional measures of coagulation. Multilevel spine surgery is associated with significant perioperative blood loss, and coagulopathy occurs frequently. The aim of this study was to correlate SEER sonorheometry results with those of equivalent rotation thromboelastometry (ROTEM) and laboratory parameters obtained during deformity correction spine surgery. METHODS: Four independent SEER sonorheometry hemostatic indices (clot time, clot stiffness, fibrinogen, and platelet contribution) were measured. SEER sonorheometry clot time, using kaolin as an activator, was correlated with ROTEM intrinsic temogram clotting time and the activated partial thromboplastin time. For clot stiffness, thromboplastin was the primary activator, and this was correlated against ROTEM external temogram amplitude at 10 minutes (A10). The assay for the fibrinogen contribution was similar to clot stiffness, but abciximab was added to inhibit platelet function. The fibrinogen contribution assay was correlated with the ROTEM fibrinogen temogram A10. Finally, the SEER sonorheometry platelet contribution was calculated by subtracting the fibrinogen contribution from the clot stiffness. This variable was correlated with both absolute platelet counts, and ROTEM determined clot elasticity attributable to platelets. RESULTS: Fifty-one patients were enrolled in this prospective observational study. SEER sonorheometry clot stiffness, fibrinogen, and platelet contribution had a very strong correlation with ROTEM external temogram A10 (rs = .92; 99% confidence interval, .85–.96), fibrinogen temogram A10 (rs = .90; 99% confidence interval, .83–.93), and ROTEM-determined clot elasticity attributable to platelets (rs = .89; 99% confidence interval, .80–.95). SEER sonorheometry clot time exhibited moderate correlation with ROTEM intrinsic temogram clotting time (rs = .62; 99% confidence interval, .44–.77) and very weak correlation with activated partial thromboplastin time (rs = .33; 99% confidence interval, .10–.51). CONCLUSIONS: SEER sonorheometry demonstrates very strong correlation with ROTEM for determining clot stiffness and assessing fibrinogen and platelet contribution to clot strength in major spine surgery. An advantage of SEER sonorheometry is direct measurement of clot elasticity with no need to transform amplitude oscillation to elasticity.http://ift.tt/2fpEVM6
Does Only Size Matter or Is There Still a Place for Single-Center Studies in the Era of Big Data?
No abstract availablehttp://ift.tt/2fpISjS
Comparison of SEER Sonorheometry With Rotational Thromboelastometry and Laboratory Parameters in Cardiac Surgery
BACKGROUND: The Quantra Hemostasis Analyzer is a novel diagnostic device that uses an ultrasound-based technology, sonic estimation of elasticity via resonance (SEER) sonorheometry, to characterize the dynamic changes in viscoelastic properties of a blood sample during coagulation. Cardiac surgery utilizing cardiopulmonary bypass (CPB) is associated with a significant impact on the coagulation system and can result in perioperative coagulopathy. The aim of this study was to correlate SEER sonorheometry results to corresponding rotational thromboelastometry (ROTEM) and laboratory parameters obtained before, during, and after CPB. METHODS: The Quantra uses a multiwell cartridge that performs 4 independent measurements with different combination of reagents. The output test results include Clot Time, Clot Stiffness, Fibrinogen and Platelet Contribution, Clot Time Ratio, and Heparinase Clot Time. Clot Time was compared with ROTEM INTEM clotting time and the adjusted partial thromboplastin time. Clot Stiffness was compared with ROTEM EXTEM. The Fibrinogen Contribution to the Clot Stiffness was correlated to ROTEM FIBTEM as well as fibrinogen concentration by the Clauss method. The Platelet Contribution to Clot Stiffness was compared with absolute platelet count and ROTEM-determined clot elasticity attributable to platelets. RESULTS: Fifty-five patients undergoing elective cardiac surgery were enrolled in this prospective observational study. Clot Time exhibited good correlation with ROTEM INTEM clotting time (pre-CPB r = 0.84, post-CPB r = 0.65) and adjusted partial thromboplastin time (pre-CPB r = 0.72, post-CPB r = 0.89); however, the majority of values were within a narrow normal range. Clot Stiffness exhibited significant correlation with ROTEM EXTEM A10 throughout the course of the study in all samples (r = 0.84). Fibrinogen Contribution correlated strongly with FIBTEM A10 (r = 0.85), and moderately with the fibrinogen concentration (r = 0.73) determined with the Clauss assay. The Platelet Contribution to Clot Stiffness showed moderate correlation to absolute platelet counts (r = 0.48). However, the correlation between Platelet Contribution and ROTEM-determined clot elasticity attributable to platelets was stronger (r = 0.78) than platelet number. All of the correlation coefficients were statistically significant with Phttp://ift.tt/2fpGGIV
EP4 Receptor-Associated Protein in Macrophages Protects against Bleomycin-Induced Pulmonary Inflammation in Mice [INNATE IMMUNITY AND INFLAMMATION]
Excessive activation of inflammatory macrophages drives the pathogenesis of many chronic diseases. EP4 receptor–associated protein (EPRAP) has been identified as a novel, anti-inflammatory molecule in macrophages. In this study, we investigated the role of EPRAP using a murine model of bleomycin (BLM)-induced pulmonary inflammation. When compared with wild-type mice, EPRAP-deficient mice exhibited significantly higher mortality, and increased accumulation of macrophages and proinflammatory molecules in the lung 7 d post-BLM administration. Accordingly, the levels of phosphorylated p105, MEK1/2, and ERK1/2 were elevated in EPRAP-deficient alveolar macrophages following BLM administration. In contrast, macrophage-specific EPRAP overexpression decreased the production of proinflammatory cytokines and chemokines, suggesting that EPRAP in macrophages plays a key role in attenuating BLM-induced pulmonary inflammation. As EPRAP is phosphorylated after translation, we examined the role of posttranslational modifications in cellular inflammatory activation using mouse embryo fibroblasts (MEFs) expressing mutant EPRAP proteins. Expression of mutant EPRAP, in which serine–108 and serine–608 were replaced with alanine (EPRAP S108A/S608A), markedly suppressed TNF-α production in LPS-treated MEFs. Conversely, the serine phosphatase 2A (PP2A) inhibitor, cantharidic acid, increased LPS-induced TNF-α production in MEFs expressing wild-type EPRAP, but not in MEFs expressing EPRAP S108A/S608A. Immunoprecipitation analyses demonstrated that EPRAP associated with PP2A in both MEFs and alveolar macrophages from BLM-treated mice. Our data suggest that PP2A dephosphorylates EPRAP, which may be a crucial step in exertion of its anti-inflammatory properties. For these reasons, we believe the EPRAP–PP2A axis in macrophages holds the key to treating chronic inflammatory disorders.
http://ift.tt/2goyVHq
IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants [IMMUNOTHERAPY AND VACCINES]
Designing modern vaccine adjuvants depends on understanding the cellular and molecular events that connect innate and adaptive immune responses. The synthetic TLR4 agonist glycopyranosyl lipid adjuvant (GLA) formulated in a squalene-in-water emulsion (GLA-SE) augments both cellular and humoral immune responses to vaccine Ags. This adjuvant is currently included in several vaccines undergoing clinical evaluation including those for tuberculosis, leishmaniasis, and influenza. Delineation of the mechanisms of adjuvant activity will enable more informative evaluation of clinical trials. Early after injection, GLA-SE induces substantially more Ag-specific B cells, higher serum Ab titers, and greater numbers of T follicular helper (TFH) and Th1 cells than alum, the SE alone, or GLA without SE. GLA-SE augments Ag-specific B cell differentiation into germinal center and memory precursor B cells as well as preplasmablasts that rapidly secrete Abs. CD169+ SIGNR1+ subcapsular medullary macrophages are the primary cells to take up GLA-SE after immunization and are critical for the innate immune responses, including rapid IL-18 production, induced by GLA-SE. Depletion of subcapsular macrophages (SCMfe) or abrogation of IL-18 signaling dramatically impairs the Ag-specific B cell and Ab responses augmented by GLA-SE. Depletion of SCMfe also drastically reduces the Th1 but not the TFH response. Thus the GLA-SE adjuvant operates through interaction with IL-18–producing SCMfe for the rapid induction of B cell expansion and differentiation, Ab secretion, and Th1 responses, whereas augmentation of TFH numbers by GLA-SE is independent of SCMfe.
http://ift.tt/2gorFLR
Therapeutic Targeting of the G-CSF Receptor Reduces Neutrophil Trafficking and Joint Inflammation in Antibody-Mediated Inflammatory Arthritis [INNATE IMMUNITY AND INFLAMMATION]
G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. G-CSF– and G-CSF receptor–deficient mice are profoundly protected in several models of rheumatoid arthritis, and Ab blockade of G-CSF also protects against disease. To further investigate the actions of blocking G-CSF/G-CSF receptor signaling in inflammatory disease, and as a prelude to human studies of the same approach, we developed a neutralizing mAb to the murine G-CSF receptor, which potently antagonizes binding of murine G-CSF and thereby inhibits STAT3 phosphorylation and G-CSF receptor signaling. Anti–G-CSF receptor rapidly halted the progression of established disease in collagen Ab-induced arthritis in mice. Neutrophil accumulation in joints was inhibited, without rendering animals neutropenic, suggesting an effect of G-CSF receptor blockade on neutrophil homing to inflammatory sites. Consistent with this, neutrophils in the blood and arthritic joints of anti–G-CSF receptor–treated mice showed alterations in cell adhesion receptors, with reduced CXCR2 and increased CD62L expression. Furthermore, blocking neutrophil trafficking with anti–G-CSF receptor suppressed local production of proinflammatory cytokines (IL-1β, IL-6) and chemokines (KC, MCP-1) known to drive tissue damage. Differential gene expression analysis of joint neutrophils showed a switch away from an inflammatory phenotype following anti–G-CSF receptor therapy in collagen Ab-induced arthritis. Importantly, G-CSF receptor blockade did not adversely affect viral clearance during influenza infection in mice. To our knowledge, we describe for the first time the effect of G-CSF receptor blockade in a therapeutic model of inflammatory joint disease and provide support for pursuing this therapeutic approach in treating neutrophil-associated inflammatory diseases.
http://ift.tt/2gov2Cu
Expansion of Th17 Cells by Human Mast Cells Is Driven by Inflammasome-Independent IL-1{beta} [MUCOSAL IMMUNOLOGY]
Mast cells (MC) are most well known for their role in innate immune responses. However, MC are increasingly recognized as important regulators of adaptive immune responses, especially in setting the outcome of T cell responses. In this study we determined the effect of MC on cytokine production by naive and memory human Th cells. CD4+ T cells were cultured with MC supernatant or control medium, after which cytokine production by T cells was determined. Supernatant of activated MC specifically increased the number of IL-17–producing T cells. This enhancement of Th17 cell number was specifically observed for the memory CD4+ T cell population and not for the naive CD4+ T cell population. The effect of MC was inhibited for ~80% by blocking Abs to IL-1β and the rIL-1R antagonist anakinra. Importantly, secretion of active IL-1β by MC was independent of caspase activity, indicating that Th17 cell expansion by MC occurred through inflammasome-independent IL-1β. Together, these studies reveal a role for human MC in setting the outcome of T cell responses through release of caspase-independent IL-1β, and provide evidence for a novel contribution of MC in boosting the Th17 axis in mucosal immune responses.
http://ift.tt/2gowmFu
Acetylation Modulates IL-2 Receptor Signaling in T Cells [IMMUNE REGULATION]
Ligand binding to the cognate cytokine receptors activates intracellular signaling by recruiting protein tyrosine kinases and other protein modification enzymes. However, the roles of protein modifications other than phosphorylation remain unclear. In this study, we examine a novel regulatory mechanism of Stat5, based on its acetylation. As for phosphorylation, IL-2 induces the acetylation of signaling molecules, including Stat5, in the murine T cell line CTLL-2. Stat5 is acetylated in the cytoplasm by CREB-binding protein (CBP). Acetylated Lys696 and Lys700 on Stat5 are critical indicators for limited proteolysis, which leads to the generation of a truncated form of Stat5. In turn, the truncated form of Stat5 prevents transcription of the full-length form of Stat5. We also demonstrate that CBP physically associates with the IL-2 receptor β-chain. CBP, found in the nucleus in resting CTLL-2 cells, relocates to the cytoplasm after IL-2 stimulation in an MEK/ERK pathway–dependent manner. Thus, IL-2–mediated acetylation plays an important role in the modulation of cytokine signaling and T cell fate.
http://ift.tt/2gowcxL
BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity [INFECTIOUS DISEASE AND HOST RESPONSE]
The AP-1 factor basic leucine zipper transcription factor, ATF-like (BATF) is important for CD4+ Th17, Th9, and follicular Th cell development. However, its precise role in Th2 differentiation and function remains unclear, and the requirement for BATF in nonallergic settings of type-2 immunity has not been explored. In this article, we show that, in response to parasitic helminths, Batf–/– mice are unable to generate follicular Th and Th2 cells. As a consequence, they fail to establish productive type-2 immunity during primary and secondary infection. Batf–/– CD4+ T cells do not achieve type-2 cytokine competency, which implies that BATF plays a key role in the regulation of IL-4 and IL-13. In contrast to Th17 and Th9 cell subsets in which BATF binds directly to promoter and enhancer regions to regulate cytokine expression, our results show that BATF is significantly enriched at Rad50 hypersensitivity site (RHS)6 and RHS7 of the locus control region relative to AP-1 sites surrounding type-2 cytokine loci in Th2 cells. Indeed, Batf–/– CD4+ T cells do not obtain permissive epigenetic modifications within the Th2 locus, which were linked to RHS6 and RHS7 function. In sum, these findings reveal BATF as a central modulator of peripheral and humoral hallmarks of type-2 immunity and begin to elucidate a novel mechanism by which it regulates type-2 cytokine production through its modification of the Th2 locus control region.
http://ift.tt/2gowncw
Age-Specific Adjuvant Synergy: Dual TLR7/8 and Mincle Activation of Human Newborn Dendritic Cells Enables Th1 Polarization [INNATE IMMUNITY AND INFLAMMATION]
Due to functionally distinct cell-mediated immunity, newborns and infants are highly susceptible to infection with intracellular pathogens. Indeed, neonatal Ag-presenting dendritic cells (DCs) demonstrate impaired Th1 responses to many candidate adjuvants, including most TLR agonists (TLRAs). Combination adjuvantation systems may provide enhanced immune activation but have typically been developed without regard to the age of the target population. We posited that distinct combinations of TLRAs and C-type lectin receptor agonists may enhance Th1 responses of newborn DCs. TLRA/C-type lectin receptor agonist combinations were screened for enhancement of TNF production by human newborn and adult monocyte-derived DCs cultured in 10% autologous plasma or in newborn cord, infant, adult, and elderly whole blood. Monocyte-derived DC activation was characterized by targeted gene expression analysis, caspase-1 and NF-B studies, cytokine multiplex and naive autologous CD4+ T cell activation. Dual activation of newborn DCs via the C-type lectin receptor, macrophage-inducible C-type lectin (trehalose-6,6-dibehenate), and TLR7/8 (R848) greatly enhanced caspase-1 and NF-B activation, Th1 polarizing cytokine production and autologous Th1 polarization. Combined activation via TLR4 (glycopyranosyl lipid adjuvant aqueous formulation) and Dectin-1 (β-glucan peptide) acted synergistically in newborns and adults, but to a lesser extent. The degree of synergy varied dramatically with age, and was the greatest in newborns and infants with less synergy in adults and elders. Overall, combination adjuvant systems demonstrate markedly different immune activation with age, with combined DC activation via Macrophage-inducible C-type lectin and TLR7/8 representing a novel approach to enhance the efficacy of early-life vaccines.
http://ift.tt/2gorAHQ
Tissue Microenvironments in the Nasal Epithelium of Rainbow Trout (Oncorhynchus mykiss) Define Two Distinct CD8{alpha}+ Cell Populations and Establish Regional Immunity [MUCOSAL IMMUNOLOGY]
Mucosal surfaces require balancing different physiological roles and immune functions. To effectively achieve multifunctionality, mucosal epithelia have evolved unique microenvironments that create unique regional immune responses without impairing other normal physiological functions. Whereas examples of regional immunity are known in other mucosal epithelia, to date, no immune microenvironments have been described in the nasal mucosa, a site where the complex functions of olfaction and immunity need to be orchestrated. In this study we identified the presence of CD8α+ cells in the rainbow trout (Oncorhynchus mykiss) nasal epithelium. Nasal CD8α+ cells display a distinct phenotype suggestive of CD8+ T cells with high integrin β2 expression. Importantly, nasal CD8α+ cells are located in clusters at the mucosal tip of each olfactory lamella but scattered in the neuroepithelial region. The grouping of CD8α+ cells may be explained by the greater expression of CCL19, ICAM-1, and VCAM-1 in the mucosal tip compared with the neuroepithelium. Whereas viral Ag uptake occurred via both tip and lateral routes, tip-resident MHC class II+ cells are located significantly closer to the lumen of the nasal cavity than are their neuroepithelial counterparts, therefore having quicker access to invading pathogens. Our studies reveal compartmentalized mucosal immune responses within the nasal mucosa of a vertebrate species, a strategy that likely optimizes local immune responses while protecting olfactory sensory functions.
http://ift.tt/2goCLjG
Lung Cancer Subtypes Generate Unique Immune Responses [TUMOR IMMUNOLOGY]
Lung cancer, the leading cause of cancer-related deaths worldwide, is a heterogeneous disease comprising multiple histologic subtypes that harbor disparate mutational profiles. Immune-based therapies have shown initial promise in the treatment of lung cancer patients but are limited by low overall response rates. We sought to determine whether the host immune response to lung cancer is dictated, at least in part, by histologic and genetic differences, because such correlations would have important clinical ramifications. Using mouse models of lung cancer, we show that small cell lung cancer (SCLC) and lung adenocarcinoma (ADCA) exhibit unique immune cell composition of the tumor microenvironment. The total leukocyte content was markedly reduced in SCLC compared with lung ADCA, which was validated in human lung cancer specimens. We further identified key differences in immune cell content using three models of lung ADCA driven by mutations in Kras, p53, and Egfr. Although Egfr-mutant cancers displayed robust myeloid cell recruitment, they failed to mount a CD8+ immune response. In contrast, Kras-mutant tumors displayed significant expansion of multiple immune cell types, including CD8+ cells, regulatory T cells, IL-17A–producing lymphocytes, and myeloid cells. A human tissue microarray annotated for KRAS and EGFR mutations validated the finding of reduced CD8+ content in human lung ADCA. Taken together, these findings establish a strong foundational knowledge of the immune cell contexture of lung ADCA and SCLC and suggest that molecular and histological traits shape the host immune response to cancer.
http://ift.tt/2gorzDR
BPTF Is Essential for T Cell Homeostasis and Function [IMMUNE REGULATION]
Bromodomain PHD finger transcription factor (BPTF), a ubiquitously expressed ATP-dependent chromatin-remodeling factor, is critical for epigenetically regulating DNA accessibility and gene expression. Although BPTF is important for the development of thymocytes, its function in mature T cells remains largely unknown. By specifically deleting BPTF from late double-negative 3/double-negative 4 stage of developing T cells, we found that BPTF was critical for the homeostasis of T cells via a cell-intrinsic manner. In addition, BPTF was essential for the maintenance and function of regulatory T (Treg) cells. Treg cell–specific BPTF deletion led to reduced Foxp3 expression, increased lymphocyte infiltration in the nonlymphoid organs, and a systemic autoimmune syndrome. These findings therefore reveal a vital role for BPTF in T and Treg cell function and immune homeostasis.
http://ift.tt/2f8Reve
Identification and Actions of the Maresin 1 Metabolome in Infectious Inflammation [INNATE IMMUNITY AND INFLAMMATION]
Maresin 1 (MaR1) is an immunoresolvent that governs resolution of acute inflammation, and its local metabolism in the context of infectious inflammation is of interest. In this study, we investigated the MaR1 metabolome in infectious exudates and its bioactions in regulating leukocyte responses in the context of bacterial infection. In Escherichia coli infectious exudates, MaR1 was temporally regulated with maximal levels at 4 h (2.2 ± 0.4 pg/lavage). In these exudates we also identified two novel products, and their structure elucidation gave 22-hydroxy-MaR1 and 14-oxo-MaR1. Using human primary leukocytes, we found that neutrophils primarily produced 22-OH-MaR1, whereas the main macrophage product was 14-oxo-MaR1. Both 22-OH-MaR1 and 14-oxo-MaR1 incubated with human primary macrophages gave dose-dependent increases in macrophage phagocytosis of ~75% at 1 pM 22-OH-MaR1 and ~25% at 1 pM 14-oxo-MaR1, whereas 14-oxo-MaR1 was less active than MaR1 at higher concentrations. Together these findings establish the temporal regulation of MaR1 during infectious inflammation, and elucidate the structures and actions of two novel MaR1 further metabolites that carry bioactivities.
http://ift.tt/2f8KzBn
Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation [INFECTIOUS DISEASE AND HOST RESPONSE]
NK cells represent a critical first-line of immune defense against a bevy of viral pathogens, and infection can provoke them to mediate supportive and suppressive effects on virus-specific adaptive immunity. In mice expressing MHC class I Dk (Dk), a major murine CMV (MCMV) resistance factor and self-ligand of the inhibitory Ly49G2 (G2) receptor, licensed G2+ NK cells provide essential host resistance against MCMV infection. Additionally G2+ NK cell responses to MCMV increase the rate and extent of dendritic cell (DC) recovery, as well as early priming of CD8+ T cell effectors in response to MCMV. However, relatively little is known about the NK cell effect on costimulatory ligand patterns displayed by DCs or on ensuing effector and memory T cell responses. In this study, we found that CD27-dependent CD8+ T cell priming and differentiation are shaped by the efficiency of NK responses to virus infection. Surprisingly, differences in specific NK responses to MCMV in Dk-disparate mice failed to distinguish early DC costimulatory patterns. Nonetheless, although CD27 deficiency did not impede licensed NK-mediated resistance, CD70 and CD27 were required to efficiently prime and regulate effector CD8+ T cell differentiation in response to MCMV, which eventually resulted in biased memory T cell precursor formation in Dk mice. In contrast, CD8+ T cells accrued more slowly in non-Dk mice and eventually differentiated into terminal effector cells regardless of CD27 stimulation. Disparity in this requirement for CD27 signaling indicates that specific virus control mediated by NK cells can shape DC costimulatory signals needed to prime CD8+ T cells and eventual T cell fate decisions.
http://ift.tt/2f8LotL
From IgE to Omalizumab [TRANSLATING IMMUNOLOGY]
IgE is the least abundant Ig isotype, yet it plays a critical role in allergic reactions and host protection from helminth infection. Although IgE was discovered 50 years ago, the ultimate evidence for its role in human allergic diseases was obtained by the efficacy of anti-IgE therapy in many clinical trials on asthma and other allergic diseases. Beginning from the discovery of IgE 50 y ago, followed by studies of IgE receptors and activation mechanisms, this review provides a historic perspective of allergy research that has led to the development of anti-IgE therapy and other strategies targeting IgE and its receptors. Current IgE studies toward future precision medicine are also reviewed.
http://ift.tt/2f8QuGd
T Cell-Independent Mechanisms Associated with Neutrophil Extracellular Trap Formation and Selective Autophagy in IL-17A-Mediated Epidermal Hyperplasia [INNATE IMMUNITY AND INFLAMMATION]
IL-17A has been strongly associated with epidermal hyperplasia in many cutaneous disorders. However, because IL-17A is mainly produced by αβ and T cells in response to IL-23, the role of T cells and IL-23 has overshadowed any IL-17A–independent actions. In this article, we report that IL-17A gene transfer induces epidermal hyperplasia in Il23r–/–Rag1–/–- and Tcr-deficient mice, which can be prevented by neutrophil depletion. Moreover, adoptive transfer of CD11b+Gr-1hi cells, after IL-17A gene transfer, was sufficient to phenocopy the disease. We further show that the IL-17A–induced pathology was prevented in transgenic mice with impaired neutrophil extracellular trap formation and/or neutrophils with conditional deletion of the master regulator of selective autophagy, Wdfy3. Our data demonstrate a novel T cell–independent mechanism that is associated with neutrophil extracellular trap formation and selective autophagy in IL-17A–mediated epidermal hyperplasia.
http://ift.tt/2f8HssX
Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy [SYSTEMS IMMUNOLOGY]
Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4+ and CD8+ T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet+CD4+ T cells, CD8+ T cells, B cells, and CD56loCD16+ NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.
http://ift.tt/2f8IcOU
Lin28b Regulates Fetal Regulatory T Cell Differentiation through Modulation of TGF-{beta} Signaling [IMMUNE SYSTEM DEVELOPMENT]
Immune tolerance between the fetus and mother represents an active process by which the developing fetus must not mount immune responses to noninherited Ags on chimeric maternal cells that reside in fetal tissue. This is, in part, mediated by the suppressive influence of CD4+FOXP3+CD25+ regulatory T cells (Tregs). Fetal secondary lymphoid organs have an increased frequency of Tregs and, as compared with adult T cells, fetal naive CD4+ T cells exhibit a strong predisposition to differentiate into Tregs when stimulated. This effect is mediated by the TCR and TGF-β pathways, and fetal T cells show significantly increased Treg differentiation in response to anti-CD3 and TGF-β stimulation. Naive fetal T cells also exhibit increased signaling through the TGF-β pathway, with these cells demonstrating increased expression of the signaling mediators TGF-βRI, TGF-βRIII, and SMAD2, and higher levels of SMAD2/SMAD3 phosphorylation. Increased fetal Treg differentiation is mediated by the RNA-binding protein Lin28b, which is overexpressed in fetal T cells as compared with adult cells. When Lin28b expression is decreased in naive fetal T cells, they exhibit decreased Treg differentiation that is associated with decreased TGF-β signaling and lowered expression of TGF-βRI, TGF-βRIII, and SMAD2. Lin28b regulates the maturation of let-7 microRNAs, and these TGF-β signaling mediators are let-7 targets. We hypothesize that loss of Lin28b expression in fetal T cells leads to increased mature let-7, which causes decreased expression of TGF-βRI, TGF-βRIII, and SMAD2 proteins. A reduction in TGF-β signaling leads to reduced Treg numbers.
http://ift.tt/2f8OcHi
Immunological Outcomes of Antibody Binding to Glycans Shared between Microorganisms and Mammals [BRIEF REVIEWS]
Glycans constitute basic cellular components of living organisms across biological kingdoms, and glycan-binding Abs participate in many cellular interactions during immune defense against pathogenic organisms. Glycan epitopes are expressed as carbohydrate-only entities or as oligomers or polymers on proteins and lipids. Such epitopes on glycoproteins may be formed by posttranslational modifications or neoepitopes resulting from metabolic–catabolic processes and can be altered during inflammation. Pathogenic organisms can display host-like glycans to evade the host immune response. However, Abs to glycans, shared between microorganisms and the host, exist naturally. These Abs are able to not only protect against infectious disease, but also are involved in host housekeeping functions and can suppress allergic disease. Despite the reactivity of these Abs to glycans shared between microorganisms and host, diverse tolerance-inducing mechanisms permit the B cell precursors of these Ab-secreting cells to exist within the normal B cell repertoire.
http://ift.tt/2gorD6z
A Role for Human Skin Mast Cells in Dengue Virus Infection and Systemic Spread [INFECTIOUS DISEASE AND HOST RESPONSE]
Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious global human disease and mortality. Skin immune cells are an important component of initial DENV infection and systemic spread. Here, we show that mast cells are a target of DENV in human skin and that DENV infection of skin mast cells induces degranulation and alters cytokine and growth factor expression profiles. Importantly, to our knowledge, we also demonstrate for the first time that DENV localizes within secretory granules in infected skin mast cells. In addition, DENV within extracellular granules was infectious in vitro and in vivo, trafficking through lymph to draining lymph nodes in mice. We demonstrate an important role for human skin mast cells in DENV infection and identify a novel mechanism for systemic spread of DENV infection from the initial peripheral mosquito injection site.
http://ift.tt/2f8La5J
Immune-Mediated Protection and Pathogenesis of Chikungunya Virus [BRIEF REVIEWS]
Chikungunya virus (CHIKV) is a re-emerging alphavirus that causes debilitating acute and chronic arthritis. Infection by CHIKV induces a robust immune response that is characterized by production of type I IFNs, recruitment of innate and adaptive immune cells, and development of neutralizing Abs. Despite this response, chronic arthritis can develop in some individuals, which may be due to a failure to eliminate viral RNA and Ag and/or persistent immune responses that cause chronic joint inflammation. In this review, based primarily on advances from recent studies in mice, we discuss the innate and adaptive immune factors that control CHIKV dissemination and clearance or contribute to pathogenesis.
http://ift.tt/2f8M6am
TLR8 Couples SOCS-1 and Restrains TLR7-Mediated Antiviral Immunity, Exacerbating West Nile Virus Infection in Mice [INNATE IMMUNITY AND INFLAMMATION]
West Nile virus (WNV) is a neurotropic ssRNA flavivirus that can cause encephalitis, meningitis, and death in humans and mice. Human TLR7 and TLR8 and mouse TLR7 recognize viral ssRNA motifs and induce antiviral immunity. However, the role of mouse TLR8 in antiviral immunity is poorly understood. In this article, we report that TLR8-deficient (Tlr8–/–) mice were resistant to WNV infection compared with wild-type controls. Efficient WNV clearance and moderate susceptibility to WNV-mediated neuronal death in Tlr8–/– mice were attributed to overexpression of Tlr7 and IFN-stimulated gene-56 expression, whereas reduced expression of the proapoptotic gene coding Bcl2-associated X protein was observed. Interestingly, suppressor of cytokine signaling (SOCS)-1 directly associated with TLR8, but not with TLR7, indicating a novel role for TLR8 regulation of SOCS-1 function, whereas selective small interfering RNA knockdown of Socs-1 resulted in induced IFN-stimulated gene-56 and Tlr7 expression following WNV infection. Collectively, we report that TLR8 coupling with SOCS-1 inhibits TLR7-mediated antiviral immunity during WNV infection in mice.
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IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod) [ALLERGY AND OTHER HYPERSENSITIVITIES]
Different models of experimental allergic asthma have shown that the TLR7/8 agonist resiquimod (R848) is a potential inhibitor of type 2 helper cell–driven inflammatory responses. However, the mechanisms mediating its therapeutic effects are not fully understood. Using a model of experimental allergic asthma, we show that induction of IL-27 by R848 is critical for the observed ameliorative effects. R848 significantly inhibited all hallmarks of experimental allergic asthma, including airway hyperreactivity, eosinophilic airway inflammation, mucus hypersecretion, and Ag-specific Ig production. Whereas R848 significantly reduced IL-5, IL-13, and IL-17, it induced IFN- and IL-27. Neutralization of IL-27 completely reversed the therapeutic effect of R848 in the experimental asthma model, demonstrating dependence of R848-mediated suppression on IL-27. In vitro, R848 induced production of IL-27 by murine alveolar macrophages and dendritic cells and enhanced expression of programmed death–ligand 1, whose expression on monocytes and dendritic cells has been shown to regulate peripheral tolerance in both murine and human studies. Moreover, in vitro IL-27 enhanced secretion of IFN- whereas it inhibited IL-5 and IL-13, demonstrating its direct effect on attenuating Th2 responses. Taken together, our study proves that R848-mediated suppression of experimental asthma is dependent on IL-27. These data provide evidence of a central role of IL-27 for the control of Th2-mediated allergic diseases.
http://ift.tt/2got3hz
NKT Cell-Deficient Mice Harbor an Altered Microbiota That Fuels Intestinal Inflammation during Chemically Induced Colitis [MUCOSAL IMMUNOLOGY]
NKT cells are unconventional T cells that respond to self and microbe-derived lipid and glycolipid Ags presented by the CD1d molecule. Invariant NKT (iNKT) cells influence immune responses in numerous diseases. Although only a few studies have examined their role during intestinal inflammation, it appears that iNKT cells protect from Th1-mediated inflammation but exacerbate Th2-mediated inflammation. Studies using iNKT cell–deficient mice and chemically induced dextran sodium sulfate (DSS) colitis have led to inconsistent results. In this study, we show that CD1d-deficient mice, which lack all NKT cells, harbor an altered intestinal microbiota that is associated with exacerbated intestinal inflammation at steady-state and following DSS treatment. This altered microbiota, characterized by increased abundance of the bacterial phyla Proteobacteria, Deferribacteres, and TM7, among which the mucin-eating Mucispirillum, as well as members of the genus Prevotella and segmented filamentous bacteria, was transmissible upon fecal transplant, along with the procolitogenic phenotype. Our results also demonstrate that this proinflammatory microbiota influences iNKT cell function upon activation during DSS colitis. Collectively, alterations of the microbiota have a major influence on colitis outcome and therefore have to be accounted for in such experimental settings and in studies focusing on iNKT cells.
http://ift.tt/2f8Js4v
Airway Epithelial KIF3A Regulates Th2 Responses to Aeroallergens [ALLERGY AND OTHER HYPERSENSITIVITIES]
KIF3A, the gene encoding kinesin family member 3A, is a susceptibility gene locus associated with asthma; however, mechanisms by which KIF3A might influence the pathogenesis of the disorder are unknown. In this study, we deleted the mouse Kif3a gene in airway epithelial cells. Both homozygous and heterozygous Kif3a gene–deleted mice were highly susceptible to aeroallergens from Aspergillus fumigatus and the house dust mite, resulting in an asthma-like pathology characterized by increased goblet cell metaplasia, airway hyperresponsiveness, and Th2-mediated inflammation. Deletion of the Kif3a gene increased the severity of pulmonary eosinophilic inflammation and expression of cytokines (Il-4, Il-13, and Il-17a) and chemokine (Ccl11) RNAs following pulmonary exposure to Aspergillus extract. Inhibition of Kif3a disrupted the structure of motile cilia and impaired mucociliary clearance, barrier function, and epithelial repair, demonstrating additional mechanisms by which deficiency of KIF3A in respiratory epithelial cells contributes to pulmonary pathology. Airway epithelial KIF3A suppresses Th2 pulmonary inflammation and airway hyperresponsiveness following aeroallergen exposure, implicating epithelial microtubular functions in the pathogenesis of Th2-mediated lung pathology.
http://ift.tt/2f8Iu8w
Mast Cells Limit the Exacerbation of Chronic Allergic Contact Dermatitis in Response to Repeated Allergen Exposure [ALLERGY AND OTHER HYPERSENSITIVITIES]
Allergic contact dermatitis is a chronic T cell–driven inflammatory skin disease that is caused by repeated exposure to contact allergens. Based on murine studies of acute contact hypersensitivity, mast cells (MCs) are believed to play a role in its pathogenesis. The role of MCs in chronic allergic contact dermatitis has not been investigated, in part because of the lack of murine models for chronic contact hypersensitivity. We developed and used a chronic contact hypersensitivity model in wild-type and MC-deficient mice and assessed skin inflammatory responses to identify and characterize the role of MCs in chronic allergic contact dermatitis. Ear swelling chronic contact hypersensitivity responses increased markedly, up to 4-fold, in MC-deficient KitW-sh/W-sh (Sash) and MCPT5-Cre+iDTR+ mice compared with wild-type mice. Local engraftment with MCs protected Sash mice from exacerbated ear swelling after repeated oxazolone challenge. Chronic contact hypersensitivity skin of Sash mice exhibited elevated levels of IFN-, IL-17α, and IL-23, as well as increased accumulation of Ag-specific IFN-–producing CD8+ tissue-resident memory T (TRM) cells. The CD8+ T cell mitogen IL-15, which was increased in oxazolone-challenged skin of Sash mice during the accumulation of cutaneous TRM cells, was efficiently degraded by MCs in vitro. MCs protect from the exacerbated allergic skin inflammation induced by repeated allergen challenge, at least in part, via effects on CD8+ TRM cells. MCs may notably influence the course of chronic allergic contact dermatitis. A better understanding of their role and the underlying mechanisms may lead to better approaches for the treatment of this common, disabling, and costly condition.
http://ift.tt/2gowfcV
Th9 and other IL-9-producing cells in allergic asthma
Abstract
Allergic asthma is a worldwide increasing chronic disease of the airways which affects more than 300 million people. It is associated with increased IgE, mast cell activation, airway hyperresponsiveness (AHR), mucus overproduction and remodeling of the airways. Previously, this pathological trait has been associated with T helper type 2 (Th2) cells. Recently, different CD4+ T cell subsets (Th17, Th9) as well as cells of innate immunity, like mast cells and innate lymphoid cells type 2 (ILC2s), which are all capable of producing the rediscovered cytokine IL-9, are known to contribute to this disease. Regarding Th9 cells, it is known that naïve T cells develop into IL-9-producing cells in the presence of interleukin-4 (IL-4) and transforming growth factor beta (TGFβ). Downstream of IL-4, several transcription factors like signal transducer and activator of transcription 6 (STAT6), interferon regulatory factor 4 (IRF4), GATA binding protein 3 (GATA3), basic leucine zipper transcription factor, ATF-like (BATF) and nuclear factor of activated T cells (NFAT) are activated. Additionally, the transcription factor PU.1, which is downstream of TGFβ signaling, also seems to be crucial in the development of Th9 cells. IL-9 is a pleiotropic cytokine that influences various distinct functions of different target cells such as T cells, B cells, mast cells and airway epithelial cells by activating STAT1, STAT3 and STAT5. Because of its pleiotropic functions, IL-9 has been demonstrated to be involved in several diseases, such as cancer, autoimmunity and other pathogen-mediated immune-regulated diseases. In this review, we focus on the role of Th9 and IL-9-producing cells in allergic asthma.
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Melanoma diagnosis may be a pitfall for optical coherence tomography assessment of equivocal amelanotic or hypomelanotic skin lesions
Amelanotic and hypomelanotic skin lesions can be difficult to diagnose clinically and dermoscopically.1-3 Evidence is emerging that optical coherence tomography (OCT) can detect superficial basal cell carcinoma (sBCC) with good sensitivity (79-95.7%) and specificity (75.3-96%).4 Given that sBCC is a common problem4, and that it may be treated noninvasively5, the potential benefits from using OCT as an adjunct to clinical diagnosis are high. However, if OCT is used without histopathological confirmation in this setting, there is a risk that more clinically aggressive malignant pathology, such as amelanotic /hypomelanotic melanoma (AHM), may be misdiagnosed and left to progress if it is inadequately treated. Indeed, this research was prompted after experiencing a clinical case where a lesion had typical clinical-dermoscopic and OCT features for sBCC, but histopathology revealed an amelanotic melanoma.
This article is protected by copyright. All rights reserved.
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Skin manifestations in ultra-marathon runners: experience in the Marathon des Sables 2014
Ultra-marathons are becoming increasingly popular (1). In 2014 (4th to 14th April), the 29th Sultan Marathon des Sables (MDS) took place in Morocco. Overall, 1100 runners, men and women aged 16 to 80, met this challenge. Their goal was an endurance race of around 250 km in 5 self-sufficient stages in the desert over 6 days. Each runner carried their own rucksack of 7-10 kg with all of the necessary equipment and food (except water). Ultra-marathons are associated with well-known problems including dehydration, changes in body mass, loss of skeletal muscle mass, rhabdomyolysis with renal failure, and an increase in total body water. Lower limb and foot injuries are frequent in ultra-marathon runners, but specific skin manifestations may occur as a consequence of the extreme conditions of the MDS: high temperature with high rate of perspiration and salt loss, sun exposure, and contact with the sand.
This article is protected by copyright. All rights reserved.
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Trends in contact allergy to fragrance mix I in consecutive Danish eczema patients over three decades; a cross-sectional study from 1986 to 2015
Summary
Background
For more than 30 years, fragrance mix I (FMI) has been the most important screening marker for fragrance contact allergy. Meanwhile, governmental and corporate initiatives have been implemented, aimed at reducing sensitization to fragrance allergens, including the single constituents of FMI.
Objectives
To examine trends in contact allergy to FMI from 1986 to 2015 in dermatitis patients, and test the hypothesis that sensitization to the fragrance screening marker has decreased within recent years.
Methods
Cross-sectional registry study on patch test results to FMI among consecutively tested dermatitis patients from a single university clinic across three 10-year periods. From 2006-2015, data on eczema location according to MOAHLFAA, clinical relevance of sensitization, and cosmetic exposures were available.
Results
Of 24,168 patients, 7.8% (95% CI: 7.4-8.1%) were sensitized to FMI. For women, a significant trend (p=0.004) was observed for an increase in sensitization to FMI across the three decades. From 2011-2015, the prevalence of contact allergy to FMI increased significantly for both women (8.0% versus 10.4%, p=0.002) and men (4.4% versus 7.3%, p=0.002) compared to the previous 5-year period. From 2006-2015, clinical relevance was established in 78.2% of FMI positive patients with no differences over time. An increase (28.6% versus 36.1%, p=0.05) in FMI positive patients suffering from facial dermatitis was observed for the period 2011-2015 compared to 2006-2010.
Conclusions
The prevalence of contact allergy to FMI has been increasing within recent years. No effect of previous preventive initiatives could be demonstrated.
This article is protected by copyright. All rights reserved.
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MYD88 mutations in a distinct type of cutaneous marginal zone lymphoma with a non-class switched IgM-immunophenotype
Somatic mutations in the MYD88 gene are involved in the molecular pathogenesis of different subtypes of Non-Hodgkin B-cell lymphomas such as diffuse large B-cell lymphoma, lymphoplasmacytic lymphoma and Waldenstrom′s macroglobulinemia1. Albeit with much lower frequency, the key driver mutation MYD88 (c.794T>C, p.L265P) has also been identified in non-cutaneous marginal zone lymphomas and chronic lymphocytic leukemia. The increasing knowledge about such molecular aberrations and their consecutive biological effects has already been implemented within the clinical routine.
This article is protected by copyright. All rights reserved.
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