Background Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy. Objective We sought to test the ...immunologic mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy. Methods Mice were epicutaneously sensitized with ovalbumin or peanut on an atopic dermatitis–like skin lesion, followed by intragastric antigen challenge. Antigen-specific serum IgE levels and TH 2 cytokine responses were measured by ELISA. Expression of type 2 cytokines and mast cell proteases in the intestine were measured by using real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by using flow cytometry. In vivo basophil depletion was achieved by using diphtheria toxin treatment of Baso-DTR mice. For cell-transfer studies, the basophil population was expanded in vivo by means of hydrodynamic tail vein injection of thymic stromal lymphopoietin (TSLP) cDNA plasmid. Results Sensitization to food allergens through an atopic dermatitis–like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific TH 2 cytokine responses, increased antigen-specific serum IgE levels, and accumulation of mast cells in the intestine, promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy, whereas transfer of TSLP-elicited basophils into intact skin promoted disease. Conclusion Epicutaneous sensitization on a disrupted skin barrier is associated with accumulation of TSLP-elicited basophils, which are necessary and sufficient to promote antigen-induced intestinal food allergy.
Basophils and allergic inflammation Siracusa, Mark C., PhD; Kim, Brian S., MD; Spergel, Jonathan M., MD, PhD ...
Journal of allergy and clinical immunology,
10/2013, Volume:
132, Issue:
4
Journal Article
Peer reviewed
Open access
Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of basophils and their phenotypic similarities with mast ...cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that basophils perform nonredundant effector functions and significantly contribute to the development and progression of TH 2 cytokine–mediated inflammation. Although the potential functions of murine and human basophils have provoked some controversy, recent genetic approaches indicate that basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal TH 2 cytokine responses in vivo . This article provides a brief historical perspective on basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting basophils in preventing or alleviating the development and progression of allergic inflammation.
...phenotypic and cytokine profile analyses of peanut-pulsed BMDCs revealed no classical activation by raw or DR peanut preparations compared with LPS (Fig 2, D and E, and see Fig E7 in this ...article's Online Repository at www.jacionline.org). ...by contrast with direct AGE-relevant modification of HEL that showed increased presentation to an HEL-specific T-cell hybridoma, DR PPE-pulsed dendritic cells (DCs) did not enhance the presentation of unmodified HEL, reinforcing the absence of DR PPE-elicited DC costimulation (Fig 2, F, and see Fig E8 in this article's Online Repository at www.jacionline.org).
Abstract Background Exaggerated TSLP production and infiltration of basophils are associated with the pathogenesis of atopic dermatitis (AD), a recognized risk factor for the development of food ...allergies. While TSLP and basophils have been implicated to promote food-induced allergic disorders in response to epicutaneous sensitization, the mechanisms by which TSLP-elicited basophils guide the progression of allergic inflammation in the skin to distant mucosal sites such as the gastrointestinal tract are poorly understood. Objective We sought to test the role of basophil-intrinsic IL-4 production in TH 2 sensitization to food antigens in the skin and effector food allergic responses in the gut. Methods Mice were epicutaneously sensitized with ovalbumin on an AD-like skin lesion, followed by intra-gastric antigen challenge to induce IgE-mediated food allergy. The requirement for basophil-derived IL-4 production for TH 2 polarization and the pathogenesis of IgE-mediated food allergy was assessed in vitro by co-culture experiments with naïve T cells and in vivo using IL-4 3’UTR mice that selectively lack IL-4 production in basophils. Results Epicutaneous food antigen sensitization is associated with the infiltration of IL-4 competent innate immune cells to the skin with basophils and eosinophils representing the predominant populations. In contrast to basophils, absence of eosinophils did not alter disease outcome. Co-culture of IL-4 competent basophils together with dendritic cells and naïve T cells was sufficient to promote TH 2 polarization in an IL-4 dependent manner in vitro, while absence of basophil-intrinsic IL-4 production in vivo was associated with reduced food allergic responses. Conclusion TSLP-elicited basophils promote epicutaneous sensitization to food antigens and subsequent IgE-mediated food allergy via IL-4. Strategies to target the TSLP-basophil-IL4 axis in patients with AD may lead to innovative therapies that can prevent the progression of allergies to distant mucosal sites.
Contribution of FLG mutations to S. aureus colonization in mild, moderate and severe AD was assessed by including interaction between EASI and FLG mutations in logistic regression models adjusting ...for total IgE, age, and sex.
Eczema Area and Severity Index (EASI), Rajka-Langeland severity score, past staphylococcal infection, past eczema herpeticum (EH) and laboratory test results were compared amongst the age of AD onset ...groups.
The aims of this study were to establish absolute ranges for right ventricular (RV) structural and functional parameters for endurance athletes and to establish any impact of body size. These data ...may help differentiate physiologic conditioning from arrhythmogenic RV cardiomyopathy.
A prospective observational study design was used, and standard two-dimensional echocardiography was performed on 102 endurance athletes, providing RV structural indices. A two-dimensional strain (ε) technique was used to provide indices of RV ε and strain rate. The association of RV chamber size to body surface area (BSA) and functional indices was examined by simple ratio scaling as well as adoption of the general, nonlinear allometric model.
The values for RV inflow, outflow, length, and diastolic area were greater than published "normal ranges" in 57%, 40%, 69%, and 59% of the population, respectively, while 28% of the population had RV outflow tract values greater than the proposed "major criteria" for arrhythmogenic RV cardiomyopathy. Simple ratio scaling for all RV dimensions to BSA did not produce size independence, whereas scaling for BSA allometrically did. Strain and strain rate values were consistent with published normal ranges, and there is no evidence to suggest that scaling is required.
RV chamber dimensions are larger in endurance athletes than those described by "normal ranges" and frequently meet the major criteria for the diagnosis of arrhythmogenic RV cardiomyopathy. Functional assessment of RV ε may aid in this differential diagnosis. RV size is allometrically related to BSA and therefore scaling for population-specific b exponents is encouraged.
Abstract Background A retrograde approach improves the success rate of percutaneous coronary interventions (PCIs) for chronic total occlusions (CTOs). Objectives The authors describe the European ...experience with and outcomes of retrograde PCI revascularization for coronary CTOs. Methods Follow-up data were collected from 1,395 patients with 1,582 CTO lesions enrolled between January 2008 and December 2012 for retrograde CTO PCI at 44 European centers. Major adverse cardiac and cerebrovascular events were defined as the composite of cardiac death, myocardial infarction, stroke, and further revascularization. Results The mean patient age was 62.0 ± 10.4 years; 88.5% were men. Procedural and clinical success rates were 75.3% and 71.2%, respectively. The mean clinical follow-up duration was 24.7 ± 15.0 months. Compared with patients with failed retrograde PCI, successfully revascularized patients showed lower rates of cardiac death (0.6% vs. 4.3%, respectively; p < 0.001), myocardial infarction (2.3% vs. 5.4%, respectively; p = 0.001), further revascularization (8.6% vs. 23.6%, respectively; p < 0.001), and major adverse cardiac and cerebrovascular events (8.7% vs. 23.9%, respectively; p < 0.001). Female sex (hazard ratio HR: 2.06; 95% confidence interval CI: 1.33 to 3.18; p = 0.001), prior PCI (HR: 1.73; 95% CI: 1.16 to 2.60; p = 0.011), low left ventricular ejection fraction (HR: 2.43; 95% CI: 1.22 to 4.83; p = 0.011), J-CTO (Multicenter CTO Registry in Japan) score ≥3 (HR: 2.08; 95% CI: 1.32 to 3.27; p = 0.002), and procedural failure (HR: 2.48; 95% CI: 1.72 to 3.57; p < 0.001) were independent predictors of major adverse cardiac and cerebrovascular events at long-term follow-up. Conclusions The number of retrograde procedures in Europe has increased, with high percents of success, low rates of major complications, and good long-term outcomes.
Objective Preterm rupture of membranes (PROM) is associated with an increased risk of preterm birth and neonatal morbidity. Prophylactic 17-hydroxyprogesterone caproate (17OHP-C) reduces the risk of ...preterm birth in some women who are at risk for preterm birth. We sought to test whether 17OHP-C would prolong pregnancy or improve perinatal outcome when given to mothers with preterm rupture of the membranes. Study Design This is a multicenter, double-blind, placebo-controlled, randomized clinical trial. The study included singleton pregnancies with gestational ages from 230/7 to 306/7 weeks at enrollment, documented PROM, and no contraindication to expectant management. Consenting women were assigned randomly to receive weekly intramuscular injections of 17OHP-C (250 mg) or placebo. The primary outcome was continuation of pregnancy until a favorable gestational age, which was defined as either 340/7 weeks of gestation or documentation of fetal lung maturity at 320/7 to 336/7 weeks of gestation. The 2 prespecified secondary outcomes were interval from randomization to delivery and composite adverse perinatal outcome. The planned sample size was 222 total women. Results From October 2011 to April 2014, 152 women were enrolled; 74 women were allocated randomly to 17OHP-C, and 78 were allocated randomly to placebo. The trial was stopped when results of a planned interim analysis suggested that continuation was futile. The primary outcome was achieved in 3% of the 17OHP-C group and 8% of the placebo group ( P = .18). There was no significant between-group difference in the prespecified secondary outcomes, randomization-to-delivery interval (17.1 ± 16.1 vs 17.0 ± 15.8 days, respectively; P = .76) or composite adverse perinatal outcome (63% vs 61%, respectively; P = .93). No significant differences were found in other outcomes, which included rates of chorioamnionitis, postpartum endometritis, cesarean delivery, individual components of the composite outcome, or prolonged neonatal length of stay. Conclusion Compared with placebo, weekly 17OHP-C injections did not prolong pregnancy or reduce perinatal morbidity in patients with PROM in this trial.
To compare efficacies of 1-day, 1-hour, and combined 1-day/1-hour preoperative topical gatifloxacin in eliminating conjunctival bacterial flora.
Prospective, comparative case series.
Sixty patients ...(120 eyes) scheduled to undergo anterior segment intraocular surgery at Stanford University Medical Center.
Cultures were collected from the palpebral conjunctival sac at baseline and after 1 day (4 doses), 1 hour (3 doses), and 1 day/1 hour (7 doses) of gatifloxacin use.
Incidence of positive bacterial samples collected pre- and post-antibiotic treatment and number of colony forming units (CFUs).
SeptiChek (Becton Dickinson, Franklin Lakes, NJ) positive cultures significantly decreased from 67% growth at baseline to 28% (P<0.0001) after 1 day and from 60% at baseline to 37% (P = 0.018) after 1 hour of gatifloxacin use. Reductions of 44% growth at baseline to 12% (P = 0.0001) after 1 day and 32% at baseline to 13% (P = 0.029) after 1 hour of gatifloxacin use were observed on blood agar. Surgical eyes that received both 1-day and 1-hour preoperative gatifloxacin had reductions from 67% growth at baseline to 18% posttreatment (P<0.0001) and 45% at baseline to 7% posttreatment (P<0.0001) on SeptiChek and blood agar media, respectively. In addition to a lower frequency of positive cultures, a significantly lower CFU count was found after 1-day (P = 0.004) and 1-hour (P = 0.049) gatifloxacin use compared with pretreatment levels. Combined 1-day/1-hour doses of gatifloxacin were associated with a greater reduction in CFUs (P = 0.001) when compared with 1-hour treatment alone.
Both 1-hour and 1-day topical gatifloxacin use are effective in reducing the frequency of conjunctival bacterial growth and the overall bacterial load as measured by CFUs, relative to baseline. Although a 1-hour pretreatment is associated with a reduction in bacterial growth, the combination of 1-day and 1-hour preoperative gatifloxacin dosing results in an even lower overall bacterial load, suggesting that the latter might be the preferred preoperative regimen for eyes undergoing anterior segment surgery.
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