In vitro induction of functional allergen-specific CD4+ CD25high Treg cells in horses affected with insect bite hypersensitivity

BACKGROUND Insect bite hypersensitivity (IBH) is a recurrent allergic dermatitis of horses with similarities to human atopic eczema, caused by bites of insects of the genus Culicoides. Previous studies suggested a dysregulated T cell tolerance to Culicoides allergen in IBH-affected horses. OBJECTIVE We have investigated whether the suppressive function of CD4(+) CD25(high) cells is impaired in IBH-affected horses and possible ways to restore it. METHODS CD4(+) CD25(-) cells sorted from peripheral blood mononuclear cells (PBMC) were stimulated with irradiated autologous PBMC pulsed with Culicoides or tetanus toxoid as control antigen, in the presence of CD4(+) CD25(high) cells. Furthermore, Culicoides-specific CD4(+) CD25(high) regulatory cells were expanded or induced from CD4(+) CD25(-) cells in vitro in the presence of a combination of rIL-2 and rTGF-β1 (rIL-2/rTGF-β1) or of retinoic acid and rapamycin (RetA/Rapa). Proliferation was determined by [(3) H] thymidine incorporation and cytokine production measured by flow cytometry. RESULTS The ability of Culicoides- but not tetanus-stimulated CD4(+) CD25(high) cells to suppress proliferation of CD4(+) CD25(-) cells was significantly lower in IBH-affected horses (28%) than in healthy controls (86%). The decreased suppression in IBH-affected horses was associated with a significantly higher proportion of IL-4(+) cells and a lower percentage of FoxP3(+) IL-10(+) compared to controls. Addition of rIL-2/rTGF-β1 or of RetA/Rapa to Culicoides-stimulated CD4(+) CD25(high) cells from IBH-affected horses significantly increased the proportion of FoxP3(+) IL-10(+) cells. We also found that RetA/Rapa induced a more significant decrease in the frequency of IL-4(+) cells than rIL-2/rTGF-β1. Moreover, the suppressive activity of Culicoides-stimulated CD4(+) CD25(high) cells was significantly restored by both rIL-2/rTGF-β1and RetA/Rapa, albeit in an antigen-unspecific manner. In contrast, in vitro induced Culicoides-specific CD4(+) CD25(high) cells suppressed proliferation of CD4(+) CD25(-) cells in an antigen-specific manner. CONCLUSION AND CLINICAL RELEVANCE The in vitro induction of functional allergen-specific Treg cells in IBH-affected horses suggests a potential therapeutic use of these cells in allergy.

Major histocompatibility complex and other allergy-related candidate genes associated with insect bite hypersensitivity in Icelandic horses

Insect bite hypersensitivity (IBH) is an allergic dermatitis of horses caused by bites of insects. IBH is a multifactorial disease with contribution of genetic and environmental factors. Candidate gene association analysis of IBH was performed in a group of 89 Icelandic horses all born in Iceland and imported to Europe. Horses were classified in IBH-affected and non-affected based on clinical signs and history of recurrent dermatitis, and on the results of an in vitro sulfidoleukotriene (sLT)-release assay with Culicoides nubeculosus and Simulium vittatum extract. Different genetic markers were tested for association with IBH by the Fisher's exact test. The effect of the major histocompatibility complex (MHC) gene region was studied by genotyping five microsatellites spanning the MHC region (COR112, COR113, COR114, UM011 and UMN-JH34-2), and exon 2 polymorphisms of the class II Eqca-DRA gene. Associations with Eqca-DRA and COR113 were identified (p < 0.05). In addition, a panel of 20 single nucleotide polymorphisms (SNPs) in 17 candidate allergy-related genes was tested. During the initial screen, no marker from the panel was significantly (p < 0.05) associated with IBH. Five SNPs associated with IBH at p < 0.10 were therefore used for analysis of combined genotypes. Out of them, SNPs located in the genes coding for the CD14 receptor (CD14), interleukin 23 receptor (IL23R), thymic stromal lymphopoietin (TSLP) and transforming growth factor beta 3 (TGFB3) molecules were associated with IBH as parts of complex genotypes. These results are supported by similar associations and by expression data from different horse populations and from human studies.

[Concurrent irradiation and DNA tumor vaccination in canine oral malignant melanoma: a pilot study].

Melanoma is the most common oral tumor in dogs, characterized by rapid growth, local invasion, and high metastatic rate. The goal of this study was to evaluate the combination of radiation therapy and DNA tumor vaccine. We hypothesized, that the concurrent use would not increase toxicity. Nine dogs with oral melanoma were treated with 4 fractions of 8 Gray at 7-day intervals. The vaccine was given 4 times every 14 days, beginning at the first radiation fraction. Local acute radiation toxicities were assessed according to the VRTOG toxicity scoring scheme over a time period of 7 weeks. In none of the evaluated dogs, mucositis, dermatitis and conjunctivitis exceeded grade 2. In 3 dogs mild fever, lethargy, and local swelling at the injection site were seen after vaccine application. In conclusion, the concurrent administration of radiation therapy and vaccine was well tolerated in all dogs.

Factors influencing the onset and progression of pododermatitis in captive flamingos (Phoenicopteridae).

Pododermatitis is a worldwide problem in captive flamingos. We performed an evaluation of different influence factors (age, sex, weight, origin, breeding status) and a comparison of foot lesions between several zoological institutions and the feet of free-ranging Greater flamingos (Phoenicopterus roseus). A scoring system was used to determine the prevalence and types of lesions and severity. Cracks and nodules developed as early as 3 months of age and papillomatous growths as early as 6 to 7 months of age in captivity. Nodules with ulceration occurred significantly more often in birds older than 31 years and heavier than 4 kg. The comparison of different institutions revealed that birds kept in enclosures with natural-floored water ponds had significantly less severe lesions than birds kept in concrete water ponds. None of the free-ranging flamingos, which live on a muddy underground, showed any lesion. This study demonstrates that flooring, weight and age are important in the onset and progression of pododermatitis in flamingos.

Neurodermitis - Ein Leitfaden für Ärzte und Patienten. 2., neubearb. Auflage

Der Krankheitsbegriff Neurodermitis oder atopische Dermatitis umfasst ein breites Spektrum von Störungen der Hautbarriere und/oder des Immunsystems. Zunehmend verstehen wir, welche Faktoren wie und bei welchen Patienten die Krankheitsentstehung, das klinische Bild und den Verlauf prägen. Die Auswahl der Themen und deren Gewichtung in diesem Buch beruht auf den langjährigen Erfahrungen aus Neurodermitisschulungen sowie auf neuen Erkenntnissen zur Krankheitsentstehung und Therapie. Auch den psychosozialen Komponenten der Krankheitsbewältigung und -anpassung wurde ein relativ grosser Stellenwert beigemessen. Zum Thema Neurodermitis existiert eine Flut an Texten und Ratschlägen, die von der Schulmedizin bis zur Alternativ- und Komplementärmedizin reichen. Dadurch ist es für Patienten oft schwierig, die Informationen zu werten, einzuordnen und vernünftige Schlussfolgerungen für eigenes Krankheitsverständnis, Verhalten und Behandlung zu ziehen. Mit dem vorliegenden Buch ist ein gelungener Leitfaden für Patienten und Ärzte gleichermassen entstanden, der alle wichtigen Facetten der Erkrankung darstellt und vertieft.

Lameness and foot lesions in Swiss dairy cows: I. Prevalence.

Prevalences of foot lesions and lameness were recorded in 1'449 Swiss dairy cows during routine claw-trimming on 78 farms from June 2010 until February 2011. Lameness was present in 14.8 % of cows and on 80.8 % of investigated farms. Highest prevalences were seen for widened white line (80.7 %/100 %), signalling foot lesion (65.6 %/98.7 %), heel-horn erosion (34.2 %/88.5 %), digital dermatitis complex (29.1 %/73.1 %), severe hemorrhages (27.9 %/87.2 %), and Rusterholz' sole ulcers (11.5 %/74.4 %) at cow and herd level, respectively. Lower prevalences were found for subclinical laminitis (5.4 %/47.4 %), chronic laminitis (3.3 %/25.6 %), white line disease (4.7 %/42.3 %), double soles (2.6 %/33.3 %), interdigital hyperplasia (3.1 %/33.3 %), sole ulcers (0.4 %/6.4 %), toe infections caused by faulty claw-trimming (3.9 %/39.7 %) and by injury (0.1 %/2.6 %), deep lacerations (0.4 %/6.4 %), and interdigital phlegmona (0.1 %/1.3 %). Lameness and foot lesions were shown to represent important health problems of dairy cows under the conditions of the typical grass-based production system in Switzerland. Digital dermatitis has developed to the most relevant foot disease with a high impact on welfare of Swiss dairy cows within the past 10 years.

Lameness and foot lesions in Swiss dairy cows: II. Risk factors.

The objective of this study was to evaluate risk factors associated with foot lesions and lameness in Swiss dairy cows. Potential risk factors were recorded by means of examination of 1'449 Swiss cows and the management systems of 78 farms during routine claw-trimming, and during personal interviews with the associated farmers. Statistical analysis of animal-based and herd level risk factors were performed using multivariate logistic regression models. The risk of being lame was increased in cows affected by digital dermatitis complex, heel-horn erosion, interdigital hyperplasia, Rusterholz' sole ulcer, deep laceration, double sole and severe hemorrhages. Cleanliness, BCS, affection with other foot lesions, breed, importance of claw health to the farmer, frequency of routine claw-trimming, producing according to the guidelines of the welfare label program RAUS, and silage feeding were shown to be associated with the occurrence of some of the evaluated foot lesions and lameness. The identified risk factors may help to improve management and the situation of lameness and claw health in dairy cows in Switzerland and other alpine areas with similar housing and pasturing systems.

Selenium for preventing cancer

BACKGROUND This review is an update of the first Cochrane publication on selenium for preventing cancer (Dennert 2011).Selenium is a metalloid with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers. OBJECTIVES Two research questions were addressed in this review: What is the evidence for:1. an aetiological relation between selenium exposure and cancer risk in humans? and2. the efficacy of selenium supplementation for cancer prevention in humans? SEARCH METHODS We conducted electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 1), MEDLINE (Ovid, 1966 to February 2013 week 1), EMBASE (1980 to 2013 week 6), CancerLit (February 2004) and CCMed (February 2011). As MEDLINE now includes the journals indexed in CancerLit, no further searches were conducted in this database after 2004. SELECTION CRITERIA We included prospective observational studies (cohort studies including sub-cohort controlled studies and nested case-control studies) and randomised controlled trials (RCTs) with healthy adult participants (18 years of age and older). DATA COLLECTION AND ANALYSIS For observational studies, we conducted random effects meta-analyses when five or more studies were retrieved for a specific outcome. For RCTs, we performed random effects meta-analyses when two or more studies were available. The risk of bias in observational studies was assessed using forms adapted from the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies; the criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions were used to evaluate the risk of bias in RCTs. MAIN RESULTS We included 55 prospective observational studies (including more than 1,100,000 participants) and eight RCTs (with a total of 44,743 participants). For the observational studies, we found lower cancer incidence (summary odds ratio (OR) 0.69, 95% confidence interval (CI) 0.53 to 0.91, N = 8) and cancer mortality (OR 0.60, 95% CI 0.39 to 0.93, N = 6) associated with higher selenium exposure. Gender-specific subgroup analysis provided no clear evidence of different effects in men and women (P value 0.47), although cancer incidence was lower in men (OR 0.66, 95% CI 0.42 to 1.05, N = 6) than in women (OR 0.90, 95% CI 0.45 to 1.77, N = 2). The most pronounced decreases in risk of site-specific cancers were seen for stomach, bladder and prostate cancers. However, these findings have limitations due to study design, quality and heterogeneity that complicate interpretation of the summary statistics. Some studies suggested that genetic factors may modify the relation between selenium and cancer risk-a hypothesis that deserves further investigation.In RCTs, we found no clear evidence that selenium supplementation reduced the risk of any cancer (risk ratio (RR) 0.90, 95% CI 0.70 to 1.17, two studies, N = 4765) or cancer-related mortality (RR 0.81, 95% CI 0.49 to 1.32, two studies, N = 18,698), and this finding was confirmed when the analysis was restricted to studies with low risk of bias. The effect on prostate cancer was imprecise (RR 0.90, 95% CI 0.71 to 1.14, four studies, N = 19,110), and when the analysis was limited to trials with low risk of bias, the interventions showed no effect (RR 1.02, 95% CI 0.90 to 1.14, three studies, N = 18,183). The risk of non-melanoma skin cancer was increased (RR 1.44, 95% CI 0.95 to 1.17, three studies, N = 1900). Results of two trials-the Nutritional Prevention of Cancer Trial (NPCT) and the Selenium and Vitamin E Cancer Trial (SELECT)-also raised concerns about possible increased risk of type 2 diabetes, alopecia and dermatitis due to selenium supplements. An early hypothesis generated by NPCT that individuals with the lowest blood selenium levels at baseline could reduce their risk of cancer, particularly of prostate cancer, by increasing selenium intake has not been confirmed by subsequent trials. As the RCT participants were overwhelmingly male (94%), gender differences could not be systematically assessed. AUTHORS' CONCLUSIONS Although an inverse association between selenium exposure and the risk of some types of cancer was found in some observational studies, this cannot be taken as evidence of a causal relation, and these results should be interpreted with caution. These studies have many limitations, including issues with assessment of exposure to selenium and to its various chemical forms, heterogeneity, confounding and other biases. Conflicting results including inverse, null and direct associations have been reported for some cancer types.RCTs assessing the effects of selenium supplementation on cancer risk have yielded inconsistent results, although the most recent studies, characterised by a low risk of bias, found no beneficial effect on cancer risk, more specifically on risk of prostate cancer, as well as little evidence of any influence of baseline selenium status. Rather, some trials suggest harmful effects of selenium exposure. To date, no convincing evidence suggests that selenium supplements can prevent cancer in humans.

Two Loci on Chromosome 5 Are Associated with Serum IgE Levels in Labrador Retrievers

Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.

Update on skin allergy.

Skin diseases with an allergic background such as atopic dermatitis, allergic contact dermatitis, and urticaria are very common. Moreover, diseases arising from a dysfunction of immune cells and/or their products often manifest with skin symptoms. This review aims to summarize recently published articles in order to highlight novel research findings, clinical trial results, and current guidelines on disease management. In recent years, an immense progress has been made in understanding the link between skin barrier dysfunction and allergic sensitization initiating the atopic march. In consequence, new strategies for treatment and prevention have been developed. Novel pathogenic insights, for example, into urticaria, angioedema, mastocytosis, led to the development of new therapeutic approaches and their implementation in daily patient care. By understanding distinct pathomechanisms, for example, the role of IL-1, novel entities such as autoinflammatory diseases have been described. Considerable effort has been made to improve and harmonize patient management as documented in several guidelines and position papers.

Urgent consultations at the dermatology department of Basel University Hospital, Switzerland: characterisation of patients and setting - a 12-month study with 2,222 patients data and review of the literature.

BACKGROUND Urgent consultations for skin disorders are commonly done in different settings. Scarce data exist about the characteristics of these patients. OBJECTIVE The aim of this study was to analyse specific characteristics of patients receiving an urgent consultation at a dermatology department in a university hospital. METHODS We prospectively recorded the data of all patients having had an urgent consultation during a period of 12 months. RESULTS We registered 2,222 urgent consultations. The most frequent diagnoses were eczemas (24.8%), dermatomycoses (5.1%) and dermatitis not otherwise specified (4.8%). The most frequent treatments were topical steroids, emollients, topical antibiotics, systemic antihistamines, antibiotics and virostatics. 2.2% of patients were hospitalized, 78.8% asked for a consultation for a disease lasting less than 4 weeks, and 6.9% presented the same day as the skin disease appeared. CONCLUSIONS This study shows the characteristics of patients receiving an urgent dermatologic consultation. It underlines the need for collaboration between dermatologists, other physicians, general practitioners and nurses.

Reliability of operational data from pig herds and performance ratings by veterinarians and pig farmers collected during telephone interviews for the evaluation of a PCV2 piglet vaccination

BackgroundThe aim of the present study was to evaluate the feasibility of using a telephone survey in gaining an understanding of the possible herd and management factors influencing the performance (i.e. safety and efficacy) of a vaccine against porcine circovirus type 2 (PCV2) in a large number of herds and to estimate customers¿ satisfaction.ResultsDatasets from 227 pig herds that currently applied or have applied a PCV2 vaccine were analysed. Since 1-, 2- and 3-site production systems were surveyed, the herds were allocated in one of two subsets, where only applicable variables out of 180 were analysed. Group 1 was comprised of herds with sows, suckling pigs and nursery pigs, whereas herds in Group 2 in all cases kept fattening pigs. Overall 14 variables evaluating the subjective satisfaction with one particular PCV2 vaccine were comingled to an abstract dependent variable for further models, which was characterized by a binary outcome from a cluster analysis: good/excellent satisfaction (green cluster) and moderate satisfaction (red cluster). The other 166 variables comprised information about diagnostics, vaccination, housing, management, were considered as independent variables. In Group 1, herds using the vaccine due to recognised PCV2 related health problems (wasting, mortality or porcine dermatitis and nephropathy syndrome) had a 2.4-fold increased chance (1/OR) of belonging to the green cluster. In the final model for Group 1, the diagnosis of diseases other than PCV2, the reason for vaccine administration being other than PCV2-associated diseases and using a single injection of iron had significant influence on allocating into the green cluster (P¿<¿0.05). In Group 2, only unchanged time or delay of time of vaccination influenced the satisfaction (P¿<¿0.05).ConclusionThe methodology and statistical approach used in this study were feasible to scientifically assess ¿satisfaction¿, and to determine factors influencing farmers¿ and vets¿ opinion about the safety and efficacy of a new vaccine.

Basophils promote innate lymphoid cell responses in inflamed skin.

Type 2 inflammation underlies allergic diseases such as atopic dermatitis, which is characterized by the accumulation of basophils and group 2 innate lymphoid cells (ILC2s) in inflamed skin lesions. Although murine studies have demonstrated that cutaneous basophil and ILC2 responses are dependent on thymic stromal lymphopoietin, whether these cell populations interact to regulate the development of cutaneous type 2 inflammation is poorly defined. In this study, we identify that basophils and ILC2s significantly accumulate in inflamed human and murine skin and form clusters not observed in control skin. We demonstrate that murine basophil responses precede ILC2 responses and that basophils are the dominant IL-4-enhanced GFP-expressing cell type in inflamed skin. Furthermore, basophils and IL-4 were necessary for the optimal accumulation of ILC2s and induction of atopic dermatitis-like disease. We show that ILC2s express IL-4Rα and proliferate in an IL-4-dependent manner. Additionally, basophil-derived IL-4 was required for cutaneous ILC2 responses in vivo and directly regulated ILC2 proliferation ex vivo. Collectively, these data reveal a previously unrecognized role for basophil-derived IL-4 in promoting ILC2 responses during cutaneous inflammation.

Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis.

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 T(H)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 T(H)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.