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The cytokines IL-5, IL-3, and GM- CSF are crucial for eosinophil development, survival, and function. To better understand their role in non-IgE-mediated eosinophilic diseases, we investigated plasma levels of these cytokines as well as cytokine expression in peripheral blood T cells. While we did not find any evidence for an involvement of T-cell-derived GM- CSF, some of these patients did show an increased proportion of IL-5- or IL-3-producing CD4+ T cells. However, in a significant proportion of patients, IL-5-producing CD8+ T cells, so-called Tc2 cells, which in healthy donors can only be detected at very low levels, were prominent. Furthermore, increased IL-3 production by CD8+ T cells was also observed, strongly supporting the notion that CD8+ T cells, not just CD4+ T cells, must also be considered as a potential source of the cytokines promoting eosinophilia. [ABSTRACT FROM AUTHOR]

Extracellular DNA traps are part of the innate immune response and are seen with many infectious, allergic, and autoimmune diseases. They can be generated by several different leukocytes, including neutrophils, eosinophils, and monocytes, as well as mast cells. Here, we review the composition of these extracellular DNA-containing structures as well as potential mechanisms for their production and function. In general, extracellular DNA traps have been described as binding to and killing pathogens, particularly bacteria, fungi, but also parasites. On the other hand, it is possible that DNA traps contribute to immunopathology in chronic inflammatory diseases, such as bronchial asthma. In addition, it has been demonstrated that they can initiate and/or potentiate autoimmune diseases. Extracellular DNA traps represent a frequently observed phenomenon in inflammatory diseases, and they appear to participate in the cross-talk between different immune cells. These new insights into the pathogenesis of inflammatory diseases may open new avenues for targeted therapies. [ABSTRACT FROM AUTHOR]

The author reflects on the current and future concepts of immunological mechanisms of allergen-specific immunotherapy, an effective treatment for immunoglobulin E (IgE) mediated allergic diseases. According to the author, allergen-specific immunotherapy strategy aims to improve efficacy and safety of the causative therapy to benefit allergic patients. The author suggests that there is growing evidence that the development on the use of allergen-specific immunotherapy is expected to move on.

Tschan MP, Simon H-U. (Department of Medical Oncology, Inselspital, Bern University Hospital; and Institute of Pharmacology, University of Bern; Bern, Switzerland) The role of autophagy in anticancer therapy: promises and uncertainties (Symposium). J Intern Med 2010; : 410-418. Autophagy (literally self-eating) is a catabolic mechanism involved in the recycling and turnover of cytoplasmic constituents. Although often referred to as type II programmed cell death, autophagy is primarily a survival rather than a cell death mechanism in response to different stress stimuli. Autophagy is a process in which part of the cytoplasm or entire organelles are sequestered into double-membrane vesicles, called autophagosomes, which ultimately fuse with lysosomes to degrade their contents. Studies show that autophagy is associated with a number of pathological conditions, including cancer, infectious diseases, myopathies and neurodegenerative disorders. With respect to cancer, it has been suggested that the early stages of tumourigenesis are associated with downregulation of autophagy-related (ATG) genes. Indeed, several ATG genes display tumour suppressor function, including Beclin1, which is frequently hemizygously deleted in breast cancer cells. Conversely, in advanced stages of tumourigenesis or during anticancer therapy, autophagy may promote survival of tumour cells in adverse environmental conditions. Therefore, a thorough understanding of autophagy in different cancer types and stages is a prerequisite to determine an autophagy-activating or autophagy-inhibiting treatment strategy. [ABSTRACT FROM AUTHOR]

Eosinophils and the gastrointestinal tract interact in an intimate and enigmatic relationship. Under healthy conditions, the presence of eosinophils is limited almost exclusively to the digestive tract mucosa where they exert several effector and immunoregulatory functions. While their precise function in the gastrointestinal tract is not completely understood, it is likely that, together with different T cell subsets, eosinophils are involved in maintaining the immunologic homeostastis across the mucosal barrier under resting conditions. Eosinophils also play a role in several inflammatory conditions, such as intestinal infections, hypersensitivity reactions, primary eosinophilic inflammations and several other chronic intestinal disorders. Depending on the responsible trigger, their effects may be beneficial or detrimental. Here, we discuss the available information regarding the physiological and pathological functions of eosinophils within the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Interferon (IFN)- α is a cytokine that possesses potent anti-viral and immunoregulatory activities. We aimed to assess clinical and immunological effects of low-dose IFN- α in patients with severe corticosteroid-resistant asthma with and without Churg–Strauss syndrome. There is currently no efficient pharmacological treatment available for this group of patients. We studied 10 patients with corticosteroid-resistant asthma, in which 3×106 IU/day IFN- α were administrated in addition to the prednisone dose given already before introduction of the cytokine therapy. The prednisone dose was gradually reduced dependent on the clinical situation and used as a clinical readout to evaluate the efficacy of the cytokine therapy. To distinguish between IFN- α- and prednisone-mediated immunological changes, the corticosteroid dose was kept constant for at least 2 weeks upon introduction of the cytokine therapy in seven patients. The effects of treatment on clinical and immunological parameters were measured at 2–4 weeks and 5–10 months depending on the availability of the patient. Interferon- α treatment rapidly improved the clinical situation as assessed by lung function parameters and required prednisone dose. Important immunological changes included: decreased leukocyte numbers, increased relative numbers of CD4+ T cells, increased differentiation of T helper (Th)1 cells, and increased expression of interleukin (IL)-10 in peripheral blood mononuclear cells. Interferon- α treatment was associated with dramatic improvements in the condition of patients with corticosteroid-resistant asthma with and without Churg–Strauss syndrome. Potential mechanisms of action include the establishment of a correct Th1/Th2 balance and the induction of the anti-inflammatory IL-10 gene. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIG) preparations are fractionated from a plasma pool of several thousand donors. IVIG contain immune antibodies and physiologic autoantibodies. Immune antibodies reflect the immunologic experience of the donor population. This fraction of IVIG preparations is useful for replacement therapy and passive immunisation. Natural autoantibodies are able to react with the immune system of the recipient of IVIG and are suggested to help to correct immune deregulation. Immunomodulatory and anti-inflammatory properties are based on multiple mechanisms of action which are described. These mechanisms are effective concomitantly and synergistically at every occasion of use of IVIG in inflammatory and autoimmune disorders. [ABSTRACT FROM AUTHOR]

Focuses on the regulation of eosinophil apoptosis in chronic allergic diseases, highlighting the effect of anti-inflammatory drugs in these pathophysiologic mechanisms. Effect of interleukin-5 in eosinophil apoptosis; Important mechanism contributing to eosinophilia; Association of glucocorticoid therapy with reduction of eosinophil numbers due to induction of apoptosis.

The article offers information on the journal's continued commitment and development which include its collaboration between the scientific and production teams of the journal.

Presents information on a study which examined the expression and function of eosinophil adhesion molecules under physiologic and pathologic conditions. Features of integrins; Impact of eosinophil differentiation on Beta 7 integrin surface protein expression.

The article reflects on the future of the journal "Allergy." It is said that to further improve the quality of the journal, the journal will be given a more global character and increase the expertise of the Associate Editors and the members of the Editorial board. Also, the journal will invite scientific leaders in the field to write reviews and opinion articles for the journal.

In spite of the progress regarding the description of immunological phenomena associated with atopic dermatitis (AD), the pathogenesis of this disease still remains unclear. The presence of eosinophils in the inflammatory infiltrate of AD has long been established. Eosinophil numbers as well as eosinophil granule protein levels in peripheral blood are elevated in most AD patients and appear to correlate with disease activity. Moreover, eosinophil granule proteins, which possess cytotoxic activity, are deposited in the skin lesions. These observations indicate a role of eosinophils in the pathogenesis of AD. Furthermore, AD is associated with increased production of T helper 2 cytokines including interleukin (IL)-5, which specifically acts on eosinophils, resulting in accelerated eosinophilopoiesis, chemotaxis, cell activation, and delayed apoptosis. Therefore, IL-5 is an interesting target for experimental therapy in this inflammatory disorder of the skin. Such studies might result in new insights into the pathogenetic role of eosinophils in AD. [ABSTRACT FROM AUTHOR]

Examines the pathophysiology of the non-immunoglobulin E (IgE)-mediated intrinsic type of atopic dematitis (IAD). Epidemiology and clinical features; Differences and similarities between the immunologic parameters of IAD and extrinsic type of atopic dermatitis; Prominence of other immunologic mechanisms over IgE-mediated ones; Role of environmental and genetic factors in the pathogenesis of atopic dermatitis.

Abstract: Background: Lesions of bullous pemphigoid (BP), an autoimmune subepidermal blistering disease characterized by the presence of tissue‐bound and circulating autoantibodies to hemidesmosomal antigens, harbor a mixed inflammatory cellular infiltrate. In various models, neutrophils, eosinophils, mast cells, monocytes as well as B and T cells have been shown to be involved in the pathogenesis of BP. However, their interactions with and effective role in blister formation remain uncertain. This study was aimed at investigating the effect of monocyte/neutrophil interaction on blister formation in an ex vivo BP model. Methods: Skin cryosections were incubated with purified human neutrophils and monocytes, in the presence or absence of BP autoantibodies. Production of reactive oxygen species (ROS), degranulation, mediator release (neutrophil elastase [NE], myeloperoxidase [MPO], matrix metalloproteinase‐9 [MMP‐9]), binding of Fcγ receptor (CD16, CD32, CD64), and cell adhesion (CD18, ICAM‐1) was investigated using appropriate inhibitors. Dermal‐epidermal separation (DES) was assessed by light microscopy and quantified by Fiji software. Results: Monocytes and neutrophils synergistically interact resulting in a significantly higher DES compared to either monocytes or neutrophils separately (P < .0001). Monocyte/neutrophil‐induced DES was associated with increased ROS production and was dependent on adhesion and FcγRIII binding. Upon stimulation by the granule‐poor fraction of monocyte supernatants, neutrophils increased their release of MMP‐9, thereby also DES at the dermal‐epidermal junction of skin cryosections. Conclusion: Our observations suggest that the interaction of cells, as shown here for monocytes and neutrophils, enhances mediator release resulting in an increased subepidermal blister formation. Thus, blocking intercellular cross talk promises a new therapeutic approach for blocking tissue damage in BP. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disease characterized by symptoms related to esophageal dysfunction and an eosinophil-predominant inflammation. This study has aimed to investigate whether the recently observed sensitization to Candida albicans in patients with EoE is owing to pre-existing disease and its underlying abnormal epithelial barrier or, alternatively, is linked to corticosteroid ( CS) therapy. Methods Medical histories, as well as serum and tissue samples of 60 patients with EoE (15 CS naive, 45 with current or previous CS therapy) and 20 controls, stored in the Swiss Eosinophilic Esophagitis Database ( SEED) and Biobank, were analyzed. We applied Immuno CAP to measure IgE levels and immunofluorescence techniques to examine epithelial barrier components. Results Patients with EoE had higher total IgE levels and were more frequently sensitized to C. albicans than controls. In EoE tissue specimens, increased numbers of eosinophils and mast cells, a higher expression levels of thymic stromal lymphopoietin ( TSLP), cathelicidin, proteases, that is, the kallikreins ( KLK)-5 and KLK-7, were observed as compared with controls, while reduced expression of lympho-epithelial Kazal-type-related inhibitor ( LEKTI), filaggrin, E-cadherin, claudin, occludin, desmoglein-1 was found, independent of CS therapy. In CS-treated EoE, significantly lower numbers of CD1a+ cells and cathelicidin expression were noted as compared to CS-naive EoE. Conclusion This study provides further evidence that EoE is associated with an abnormal epithelial barrier and postulates that CS therapy, by reducing innate immune mechanisms, may promote C. albicans colonization and likely subsequent sensitization. [ABSTRACT FROM AUTHOR]

Background Bullous pemphigoid ( BP) is an autoimmune bullous disease of the skin characterized by subepidermal blister formation due to tissue-bound and circulating autoantibodies to the hemidesmosomal antigens BP180 and BP230. Although eosinophils and their toxic mediators are found abundantly in BP lesions, their role in blister formation has remained unclear. Objective To investigate the role of eosinophils in the pathogenesis of BP with a specific focus on blister formation and to define conditions inducing dermal-epidermal separation ( DES). Methods In an ex vivo human model of BP, normal human skin cryosections were incubated with purified human peripheral blood eosinophils with or without activation in the presence or absence of BP autoantibodies, brefeldin A, diphenyleneiodonium, DNase or blocking F(ab′)2 fragments to CD16, CD18, CD32 and CD64. Dermal-epidermal separation was assessed by light microscopy studies and quantified using Fiji software. Results Following activation with IL-5 and in the presence of BP autoantibodies, eosinophils induced separation along the dermal-epidermal junction of ex vivo skin. Dermal-epidermal separation was significantly reduced by blocking any of the following: Fcγ receptor binding ( P = 0.048), eosinophil adhesion ( P = 0.046), reactive oxygen species ( ROS) production ( P = 0.002), degranulation ( P < 0.0001) or eosinophil extracellular trap ( EET) formation ( P = 0.048). Conclusions Our results provide evidence that IL-5-activated eosinophils directly contribute to BP blister formation in the presence of BP autoantibodies. Dermal-epidermal separation by IL-5-activated eosinophils depends on adhesion and Fcγ receptor activation, requires elevated ROS production and degranulation and involves EET formation. Thus, targeting eosinophils may be a promising therapeutic approach for BP. [ABSTRACT FROM AUTHOR]

This consensus document summarizes the current knowledge on the potential for precision medicine in food allergy, drug allergy, and anaphylaxis under the auspices of the PRACTALL collaboration platform. PRACTALL is a joint effort of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology, which aims to synchronize the European and American approaches to allergy care. Precision medicine is an emerging approach for disease treatment based on disease endotypes, which are phenotypic subclasses associated with specific mechanisms underlying the disease. Although significant progress has been made in defining endotypes for asthma, definitions of endotypes for food and drug allergy or for anaphylaxis lag behind. Progress has been made in discovery of biomarkers to guide a precision medicine approach to treatment of food and drug allergy, but further validation and quantification of these biomarkers are needed to allow their translation into practice in the clinical management of allergic disease. [ABSTRACT FROM AUTHOR]

Background Cutaneous ( CLP) and oral lichen planus ( OLP) as the main subtypes of lichen planus ( LP) present with different clinical manifestation and disease course, although their histopathologic features such as the band-like lymphocyte infiltrate and keratinocyte apoptosis are similar. So far, the underlying cellular and molecular mechanisms remain poorly understood. Objective The aim of this study was to characterize and compare the in situ cellular infiltrates, cytokine expression profiles and apoptosis markers in CLP and OLP. Methods Using immunofluorescence staining and laser scanning microscopy, we evaluated the cellular infiltrate ( CD1a, CD3, CD4, CD8, CD21, CD57, CD123), cytokine expression (interleukin ( IL)-1, IL-6, IL-9, IL-10, IL-17, IL-22, IL-23, tumour necrosis factor-α, transforming growth factor-β, interferon ( IFN)-γ), and apoptosis markers (Fas, Fas ligand, cleaved caspase-3, TUNEL) of 21 anonymized biopsy specimens of LP (11 CLP, 10 OLP). Results Among infiltrating cells mainly T cells and natural killer ( NK) cells as well as plasmacytoid dendritic cells ( DC) were observed. A predominance of CD8+ T cells was noted in OLP. In both CLP and OLP, T helper (Th)1, Th9, Th17, and Th22-type cytokines were expressed. The expression of IL-9, IFN-γ and IL-22 was higher in CLP compared to that of OLP ( P = 0.0165; P = 0.0016; P = 0.052 respectively). Expression of Fas and Fas ligand as well as cleaved caspase-3-positive cells was observed in the epithelium of all LP samples. Conclusions The cell and cytokine patterns of CLP and OLP were partially distinct and generally resembled those reported for autoimmune diseases. The presence of CD8+ and NK cells as well as Fas/Fas ligand expression suggested that various pathways involved in keratinocyte apoptosis are relevant for LP. These results might help to establish targeted therapies for LP. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the oesophagus. Recognized as a distinct entity only two decades ago, the emergence of the disease along with the availability of new technologies has rapidly opened new research avenues and outlined the main features of the pathogenesis of EoE. Yet, each advance in our understanding of the disease has raised new questions about the previous consensus. Currently, new subsets of the disease challenge our diagnostic criteria. For instance, it was believed that EoE did not respond to proton pump inhibitor (PPI) therapy; however, it has now been shown that a substantial proportion of EoE patients indeed respond to PPIs. In addition, a new subset of patients not even presenting eosinophil infiltrates in the oesophagus has also been described. Moreover, approaches for better understanding the heritability of the disease bring into question the dogma of predominant genetic involvement. Furthermore, the specificity and sensitivity of allergy testing for targeted food avoidance is highly controversial, and the production of specific antibodies in EoE now includes IgG4 in addition to IgE. In conclusion, EoE is perceived as 'a moving target' and the aim of this review was to summarize the current understanding of EoE pathogenesis. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis (EoE) is a rapidly emerging, chronic inflammatory, genetically impacted disease of the esophagus, defined clinically by symptoms of esophageal dysfunction and, pathologically, by an eosinophil-predominant tissue infiltration. However, in four EoE families, we have identified patients presenting with EoE-typical and corticosteroid-responsive symptoms, but without tissue eosinophilia. The aim of this study was to clinically and immunologically characterize these patients with EoE-like disease. Methods Five patients suffering from an EoE-like disease were evaluated with endoscopic, histologic, functional, and quantitative immunohistological examinations, and mRNA expression determination. Results The frequency of first-generation offspring of patients affected by EoE or EoE-like disease was 40%. Immunofluorescence analysis confirmed an almost complete absence of eosinophils in the esophageal tissues of patients with EoE-like disease, but revealed a considerable T-cell infiltration, comparable to EoE. In contrast to EoE, eotaxin-3 mRNA and protein were markedly reduced in EoE-like disease ( P < 0.05). The mRNA expression levels of three selected EoE genes ( eotaxin-3, MUC4, and CDH26) allowed to discriminate between EoE-like disease, EoE, and normal epithelium. Conclusions Patients suffering from 'EoE without eosinophilia' do not fulfill formally the diagnostic criteria for EoE. However, their clinical manifestation, immunohistology, and gene expression pattern, plus the fact that they bequeath EoE to their offspring, suggest a uniform underlying pathogenesis. Conventional EoE, with its prominent eosinophilia, therefore appears to be only one phenotype of a broader 'inflammatory dysphagia syndrome' spectrum. In this light, the role of the eosinophils, the definition of EoE, and its diagnostic criteria must likely be reconsidered. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. EoE is frequently associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross-reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE-mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures. [ABSTRACT FROM AUTHOR]

Basophils are primarily associated with immunomodulatory functions in allergic diseases and parasitic infections. Recently, it has been demonstrated that both activated human and mouse basophils can form extracellular DNA traps ( BETs) containing mitochondrial DNA and granule proteins. In this report, we provide evidence that, in spite of an apparent lack of phagocytic activity, basophils can kill bacteria through BET formation. [ABSTRACT FROM AUTHOR]

The article presents a study on the effect of T regulatory cells and corticosteroid therapy in treating adult patients with eosinophilic esophagitis (EoE). The study used confocal microscopy and immunofluorescence to assess T cells and T regulatory cells as well as indirect immunostainings. Results showed that EoE is linked with the lack of T regulatory cells and that corticosteroids do not affect the lack of T regulatory cells in EoE.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 ( IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin ( TSLP); pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor ( TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) exhibits esophageal dysfunction owing to an eosinophil-predominant inflammation. Activated eosinophils generate eosinophil extracellular traps (EETs) able to kill bacteria. There is evidence of an impaired barrier function in EoE that might allow pathogens to invade the esophagus. This study aimed to investigate the presence and distribution of EETs in esophageal tissues from EoE patients and their association with possible epithelial barrier defects. Methods: Anonymized tissue samples from 18 patients with active EoE were analyzed. The presence of DNA nets associated with eosinophil granule proteins forming EETs and the expression of filaggrin, the protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI), antimicrobial peptides, and cytokines were evaluated by confocal microscopy following immune fluorescence staining techniques. Results: Eosinophil extracellular trap formation occurred frequently and was detected in all EoE samples correlating with the numbers of infiltrating eosinophils. While the expression of both filaggrin and LEKTI was reduced, epithelial antimicrobial peptides (human beta-defensin-2, human beta-defensin-3, cathelicidin LL-37, psoriasin) and cytokines (TSLP, IL-25, IL-32, IL-33) were elevated in EoE as compared to normal esophageal tissues. There was a significant correlation between EET formation and TSLP expression (P = 0.02) as well as psoriasin expression (P = 0.016). On the other hand, a significant negative correlation was found between EET formation and LEKTI expression (P = 0.016). Conclusion: Active EoE exhibits the presence of EETs. Indications of epithelial barrier defects in association with epithelial cytokines are also present which may have contributed to the activation of eosinophils. The formation of EETs could serve as a firewall against the invasion of pathogens. [ABSTRACT FROM AUTHOR]

Background Eczematous skin lesions of atopic dermatitis ( AD) as well as allergic and irritant contact dermatitis (ACD, ICD) are characterized by the same typical clinical signs, although due to different causes. In both AD and ACD, the presence of T helper 17 cells which play an important role in host defense, has been reported. Furthermore, IL-17 is involved in tissue repair and remodeling. This study aimed to investigate IL-17 expression in acute eczematous skin lesions and correlate it with markers of remodeling in AD, ACD, and ICD. Methods Skin specimens were taken from positive patch test reactions to aeroallergens, contact allergens, and irritants at days 2, 3, and 4. Inflammatory cells as well as the expression of cytokines and extracellular matrix proteins were evaluated by immunofluorescence staining and confocal microscopy. Results Allergic contact dermatitis and ICD were characterized by IFN-γ expression, whereas in AD lesions, IL-13 expression and high numbers of eosinophils were the prominent phenotype. Expression of IL-17, but also IL-21 and IL-22, was observed in all eczema subtypes. The number of IL-22+ T cells correlated with the number of eosinophils. Markers of remodeling such as MMP-9, procollagen-3, and tenascin C were observed in all acute eczematous lesions, while a correlation of IL-17+ T cell numbers with tenascin C-expressing cells and MMP-9+ eosinophils was apparent. Conclusion The expression of IL-17 and related cytokines, such as IL-22, was demonstrated in acute eczematous lesions independent of their pathogenesis. Our results suggest a potential role for IL-17 in remodeling of the skin. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis ( Eo E) is often associated with atopic airway and skin diseases. More than 80% of Eo E patients are sensitized to aero- and/or food allergens. Immunoglobulin ( Ig) E-mediated immune responses to microbes have been reported to be deleterious in connection with atopic diseases. Aim The aim of this study was to obtain a comprehensive overview about the sensitization spectrum of adult Eo E patients. Methods Ig E in sera of 35 patients with active Eo E were analyzed for reactivity to Candida albicans, as well as to a panel of recombinant and purified natural allergen components, using a microarray. Results Ig E sensitization to Candida albicans was found in 43% of Eo E patients. More than 80% of Eo E patients were sensitized to aeroallergens and 22% to food-specific allergen components, whereas 69% of the patients exhibited specific Ig E to cross-reactive allergens. Among the latter, profilins were identified as most frequent Ig E cross-reactive allergen components. Interestingly, dysphagia, the main symptom of adult Eo E patients following rice and/or bread ingestion, was associated with sensitization to cross-reactive allergens such as profilins, pathogenesis-related ( PR) 10 and lipid transfer proteins ( LTP). Intolerance toward meat rarely correlated with sensitization to animal food allergens. Conclusion Candida albicans and cross-reactive plant allergen components, in particular profilins, were identified as frequent sensitizers in adult Eo E patients. Specific elimination therapies are suggested to reveal their actual roles in the pathogenesis of Eo E. [ABSTRACT FROM AUTHOR]

Background Basophils constitute a rare leukocyte population known for their effector functions in inflammation and allergy, as well as more recently described immunoregulatory roles. Besides their low frequency, functional analysis of basophils is hindered by a short life span, inefficient ex vivo differentiation protocols, and lack of suitable cell models. A method to produce large quantities of basophils in vitro would facilitate basophil research and constitute a sought-after tool for diagnostic and drug testing purposes. Methods A method is described to massively expand bone marrow-derived basophils in vitro. Myeloid progenitors are conditionally immortalized using Hoxb8 in the presence of interleukin-3 ( IL-3) and outgrowing cell lines selected for their potential to differentiate into basophils upon shutdown of Hoxb8 expression. Results IL-3-dependent, conditional Hoxb8-immortalized progenitor cell lines can be expanded and maintained in culture for prolonged periods. Upon shutdown of Hoxb8 expression, near-unlimited numbers of mature functional basophils can be differentiated in vitro within six days. The cells are end-differentiated and short-lived and express basophil-specific surface markers and proteases. Upon IgE- as well as C5a-mediated activation, differentiated basophils release granule enzymes and histamine and secrete Th2-type cytokines ( IL-4, IL-13) and leukotriene C4. IL-3-deprivation induces apoptosis correlating with upregulation of the BH3-only proteins BCL-2-interacting mediator of cell death ( BIM) and p53 upregulated modulator of apoptosis ( PUMA) and downregulation of proviral integration site for Moloney murine leukemia virus 1 kinase (PIM-1). Conclusion A novel method is presented to generate quantitative amounts of mouse basophils in vitro, which moreover allows genetic manipulation of conditionally immortalized progenitors. This approach may represent a useful alternative method to isolating primary basophils. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis ( Eo E) is a chronic, Th2-type inflammatory disease. Chemoattractant receptor-homologous molecule on Th2 cells ( CRTH2) is a prostaglandin D2 ( PGD2) receptor, expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, that mediates chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and would be expected to suppress eosinophilic tissue inflammation. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active, corticosteroid-dependent or corticosteroid-refractory Eo E. Methods In this randomized, double-blind, placebo-controlled trial, 26 adult patients (m/f = 22/4; mean age 41 years, range 22-69 years) with active Eo E, dependent or resistant to corticosteroids, were treated either with 100 mg OC000459 ( n = 14) or placebo ( n = 12) twice daily. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary end point was the reduction in esophageal eosinophil infiltration. Results After an 8-week OC000459 treatment, the esophageal eosinophil load decreased significantly, from 114.83 to 73.26 eosinophils per high-power field [(eos/hpf), P = 0.0256], whereas no reduction was observed with placebo (102.80-99.47 eos/hpf, P = 0.870). With OC000459, the physician's global assessment of disease activity improved from 7.13 to 5.18 ( P = 0.035). OC000459 likewise reduced extracellular deposits of eosinophil peroxidase and tenascin C, the effects not seen with placebo. No serious adverse events were observed. Conclusions An 8-week treatment with the CRTH2-antagonist, OC000459, exerts modest, but significant, anti-eosinophil and beneficial clinical effects in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE and is well tolerated. [ABSTRACT FROM AUTHOR]

Background Thymic stromal lymphopoietin ( TSLP) that is released by epithelial cells upon certain environmental triggers activates cells of the innate and adaptive immune system resulting in a preferential T helper 2 immune response. By releasing eosinophil extracellular traps ( EETs), eosinophils achieve an efficient extracellular bacterial killing. Eosinophil extracellular traps release, however, has been observed in both infectious and noninfectious eosinophilic diseases. Here, we aim to investigate whether eosinophils generate functional EETs as a direct response to TSLP, and further to study the extra- and intracellular mechanisms involved in this process as well as TSLP receptor ( TSLPR) expression by eosinophils in vitro and in vivo. Methods Thymic stromal lymphopoietin receptor expression on blood and tissue eosinophils was assessed by immunoblotting, flow cytometry, and immunofluorescence staining. Purified eosinophils were stimulated with recombinant human TSLP. The release of extracellular DNA in association with eosinophilic cationic protein ( ECP) was detected by fluorescence staining techniques and confocal microscopy. In addition, cell survival, cell adhesion, production of reactive oxygen species ( ROS), and the inhibition of bacterial growth by TSLP-stimulated eosinophils were measured. Results Thymic stromal lymphopoietin receptor was observed on peripheral blood eosinophils as well as on tissue infiltrating eosinophils in skin diseases. TSLP did not affect eosinophil survival, but induced the formation of EETs consisting of mitochondrial DNA in association with ECP in a concentration- and time-dependent manner. Eosinophil extracellular trap release could be inhibited by blocking either cell adhesion or ROS production. While eosinophils prevented the growth of both Staphylococcus aureus and Staphylococcus epidermidis, the latter were unable to elicit EET formation and eosinophils required additional TSLP stimulation to achieve this antibacterial activity. Conclusions thymic stromal lymphopoietin directly stimulates eosinophils to produce EETs. Our observations link epithelial TSLP expression triggered by environmental factors with pathogen defense mechanisms involving eosinophils. [ABSTRACT FROM AUTHOR]

Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil-predominant infiltration, thereby conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis ( Eo E) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that Eo E represents a T-helper ( Th)2-type inflammatory disease. Remodeling of the esophagus is a hallmark of Eo E, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single-nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the Eo E population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, Eo E seems to be primarily a food antigen-driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for Eo E include the 3 Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric Eo E are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between Eo E in adults and children. [ABSTRACT FROM AUTHOR]

To cite this article: Roth N, Städler S, Lemann M, Hösli S, Simon H-U, Simon D. Distinct eosinophil cytokine expression patterns in skin diseases - the possible existence of functionally different eosinophil subpopulations. Allergy 2011; 66: 1477-1486. Abstract Background: The function of eosinophils has been attributed to host defense, immunomodulation, and fibrosis. Although eosinophils are found among infiltrating cells in a broad spectrum of skin diseases, their pathogenic role remains uncertain. This study aimed to analyze the cytokine expression by eosinophils in different skin diseases. Methods: Skin specimens from different skin diseases [allergic/reactive, infectious, autoimmune, and tumors/lymphomas (LY)] were stained by antibodies directed to eosinophil cationic protein, cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-10, IL-11, IL-13, IL-17, IL-25, IL-33, interferon-γ, transforming growth factor (TGF)-β, and thymic stromal lymphopoietin], eotaxins (CCL11, CCL24, and CCL26), metalloproteinase (MMP)-9 as well as extracellular matrix proteins (tenascin-C and procollagen-3) and then analyzed by laser scanning microscopy. Results: The number of eosinophils varied considerably in and between disease groups and did not correlate with the numbers of accompanying inflammatory cells. The expression of IL-5, IL-6, IL-11, TGF-β, CCL24, and MMP-9 by eosinophils significantly differed between disease groups. Eosinophils in tumors/LY predominantly expressed IL-6, TGF-β, and CCL24, but not IL-11. On the other hand, in autoimmune diseases, eosinophils largely contributed to MMP-9 production. IL-5-generating eosinophils were particularly obvious in allergic and infectious diseases. Conclusion: In skin diseases, eosinophil expresses a broad spectrum of cytokines. The different cytokine expression patterns suggest distinct functional roles of eosinophils in these diseases that might be related to host defense, immunomodulation, fibrosis, and/or tumor development. [ABSTRACT FROM AUTHOR]

Background: Intravenous immunoglobulin (IVIG) preparations are increasingly used for the treatment of autoimmune and chronic inflammatory diseases. Naturally occurring autoantibodies against Siglec-9 and Fas are thought to contribute to the anti-inflammatory effects of IVIG via cell death regulation of leukocytes and tissue cells. Dimeric IVIG fractions are suspected to contain idiotypic (Id)- anti-idiotypic complexes of antibodies, which might also include anti-Siglec-9 and anti-Fas autoantibodies. Methods: Dimeric IVIG fractions were separated from monomeric IVIG by sizeexclusion chromatography and remonomerized by low pH treatment. Binding studies of total, monomeric, and dimeric IVIG were performed using surface plasmon resonance and flow cytometry on primary human neutrophils. Results: Anti-Siglec-9 and anti-Fas autoantibodies were contained in both monomeric and dimeric IVIG fractions, but anti-Siglec-9 antibodies were highly enriched in dimeric IVIG. The propensity to engage in dimer formation was paratope dependent. IVIG binding to Siglec-9 was specific and sialylation independent. Interestingly, we detected anti-idiotypic antibodies (anti-Ids) against anti- Siglec-9 autoantibodies in dimeric, but not in monomeric fractions of IVIG. Conclusions: Our study supports the concept that idiotype-anti-idiotype (Id-anti- Id) interactions contribute to the dimer formation in IVIG preparations. To our knowledge, this is the first description of Id-anti-Id dimers of death receptor-specific antibodies in IVIG. Such Id-anti-Id interactions might determine the activity of immunomodulatory antibodies present both in IVIG and the patient. [ABSTRACT FROM AUTHOR]

The methodology of randomized clinical trials is essential for the critical assessment and registration of therapeutic interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement was developed to alleviate the problems arising from the inadequate reporting of randomized controlled trials. The present article reflects on the items that we believe should be included in the CONSORT checklist in the context of conducting and reporting trials in allergen-specific immunotherapy. Only randomized, blinded (in particular blinding of patients, health care providers, and outcome assessors), placebo-controlled Phase III studies in this article. Our analysis focuses on the definition of patients’ inclusion and exclusion criteria, allergen standardization, primary, secondary and exploratory outcomes, reporting of adverse events and analysis. [ABSTRACT FROM AUTHOR]

Background: The Fip1-like-1–platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) gene fusion is a common cause of chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), and patients suffering from this particular subgroup of CEL/HES respond to low-dose imatinib therapy. However, some patients may develop imatinib resistance because of an acquired T674I mutation, which is believed to prevent drug binding through steric hindrance. Methods: In an imatinib resistant FIP1L1-PDGFRA positive patient, we analyzed the molecular structure of the fusion gene and analyzed the effect of several kinase inhibitors on FIP1L1-PDGFRA-mediated proliferative responses in vitro. Results: Sequencing of the FIP1L1-PDGFRA fusion gene revealed the occurrence of a S601P mutation, which is located within the nucleotide binding loop. In agreement with the clinical observations, imatinib did not inhibit the proliferation of S601P mutant FIP1L1-PDGFRA-transduced Ba/F3 cells. Moreover, sorafenib, which has been described to inhibit T674I mutant FIP1L1-PDGFRA, failed to block S601P mutant FIP1L1-PDGFRA. Structural modeling revealed that the newly identified S601P mutated form of PDGFRA destabilizes the inactive conformation of the kinase domain that is necessary to bind imatinib as well as sorafenib. Conclusions: We identified a novel mutation in FIP1L1-PDGFRA resulting in both imatinib and sorafenib resistance. The identification of novel drug-resistant FIP1L1-PDGFRA variants may help to develop the next generation of target-directed compounds for CEL/HES and other leukemias. [ABSTRACT FROM AUTHOR]

The article introduces the topics discussed in the issue, including the global distribution of rhinoconjunctivitis, the relationship between topical corticosteroids and COX-1 positive cells in nasal polyps, and the pharmacoeconomics of allergic rhinitis.

Background: Mast cells activation through FcℇRI cross-linking has a pivotal role in the initiation of allergic reactions. The influence of this activation on programmed cell death of human mast cells has not yet been clarified. This study evaluates the influence of IgE-dependent activation alone and in synergy with TRAIL on the expression of molecules involved in the apoptotic signal transduction. Methods: Human cord blood derived mast cells (CBMC) were cultured with myeloma IgE followed by activation with anti-human IgE. The expression of proteins involved in apoptotic signal transduction was assessed by immunoblot analysis. To test the effect of activation on a pro-apoptotic stimulus, activated, IgE-treated and resting CBMC were incubated with TRAIL, or in a medium with suboptimal concentrations of stem cell factor (SCF). Results: In accordance with a previous study of ours, it was found that IgE-dependent activation increased TRAIL-induced caspase-8 and caspase-3 cleavage. However, it did not have a significant influence on CBMC death induced by SCF withdrawal. IgE-dependent activation increased the expression of FLIP and myeloid cell leukemia 1 (MCL-1) anti-apoptotic molecules as well as the pro-apoptotic one, BIM. In addition, a decrease in BID expression was observed. TRAIL could reverse the increase in FLIP but did not influence the upregulation of MCL-1 and of BIM. Conclusions: These findings suggest that IgE-dependent activation of human mast cells induces an increase in both pro-survival and pro-apoptotic molecules. We therefore hypothesized that IgE-dependent activation may regulate human mast cell apoptosis by fine-tuning anti-apoptotic and pro-apoptotic factors. [ABSTRACT FROM AUTHOR]

The authors reflect on the significance of allergy research in promoting health care programs in Europe. They define allergy as a multifactorial disease that needs to be treated. They cite the influential role played by the European Union in all allergies research projects. They recognize the European Community Respiratory Health Survey as the first and most successful allergy research project. They further discuss other allergy issues like drug allergy, allergic rhinitis and atopic dermatitis.

The article discusses the relations between consensus statements (CS), evidence-based medicine (EBM) and guidelines in allergic diseases. According to the authors, CS is a document that corresponds the collective opinion of a convened expert panel, while EBM is an essential component in the preparation of guidelines. They note that EBM attempts to provide a logical framework from which the quality and relevance of clinical studies may be assessed in an unbiased manner.

Background: Eosinophilic esophagitis (EE) is often associated with concomitant atopic diseases. In children with EE in whom food allergens have been identified as causative factors, elemental and elimination diets result in an improvement or resolution of symptoms. Most adult EE patients are sensitized to aeroallergens, which cross-react with plant-derived food allergens, most commonly to grass pollen and cereals. Aims of the study: To investigate the clinical relevance of the sensitization to wheat and rye, and the efficacy of an allergen-specific elimination diet in adult EE patients. Methods: Six patients (five men, one women) with permanently active EE sensitized to grass pollen and the cereals wheat and rye underwent a double-blind placebo-controlled food challenge and were kept on an elimination diet avoiding wheat and rye for 6 weeks. Results: The challenge tests with wheat and rye did not provoke any EE symptoms in all patients. The elimination diet failed in reducing disease activity. Although one patient noticed an improvement of symptoms, endoscopic and histopathologic findings remained unchanged. Conclusions: In adult EE patients, sensitization to wheat and rye does not seem causative for EE. Elimination diet is not a reliable and efficient therapeutic measure in EE patients sensitized to wheat and rye. Low specific immunoglobulin-E levels to wheat and rye may be a consequence of the underlying grass pollen allergy. [ABSTRACT FROM AUTHOR]

In several clinical trials the topical application of pimecrolimus was shown to be effective in the treatment of atopic dermatitis (AD). By targeting calcineurin-dependent signaling pathways, pimecrolimus controls cytokine gene expression. The purpose of this study was to investigate the effect of pimecrolimus on the inflammatory infiltrate and cytokine expression pattern in AD upon topical therapy.From 10 patients with acute AD, skin biopsies as well as immunophenotype and cytokine production of peripheral blood mononuclear cells (PBMC) were examined before and 3 weeks after therapy.The clinical improvement was associated with a marked regression of histopathological features. In particular, the density of the inflammatory infiltrate mostly containing lymphocytes and eosinophils declined. By double immunofluorescent staining, a reduced expression of the T helper (Th) 2 cytokines interleukin (IL)-5, IL-10, and IL-13 in both CD4+ and CD8+ T cells was demonstrated after therapy. Pimecrolimus therapy was also associated with a reduced expression of the Th1 cytokine interferon (IFN)-γ. Interestingly, the numbers of epidermal CD1a+ dendritic cells increased following treatment. In the peripheral blood, a decrease of lymphocytes and eosinophils was noticed, but the distribution of lymphocyte subpopulations and their capacity of cytokine production did not change.Topical pimecrolimus exhibits anti-inflammatory effects in AD by reducing the inflammatory cell infiltrate and cytokine expression in the dermis. [ABSTRACT FROM AUTHOR]

Background: A subgroup of patients with allergic atopic eczema/dermatitis syndrome (AEDS) are known to have normal total and specific IgE levels and negative skin prick tests towards common environmental allergens. This form of the disease has been termed non-IgE-associated allergic AEDS. Although allergic mechanisms appear to be important, the pathogenesis of both IgE- and non-IgE-associated forms of the disease is unknown. Methods: We have compared the cytokine production pattern of peripheral blood mononuclear cells (PBMC) from IgE-associated AEDS, non-IgE-associated AEDS, and normal control individuals. PBMC were stimulated with anti-CD3 and/or anti-CD28 monoclonal antibodies (mAb) and cytokine production was measured by immunoassays in supernatants of 24-h cultures. Results: Compared to healthy subjects and non-IgE-associated AEDS patients, stimulated PBMC from IgE-associated AEDS patients produced less interferon (IFN)-γ. However, stimulated PBMC from both IgE-associated AEDS and non-IgE-associated AEDS patients produced more interleukin (IL)-13 than PBMC from control individuals. Moreover, IL-5 production was significantly increased in non-IgE-associated AEDS but not in IgE-associated AEDS patients. Conclusions: The underlying mechanism leading to increased differentiation of T helper (Th) 2 cells may involve a deficient capacity in producing IFN-γ in IgE-associated AEDS but not in non-IgE-associated AEDS patients. IL-13 may be a key cytokine in the pathogenesis of both allergic forms of AEDS. Background: A subgroup of patients with allergic atopic eczema/dermatitis syndrome (AEDS) are known to have normal total and specific IgE levels and negative skin prick tests towards common environmental allergens. This form of the disease has been termed non-IgE-associated allergic AEDS. Although allergic mechanisms appear to be important, the pathogenesis of both IgE- and non-IgE-associated forms of the disease is unknown. Methods:We have compared the... [ABSTRACT FROM AUTHOR]

BackgroundPriming of eosinophils with granulocyte-macrophage colony-stimulating factor (GM-CSF) and subsequent stimulation with platelet-activating factor (PAF) or the anaphylatoxin C5a is associated with a rapid production of leukotrienes (LTs) and release of eosinophil cationic protein (ECP). ObjectiveThis study was designed to determine the effects of the sesquiterpene esters petasin, isopetasin and neopetasin on LT generation and ECP release in eosinophils in vitro. MethodsThe model of eosinophil activation described above was used to induce LT production and ECP release. Cells were incubated with petasins and control inhibitors prior to priming and stimulation. To analyse intracellular steps of eosinophil activation and determine potential drug targets, some key signalling events were studied. Activity of cytosolic phospholipase A2 (cPLA2) was measured by analysing the generation of arachidonic acid (AA). Translocation of 5-lipoxygenase (5-LO) was observed using immunofluorescence microscopy. Intracellular calcium concentrations [Ca2+]i were measured by a bulk spectrofluorometric assay. ResultsWhereas all three compounds inhibited LT synthesis, ECP release from eosinophils was blocked by petasin only, but not isopetasin or neopetasin. Similarly, PAF- or C5a-induced increases in [Ca2+]i were completely abrogated by petasin only, whereas isopetasin and neopetasin had significant lower blocking efficacy. Moreover, only petasin, but not isopetasin or neopetasin, prevented increases in cPLA2 activity and 5-LO translocation from the cytosolic compartment to the nucleus envelope in calcium ionophore-stimulated eosinophils. ConclusionThese data suggest that different petasins may at least partially block different intracellular signalling molecules. To reduce LT synthesis, isopetasin and neopetasin may act at the level of or distal to 5-LO. In contrast, petasin may inhibit inflammatory... [ABSTRACT FROM AUTHOR]

The author reflects on the prevalence of allergic disease. The author relates that allergic disease has grown in all countries of the world resulting in a global health problem. The author added that the increase in allergic disease is not restricted to developed countries although in countries with endemic parasitosis, mechanisms associated with the increased allergy prevalence may differ.

The article focuses on the subject matter of the journal's publication. According to the author, the format of the journal took up the diversity of allergic diseases into account by introducing a specific theme into some of its issues. These special themes would include one or two review papers as well as three to five original papers already accepted for publication. This year, two themes were proposed, for food allergy and for atopic dermatitis.

The article focuses on the grouping and publication of papers concerning the mechanisms, epidemiology, risk factors, prevention, diagnosis, control or pharmacoeconomics of allergic diseases. The format of "Allergy," the Official Organ of the European Academy of Allergy and Clinical Immunology, will take into account the diversity of allergic diseases by introducing in some issues a specific theme. The fist theme is devoted to the immune mechanisms of the Immoglobulin E mediated allergic reaction. Themes showing the widespread coverage of our journal, and it is of importance to mention that authors from Central European countries increasingly contribute to the field.

Highlights the 4th biennial meeting of the International Eosinophil Society in Bern, Switzerland. Guest speaker; Programs and activities; Topics discussed during the meeting.