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With the development of targeted therapies for allergic diseases, the need for biomarkers supporting disease diagnosis and management has increased. Recent research has elucidated the pattern of cytokines and their distinct roles in the pathogenesis of allergic diseases. This means that cytokines should be considered as biomarkers. In this review article, we summarize published findings and critically discuss the use of cytokine measurements in association with disease diagnosis and management. Among the variety of suggested cytokines, thymus and activation-regulated chemokine (TARC) stands out and can indeed serve as a biomarker of atopic dermatitis. Both biologic characteristics and technical issues determine the reliability and limit the use of blood cytokines as biomarkers. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) most often affects young patients of reproductive age, yet little is known about its effects during pregnancy. We examined the course of EoE during pregnancy, outcomes of pregnancies, and patient concerns related to pregnancy and EoE. We sent a survey that queried demographic and disease-specific characteristics as well as pregnancy-related topics to all 151 female patients treated at 2 EoE centers in Switzerland. We analyzed cross-sectional survey data. Of 72 patients that returned the survey, we identified 20 patients that had at least 1 pregnancy and analyzed the data on 34 pregnancies. During pregnancy, improvement of dysphagia was reported in 56% (19/34) of all pregnancies, whereas deterioration was reported in 20% (7/34) of all pregnancies. After delivery, dysphagia returned to the pre-pregnancy level in 68% (13/19) of all pregnancies for patients with improvement of dysphagia and 57% (4/7) of all pregnancies for patients with deterioration of dysphagia during pregnancy. Esophagogastroduodenoscopy during pregnancy was required in less than 10% (3/34) of all pregnancies. Pregnancy-related complications occurred in 12% of pregnancies (4/34). The leading patient-reported concerns were fear of heritability (40% of patients, 8/20) and concerns of that use of medication would harm the fetus (30% of patients, 6/20). Pregnancy affects the course of EoE, with improvement of symptoms reported in most patients. Dysphagia returned to the pre-pregnancy level following delivery. EoE has likely no negative effects on outcomes of pregnancies. [ABSTRACT FROM AUTHOR]

• The management of eosinophilic dermatoses should consider the underlying pathomechanism. • Causes of eosinophilia are either intrinsic (in eosinophils), or extrinsic (via cytokines). • Antibodies against IL-5 or its receptor target eosinophil numbers and activation. • Dexpramipexole efficiently reduces eosinophil numbers. • Tyrosine kinase inhibitors are effective in FIP1L1-PDGFRA positive hypereosinophilia. Eosinophil infiltration is observed in a broad spectrum of skin diseases of various origins. Eosinophils are thought to actively contribute to pathogenesis as they are able to defend against microbes, to regulate inflammation, cause tissue damage, promote remodeling and fibrosis, and initiate pruritus. Therefore, targeting eosinophils would seem a worthwhile therapeutic approach. A promising strategy is to target the production, activation and survival of eosinophils, example with antibodies directed against IL-5 or its receptor, and Siglec-8. Dexpramipexole and tyrosine kinase inhibitors have been shown to reduce eosinophil numbers in patients with hypereosinophilia. Janus kinase inhibitors block signal transduction and thus activation of inflammatory cells including eosinophils. A further approach is to target cells and cytokines acting on or mediators released by eosinophils, for example, CD52, IL-13, IL-31, TSLP, and eotaxins. This review summarizes current therapeutic strategies, including novel agents affecting eosinophils directly that are under clinical investigation. [ABSTRACT FROM AUTHOR]

Eosinophil extracellular traps (EETs) are part of the innate immune response and are seen in multiple infectious, allergic, and autoimmune eosinophilic diseases. EETs are composed of a meshwork of DNA fibers and eosinophil granule proteins, such as major basic protein (MBP) and eosinophil cationic protein (ECP). Interestingly, the DNA within the EETs appears to have its origin in the mitochondria of eosinophils, which had released most their mitochondrial DNA, but were still viable, exhibiting no evidence of a reduced life span. Multiple eosinophil activation mechanisms are represented, whereby toll-like, cytokine, chemokine, and adhesion receptors can all initiate transmembrane signal transduction processes leading to the formation of EETs. One of the key signaling events required for DNA release is the activation of the NADPH oxidase. Here, we review recent progress made in the understanding the molecular mechanisms involved in DNA and granule protein release, discuss the presence of EETs in disease, speculate on their potential role(s) in pathogenesis, and compare available data on other DNA-releasing cells, particularly neutrophils. [ABSTRACT FROM AUTHOR]

Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders. [Copyright &y& Elsevier]

Eosinophils are multifunctional leukocytes that increase in various tissues in patients with a variety of disorders. Locally, they can be involved in the initiation and propagation of diverse inflammatory responses. In this review the clinical association of eosinophils with diseases of the skin, lung, and gastrointestinal tract is summarized. An approach to determining the causal role of eosinophils in these diseases is presented. Recent findings concerning molecular diagnosis, cause, and treatment are discussed. [Copyright &y& Elsevier]

Background: Atopic eczema (AE) is a chronic inflammatory skin disorder characterized by eczematous skin lesions, pruritus, and typical histopathologic features. Objective: We asked whether depletion of B cells by monoclonal anti-CD20 antibody therapy (rituximab) would improve severe AE. Methods: Six patients (4 women and 2 men) with severe AE received 2 intravenous applications of rituximab, each 1000 mg, 2 weeks apart. To evaluate the efficacy of rituximab, we monitored clinical parameters (eczema area and severity index, pruritus), total and allergen-specific IgE levels, skin histology, and inflammatory cells and cytokine expression in the skin and peripheral blood before and after therapy (ClinicalTrials.gov Identifier: NCT00267826). Results: All patients showed an improvement of their skin symptoms within 4 to 8 weeks. The eczema area and severity index significantly decreased (before therapy, 29.4 ± 4.3; week 8, 8.4 ± 3.6; P < .001). Histologic alterations such as spongiosis, acanthosis, and dermal infiltrate, including T and B cell numbers, also dramatically improved. However, whereas blood B cells were below detectable levels as a consequence of rituximab administration, skin B cells were reduced by approximately 50% only. Expression of IL-5 and IL-13 was reduced after therapy. Moreover, whereas allergen-specific IgE levels were not altered, we observed a slight reduction in total IgE concentrations in blood. Conclusions: B cells play a major role in AE pathogenesis. Treatment with an anti-CD20 antibody leads to an impressive improvement of AE in patients with severe disease. [Copyright &y& Elsevier]

Eosinophilic inflammatory responses occur in association with multiple disorders. Although the initial cause and the affected organs vary among the different eosinophilic disorders, there are only 2 major pathways that mediate eosinophilia: (1) cytokine-mediated increased differentiation and survival of eosinophils (extrinsic eosinophilic disorders), and (2) mutation-mediated clonal expansion of eosinophils (intrinsic eosinophilic disorders). Independent from the original trigger, the most common cause of eosinophilia is the increased generation of IL-5–producing T cells. In some cases, tumor cells are the source of eosinophil hematopoietins. The intrinsic eosinophilic disorders are characterized by mutations in pluripotent or multipotent hematopoietic stem cells leading to chronic myeloid leukemias with eosinophils as part of the clone. Here, we propose a new classification of eosinophilic disorders on the basis of these obvious pathogenic differences between the 2 groups of patients. We then discuss many known eosinophilic disorders, which can be further subdivided by differences in T-cell activation mechanisms, origin of the cytokine-producing tumor cell, or potency of the mutated stem cell. Interestingly, many subgroups of patients originally thought to have the idiopathic hypereosinophilic syndrome can be integrated in this classification. [Copyright &y& Elsevier]

The newly observed nongenomic effects of glucocorticoids on signaling pathways operating in neutrophils in vitro will stimulate further investigations on pathogenic mechanisms and drug actions in bullous skin diseases. [ABSTRACT FROM AUTHOR]

A subgroup of patients with atopic dermatitis are known to have normal serum total immunoglobulin E levels, undetectable specific immunoglobulin E, and negative skin prick tests towards allergens. This form of the disease has been termed nonallergic atopic dermatitis. In this study, we found that, among 1151 chronic atopic dermatitis patients, about 10% had normal serum immunoglobulin E levels with no evidence for immunoglobulin E sensitization. We investigated immunologic mechanisms of patients with “allergic” and “nonallergic” atopic dermatitis using peripheral blood and skin biopsy samples. Our data suggest that T cells are likely involved in the pathogenesis of both forms of atopic dermatitis. Skin T cells equally responded to superantigen, staphylococcal enterotoxin B, and produced interleukin-2, interleukin-5, interleukin-13, and interferon-γ in both forms of the disease. Interleukin-4, however, was not detectable in the skin biopsies of both atopic dermatitis types and was secreted in very low amounts by T cells cultured from the skin biopsies. Moreover, skin T cells from nonallergic atopic dermatitis patients expressed lower interleukin-5 and interleukin-13 levels compared with allergic atopic dermatitis patients. Accordingly, T cells isolated from skin biopsies of atopic dermatitis, but not from the nonallergic atopic dermatitis, induced high immunoglobulin E production in cocultures with normal B cells that was mediated by interleukin-13. In addition, B cell activation with high CD23 expression was observed in the peripheral blood of atopic dermatitis, but not nonallergic atopic dermatitis patients. These data suggest, although high numbers of T cells are present in lesional skin of both types, a lack of interleukin-13-induced B cell activation and consequent immunoglobulin E production in nonallergic atopic dermatitis. [ABSTRACT FROM AUTHOR]

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of many transformed but also of non-transformed cells. In addition, TRAIL receptor activation has been reported to activate non-apoptotic signaling pathways. Here, we report an increased expression of TRAIL in peripheral blood T cells and monocytes from patients with atopic dermatitis (AD) compared with control individuals. High TRAIL expression was also observed in skin-infiltrating T cells of AD patients. Topical tacrolimus treatment reduced the total number of T cells in the skin, but the relative proportion of TRAIL-positive cells within both CD4+ and CD8+ cell populations did not change. TRAIL was demonstrated to induce the expression of interleukin-1 receptor antagonist (IL-1Ra) in keratinocytes in a caspase-independent manner in vitro. Moreover, increased expression of IL-1Ra was observed in keratinocytes of AD lesional skin. These data suggest that TRAIL-expressing inflammatory skin cells may contribute to the epidermal activation of the IL-1Ra gene in AD. [ABSTRACT FROM AUTHOR]