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Studies have linked daily pollen counts to respiratory allergic health outcomes, but few have considered allergen levels. We sought to assess associations of grass pollen counts and grass allergen levels (Phl p 5) with respiratory allergic health symptoms in a panel of 93 adults with moderate-severe allergic rhinitis and daily asthma hospital admissions in London, United Kingdom. Daily symptom and medication scores were collected from adult participants in an allergy clinical trial. Daily counts of asthma hospital admissions in the London general population were obtained from Hospital Episode Statistics data. Daily grass pollen counts were measured using a volumetric air sampler, and novel Phl p 5 levels were measured using a ChemVol High Volume Cascade Impactor and ELISA analyses (May through August). Associations between the 2 pollen variables and daily health scores (dichotomized based on within-person 75th percentiles) were assessed using generalized estimating equation logistic models and with asthma hospital admissions using Poisson regression models. Daily pollen counts and Phl p 5 levels were each positively associated with reporting a high combined symptom and medication health score in separate models. However, in mutually adjusted models including terms for both pollen counts and Phl p 5 levels, associations remained for Phl p 5 levels (odds ratio [95% CI]: 1.18 [1.12, 1.24]), but were heavily attenuated for pollen counts (odds ratio [95% CI]: 1.00 [0.93, 1.07]). Similar trends were not observed for asthma hospital admissions in London. Grass allergen (Phl p 5) levels are more consistently associated with allergic respiratory symptoms than grass pollen counts. [ABSTRACT FROM AUTHOR]

Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type 2 inflammatory conditions such as allergic asthma was not known. We sought to decipher macrophage-trained immunity in allergic asthma. We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation in mice, and an in vitro training setup to analyze persistent changes in macrophage eicosanoid, cytokine, and chemokine production as well as the underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or metabolic flux analysis and liquid chromatography–tandem mass spectrometry analysis, respectively. We found that macrophages differentiated from bone marrow or blood monocyte progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE 2 , IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type 2 imprint, which shifted toward a classical inflammatory training over time. HDM-induced allergic airway inflammation elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl peptide receptor 2–TNF–2-HG–PGE 2 /PGE 2 receptor 2 axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow–derived macrophages from HDM-allergic mice. Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type 2 airway inflammation and thus represents a target for asthma therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drug–exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD. This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages. Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD. [ABSTRACT FROM AUTHOR]

Background: IL-22 controls tissue homeostasis by both proinflammatory and anti-inflammatory effects. However, the anti-inflammatory mechanisms of IL-22 remain poorly investigated. Objective: We sought to investigate the anti-inflammatory role for IL-22 in human asthma. Methods: T-cell lines derived from lung biopsy specimens of asthmatic patients were characterized by means of flow cytometry. Human bronchial epithelial cells from healthy and asthmatic subjects were stimulated with IL-22, IFN-γ, or the combination of both cytokines. Effects of cytokine stimulation were investigated by using whole-genome analysis, ELISA, and flow cytometry. The functional consequence of cytokine stimulation was evaluated in an in vitro wound repair model and T cell–mediated cytotoxicity experiments. In vivo cytokine expression was measured by using immunohistochemistry and Luminex assays in bronchoalveolar lavage fluid of healthy and asthmatic patients. Results: The current study identifies a tissue-restricted antagonistic interplay of IL-22 and the proinflammatory cytokine IFN-γ. On the one hand, IFN-γ antagonized IL-22–mediated induction of the antimicrobial peptide S100A7 and epithelial cell migration in bronchial epithelial cells. On the other hand, IL-22 decreased epithelial susceptibility to T cell–mediated cytotoxicity by inhibiting the IFN-γ–induced expression of MHC-I, MHC-II, and CD54/intercellular adhesion molecule 1 molecules. Likewise, IL-22 inhibited IFN-γ–induced secretion of the proinflammatory chemokines CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vitro. Consistently, the IL-22 expression in bronchoalveolar lavage fluid of asthmatic patients inversely correlated with the expression of CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vivo. Conclusions: IL-22 might control the extent of IFN-γ–mediated lung inflammation and therefore play a tissue-restricted regulatory role. [Copyright &y& Elsevier]

Background: TH17 cells are of pathologic relevance in autoimmune disorders and presumably also in allergy and asthma. Regulatory T (Treg) cells, in contrast, suppress inflammatory and allergen-driven responses. Despite these disparate functions, both T-cell subsets have been shown to be dependent on TGF-β for their development. Objective: The aim of the study was to analyze the differentiation and function of human TH17 cells in comparison with other TH cell subsets. Methods: Naive human CD4+ T cells were differentiated in vitro, and gene expression was analyzed by means of quantitative real-time PCR, ELISA, and immunofluorescence. The function of TH cell subsets was assessed by monitoring the response of primary bronchial epithelial cells in coculture experiments. Results: In vitro differentiated TH17 cells differ from Treg and other TH cells in their potency to induce IL-6 and IL-1β expression in primary bronchial epithelial cells. TGF-β, IL-1β, IL-6, and IL-23 are necessary during TH17 cell differentiation to acquire these functions, including IL-17 production. In contrast, TGF-β alone is necessary and sufficient to induce the transcription factor RORC2. This transcription factor, previously thought to be specific for TH17 cells, is also expressed in Treg cells, CD25+ cells, cytotoxic T cells, and natural killer T cells. Conclusion: This study demonstrates mechanisms of differentiation to human TH17 cells, a subset that effectively and uniquely modulates the function of primary bronchial epithelial cells. [Copyright &y& Elsevier]

The pathogenesis of chronic inflammatory diseases is assumed to depend on activated T cells interacting with resident tissue cells or migratory inflammatory cells. The discovery of new T-cell subsets such as the IL-17–producing TH17 and T-regulatory cells innovated our understanding of T-cell biology. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. The understanding of IL-17 and TH17 differentiation pathways has also changed the perspective of immunologists regarding the basis of chronic tissue inflammation, particularly where TH1 cells were considered as driving force of the pathology. This review summarizes the recent developments on TH cell subsets and integrates these findings into existing concepts of immunopathologic mechanisms. [Copyright &y& Elsevier]

Background: Allergic asthma typically shows activated, allergen-specific CD4+ T cells in the early phase and airway remodeling in the late phase of the disease. Although TGF-β plays a crucial role in airway remodeling, it is only marginally induced in CD4+ T cells in the early allergen-dependent activation of the immune system. Objective: To elucidate the transition between early- and late-phase events, we investigated the role of activin A, a close family member of TGF-β. Methods: Activin A and TGF-β1 levels were measured systemically in the serum and in CD4+ T cells of asthmatic patients, as well as locally in the lung. Results: Activin A serum levels were increased in patients with severe asthma compared with levels in patients with moderate asthma and healthy control subjects, whereas all patients showed significantly increased TGF-β1 serum levels independent of disease severity. In T cells only patients with moderate asthma showed increased activin A mRNA expression, whereas TGF-β1 expression was equal to that seen in healthy subjects. Accordingly, ovalbumin sensitization in a mouse model of allergic asthma could induce activin A mRNA expression, but not TGF-β1 expression, in the lung. Immunohistochemistry of mice and human specimens revealed an abundant expression of activin A by infiltrating lymphocytes and structural cells of the lung. Although TGF-β1 more potently enhanced proliferation and Smad 2/3–dependent reporter genes in fibroblasts, activin A was capable of inducing TGF-β1 and vice versa. Conclusion: Activin A provides a link between acute allergen-specific T-cell responses and chronic TGF-β1–mediated airway remodeling in asthma. [Copyright &y& Elsevier]

Background A standardized human model to study early pathogenic events in patients with psoriasis is missing. Activation of Toll-like receptor 7/8 by means of topical application of imiquimod is the most commonly used mouse model of psoriasis. Objective We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis. Methods Imiquimod (Aldara 5% cream; 3M Pharmaceuticals, St Paul, Minn) was applied twice a week to the backs of volunteers (n = 18), and development of skin lesions was monitored over a period of 4 weeks. Consecutive biopsy specimens were taken for whole-genome expression analysis, histology, and T-cell isolation. Plasmacytoid dendritic cells (pDCs) were isolated from whole blood, stimulated with Toll-like receptor 7 agonist, and analyzed by means of extracellular flux analysis and real-time PCR. Results We demonstrate that imiquimod induces a monomorphic and self-limited inflammatory response in healthy subjects, as well as patients with psoriasis or eczema. The clinical and histologic phenotype, as well as the transcriptome, of imiquimod-induced inflammation in human skin resembles acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics the hallmarks of psoriasis. In contrast to classical contact dermatitis, in which myeloid dendritic cells sense haptens, pDCs are primary sensors of imiquimod. They respond with production of proinflammatory and T H 17-skewing cytokines, resulting in a T H 17 immune response with IL-23 as a key driver. In a proof-of-concept setting systemic treatment with ustekinumab diminished imiquimod-induced inflammation. Conclusion In human subjects imiquimod induces contact dermatitis with the distinctive feature that pDCs are the primary sensors, leading to an IL-23/T H 17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in patients with psoriasis. [ABSTRACT FROM AUTHOR]

Background Airway remodeling is a detrimental and refractory process showing age-dependent clinical manifestations that are mechanistically undefined. The leukotriene (LT) and wingless/integrase (Wnt) pathways have been implicated in remodeling, but age-specific expression profiles and common regulators remained elusive. Objective We sought to study the activation of the LT and Wnt pathways during early- or late-onset allergic airway inflammation and to address regulatory mechanisms and clinical relevance in normal human bronchial epithelial cells (NHBEs) and nasal polyp tissues. Methods Mice were sensitized with house dust mite (HDM) allergens from days 3, 15, or 60 after birth. Remodeling factors in murine bronchoalveolar lavage fluid, lung tissue, or human nasal polyp tissue were analyzed by means of Western blotting, immunoassays, or histology. Regulatory mechanisms were studied in cytokine/HDM-stimulated NHBEs and macrophages. Results Bronchoalveolar lavage fluid LT levels were increased in neonatal and adult but reduced in juvenile HDM-sensitized mice. Lungs of neonatally sensitized mice showed increased 5-lipoxygenase levels, whereas adult mice expressed more group 10 secretory phospholipase A 2 , Wnt5a, and transglutaminase 2 (Tgm2). Older mice showed colocalization of Wnt5a and LT enzymes in the epithelium, a pattern also observed in human nasal polyps. IL-4 promoted epithelial Wnt5a secretion, which upregulated macrophage Tgm2 expression, and Tgm2 inhibition in turn reduced LT release. Tgm2, group 10 secretory phospholipase A 2 , and LT enzymes in NHBEs and nasal polyps were refractory to corticosteroids. Conclusion Our findings reveal age differences in LT and Wnt pathways during airway inflammation and identify a steroid-resistant cascade of Wnt5a, Tgm2, and LTs, which might represent a therapeutic target for airway inflammation and remodeling. [ABSTRACT FROM AUTHOR]

Background Allergen immunotherapy is currently the only disease-modifying treatment available for allergic rhinitis and allergic asthma. Objectives We sought to evaluate the induction of sustained tolerance to allergen when anti–IL-4 was combined with a suboptimal course of grass pollen subcutaneous immunotherapy (SCIT) using the allergen-induced skin late-phase response (LPR) and exploratory immune monitoring as surrogate markers of therapeutic response. Methods In this randomized, double-blind, 3-group parallel design trial, 37 participants with seasonal allergic rhinitis received suboptimal SCIT (30,000 standardized quality units) in combination with anti–IL-4 (VAK694) and suboptimal SCIT (30,000 standardized quality units) plus placebo antibody or double placebo (placebo SCIT and placebo antibody) restricted to 13 weeks before the grass pollen season. The primary end point was the size of the LPR at 12 months. Exploratory end points included measures of the immunomodulatory activity of treatment by using IL-4 and IL-10 FluoroSpot assays, flow cytometry of T cells, and measurement of IgE, IgG 4 , and facilitated antigen binding. Results Both active treatment arms led to a substantial and sustained reduction of the LPR with no additional suppression with addition of anti–IL-4. Treatment with anti–IL-4 and SCIT compared with SCIT alone led to a sustained reduction in allergen-specific IL-4–producing cell counts ( P < .01). Both active treatment arms led to induction of dual IL-4/IL-10–producing cells during the pollen season. Conclusion The combination of anti–IL-4 with SCIT provided no additional benefit over SCIT alone in suppressing the allergen-induced skin LPR. A larger trial is needed to assess whether the observed ex vivo downregulation of T H 2 responses might translate into clinical benefit. [ABSTRACT FROM AUTHOR]

Background: The pruritic cytokine IL-31 has been shown to be expressed by murine activated effector T Lymphocytes of a TH2 phenotype. Like IL-17 and IL-22, IL-31 is a tissue-signaling cytokine the receptor of which is mainly found on nonimmune cells. An overabundance of IL-31 has been shown in patients with atopic disorders, including dermatitis, as well as asthma, and therefore represents a promising drug target, although its regulation in the context of the human TH2 clusters is not yet known. Objective: We sought to address the gene regulation of human IL-31 and to test whether IL-31 possesses a similar proallergic function as members of the human TH2 cytokine family, such as IL-4, IL-5, and IL-13. Methods: Polyclonal and purified protein derivative of tuburculin–specific T-cell clones were generated. TH phenotype was determined, and IL-31 was measured by means of ELISA. Gene expression of primary bronchial epithelial cells treated with IL-31 was also measured. Results: IL-31 was expressed by all of the TH2 clones and not by TH1, TH17, or TH22. This expression was dependent on autocrine IL-4 expression from these clones because it could be reduced if blocking antibodies to IL-4 were present. Interestingly, TH1 clones were able to express IL-31 if IL-4 was added to culture. This IL-31 expression was transient and did not affect the phenotype of the TH1 clones. IL-31 was able to induce proinflammatory genes, such as CCL2 and granulocyte colony-stimulating factor. Conclusion: IL-31 is not a TH2 cytokine in the classical sense but is likely to be expressed by a number of cells in an allergic situation in which IL-4 is present and possibly contribute to the allergic reaction. [Copyright &y& Elsevier]

Background: Allergic rhinitis symptoms of itching, sneezing, rhinorrhea, and nasal obstruction significantly decrease patients’ quality of life. Compared with histamine and leukotriene receptor antagonists, the petasol butenoate complex Ze 339 displays pharmacologically distinct properties. In vitro it inhibits the biosynthesis of leukotrienes and mediator release from activated eosinophils. Objective: This study aimed to assess the efficacy and mode of action of Ze 339, desloratadine, and placebo on allergic rhinitis symptoms, nasal airflow, and local mediator levels after unilateral nasal allergen provocation. Methods: In this double-blind, randomized, crossover study 18 subjects with allergic rhinitis to grass pollen received Ze 339, desloratadine, and placebo for 5 days before nasal allergen challenge with grass pollen extract. Rhinomanometry, symptom assessment, and local inflammatory mediator measurement were performed during the 24 hours after allergen challenge. Results: With Ze 339, the patient’s time to recovery (5.4 ± 1.6 hours) from nasal obstruction after allergen challenge (time for return to 90% of baseline value ± SEM) was significantly shorter than with placebo (9.1 ± 2.3 hours, P = .035) and desloratadine (10.7 ± 2.5 hours, P = .022). Likewise, Ze 339’s standardized symptom assessment for nasal obstruction (3.2 ± 1.3 hours) showed significantly faster relief (time for return to baseline value ± SEM compared with placebo, 8.3 ± 2.4 hours; P = .027) and desloratadine (4.5 ± 1.2 hours, P = .030). One interesting finding was that Ze 339 significantly reduced IL-8 and leukotriene B4 levels in nasal secretions before challenge. Conclusion: When compared with desloratadine and placebo, Ze 339 shows better efficacy in relieving nasal obstruction symptoms and inhibiting critical components of the chemokine network and as such represents a novel symptomatic and possible prophylactic treatment for allergic rhinitis. [Copyright &y& Elsevier]