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Airway epithelial cells are important in immune homeostasis in that they dampen immune activation by clearing dying cells and producing anti-inflammatory cytokines. Immune-protective action of lung cells Airway epithelial cells have been shown to activate immune responses on exposure to inhaled antigens. Kodi Ravichandran and colleagues now demonstrate that they also have an important role in immune homeostasis by dampening immune activation through clearing dying cells and secreting anti-inflammatory cytokines. These functions depend on the GTPase Rac1. Activated epithelial cells lacking Rac1 produce less of the anti-inflammatory cytokine interleukin-10, and express higher levels of interleukin-33, correlating with higher numbers of innate lymphocytes and enhanced airway inflammation in response to inhaled allergens. This work also suggests that apart from a physical barrier, phagocytosis in the airways may be part of an additional line of immune protection against innocuous antigens. Lung epithelial cells can influence immune responses to airway allergens 1 , 2 . Airway epithelial cells also undergo apoptosis after encountering environmental allergens 3 ; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells 1 , 4 , 5 . Administration of exogenous IL-10 ‘rescued’ the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.

Although interleukin-18 is structurally homologous to IL-1 and its receptor belongs to the IL-1R/Toll-like receptor (TLR) superfamily, its function is quite different from that of IL-1. IL-18 is produced not only by types of immune cells but also by non-immune cells. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-γ. However, the overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-18 is a potent proinflammatory cytokine that has pathophysiological roles in several inflammatory conditions. IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglias. Thus, the pathophysiological role of IL-18 has been extensively tested in the organs that contain these cells. Somewhat surprisingly, IL-18 alone can stimulate Th2 cytokine production as well as allergic inflammation. Therefore, the functions of IL-18 in vivo are very heterogeneous and complicated. In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.

Although immunologists have found the dichotomous helper T cell subset model a useful construct, it is beginning to show its age. Some suggest that proponents of the T H 1-T H 2 dichotomy are overzealous in making the data conform to the scheme, like Procrustes who stretched or truncated his guests so that they would fit his guest bed.

Abstract Rationale Epidemiologic studies have shown that, in atopic children, wheezing is more likely to persist into adulthood, eventually becoming asthma, whereas it appears to resolve by adolescence in nonatopic children. Objectives To investigate whether among children with multitrigger wheeze responsive to bronchodilators the airway pathology would be different in nonatopic wheezers, who are often considered nonasthmatic, compared with atopic wheezers, who are more frequently diagnosed as having asthma. Methods Bronchial biopsies were obtained from 55 children undergoing bronchoscopy for appropriate clinical indications: 18 nonatopic children with multitrigger wheeze (median age, 5 yr; range, 2–10 yr), 20 atopic children with multitrigger wheeze (medan age, 5 yr; range, 2–15 yr), and 17 control children with no atopy or wheeze (median age, 4; range, 2–14 yr). By histochemistry and immunohistochemistry, we quantified epithelial loss, basement membrane thickness, angiogenesis, inflammatory cells, IL-4+, and IL-5+ cells in subepithelium. Measurements and Main Results Unexpectedly, all pathologic features examined were similar in atopic and nonatopic wheezing children. Compared with control subjects, both nonatopic and atopic wheezing children had increased epithelial loss (P = 0.03 and P = 0.002, respectively), thickened basement membrane (both P < 0.0001), and increased number of vessels (P = 0.003 and P = 0.03, respectively) and eosinophils (P < 0.0001 and P = 0.002, respectively). Moreover, they had increased cytokine expression, which was highly significant for IL-4 (P = 0.002 and P = 0.0001, respectively) and marginal for IL-5 (P = 0.02 and P = 0.08, respectively). Conclusions This study shows that the airway pathology typical of asthma is present in nonatopic wheezing children just as in atopic wheezing children. These results suggest that, when multitrigger wheezing responsive to bronchodilators is present, it is associated with pathologic features of asthma even in nonatopic children.

Histamine drives pruritus in allergic skin diseases which clinically constitutes a most disruptive symptom. Skin pathology in allergic skin diseases is crucially influenced by different T-helper subsets. However, the contribution of different histamine-receptors to T-helper cell dependent skin pathology has not been definitively answered. Models which can specifically address the functional role of T-helper subsets and the mediators involved are therefore valuable to gain further insights into molecular pathways which contribute to allergic skin disease. They might also be helpful to probe amendable therapeutic interventions such as histamine-receptor antagonism. Establishing an adoptive transfer model for antigen-specific Th cells, we aimed to delineate the role of histamine H1- and H4-receptors in Th2-dependent skin inflammation. In-vitro differentiated and OVA primed Th2 cells were adoptively transferred into congenic recipient mice. In vivo treatment with specific histamine H1- and H4-receptor antagonists was performed to analyze the contribution of these histamine-receptors to Th2-dependent skin pathology in our model. Analysis four days after epicutaneous challenge comprised skin histology, flow cytometric detection of transferred T-helper cells and analysis of antigen-cytokine profiles in skin-draining lymph nodes. Use of specific H1- and H4-receptor antagonists revealed a crucial role for H1- and H4-receptors for Th2 migration and cytokine secretion in a Th2-driven model of skin inflammation. While H1- and H4-receptor antagonists both reduced Th2 recruitment to the site of challenge, local cytokine responses in skin-draining lymph nodes were only reduced by the combined application of H1- and H4-receptor antagonists and mast cell counts remained altogether unchanged by either H1R-, H4R- or combined antagonism. Our model demonstrates a role for H1- and H4-receptors in Th2 cell infiltration and cytokine secretion in allergic skin diseases and suggests further studies to evaluate these findings for therapeutic approaches.

Mast cells (MCs) are among the first cell types associated with allergies and asthma. Studies in human asthma have identified their presence in the lung submucosa and smooth muscle and also in the airway epithelium. As our understanding of the distribution and location of these MCs in the human airway has increased, it is clear that much remains to be understood regarding the presence and subtype of these MCs in relationship to asthma phenotypes, defined both clinically and on the basis of immunologic pathways. Human MCs have traditionally been divided into two major subtypes based on the protease granule content, with tryptase representing total MCs. There is emerging evidence that in the epithelium, MCs of an altered subtype (with tryptase, chymase, and/or carboxypeptidase A3) may play a role in the pathophysiology of poorly controlled, severe, Th2-associated asthma.

The differentiation of T cells along different lineages is central to the control of immunity. Here we have used a conditional gene knockout system to delete PKCλ/ι selectively in activated T cells. With this system we have demonstrated that PKCλ/ι is necessary for T-helper cell (Th2) cytokine production and optimal T-cell proliferation and allergic airway inflammation in vivo. Our data demonstrate that the activation of the transcription factors nuclear factor of activated T cells and NF-κB is impaired in PKCλ/ι-deficient activated T cells. In addition, we present genetic knockout evidence in ex vivo experiments with primary T cells that PKCλ/ι is critical for the control of cell polarity during T-cell activation. Therefore PKCλ/ι emerges as a critical regulator of Th 2 activation.

Factors predisposing to individual susceptibility to contact allergic dermatitis are ill defined. This study was designed to characterize the response of allergic and tolerant individuals’ T-lymphocytes after exposure to p-phenylenediamine (PPD). Peripheral blood mononuclear cells (PBMCs) from allergic patients proliferated when treated with PPD and Bandrowski's base (BB) and secreted IL-1α, -1β, -4, -5, -6, -8, -10, and -13; IFN-γ; tumor necrosis factor-α; MIP-1α/β; MCP-1 (monocyte chemotactic protein-1); and RANTES. PBMCs from tolerant individuals were stimulated to proliferate only with BB, and they secreted significantly lower levels of Th2 cytokines. Principal component analysis showed that genes are differentially expressed between the patient groups. A network-based analysis of microarray data showed upregulation of T helper type 2 (Th2) gene pathways, including IL-9, in allergic patients, but a regulatory gene profile in tolerant individuals. Real-time PCR confirmed the observed increase in Th2 cytokine gene transcription in allergic patients. Purified CD4+ and CD8+ T cells from allergic patients were stimulated to proliferate and secrete Th2 cytokines following antigen exposure. Only CD4+ T cells from tolerant individuals were stimulated by BB, and levels of Th2 cytokines were 80% lower. The nature of the antigenic determinant stimulating PBMCs and levels of Th2 cytokines, including IL-9, was confirmed in a validation cohort. These studies show increased activity of Th2 cytokines in CD4+ and CD8+ T cells from individuals with allergic contact dermatitis.

BOB.1/OBF.1 is a transcriptional coactivator essential at several stages of B‐cell development. In T cells, BOB.1/OBF.1 expression is inducible by co‐stimulation. However, a defined role of BOB.1/OBF.1 for T‐cell function had not been discovered so far. Here, we show that BOB.1/OBF.1 is critical for T helper cell function. BOB.1/OBF.1 −/− mice showed imbalanced immune responses, resulting in increased susceptibility to Leishmania major infection. Functional analyses revealed specific defects in TH1 and TH2 cells. Whereas expression levels of TH1 cytokines were reduced, the secretion of TH2 cytokines was increased. BOB.1/OBF.1 directly contributes to the IFNγ and IL2 promoter activities. In contrast, increased TH2 cytokine production is controlled indirectly, probably via the transcription factor PU.1, the expression of which is regulated by BOB.1/OBF.1. Thus, BOB.1/OBF.1 regulates the balance of TH1 versus TH2 mediated immunity.

Asthma is a serious health problem causing significant mortality and morbidity globally. Persistent airway inflammation, airway hyperresponsiveness, increased immunoglobulin E (IgE) levels and mucus hypersecretion are key characteristics of the condition. Asthma is mediated via a dominant T-helper 2 (Th2) immune response, causing enhanced expression of Th2 cytokines. These cytokines are responsible for the various pathological changes associated with allergic asthma. To investigate the anti-asthmatic potential of afzelin, as well as the underlying mechanisms involved, its anti-asthmatic potential were investigated in a murine model of asthma. In the present study, BALB/c mice were systemically sensitized using ovalbumin (OVA) followed by aerosol allergen challenges. The effect of afzelin on airway hyperresponsiveness, eosinophilic infiltration, Th2 cytokine and OVA-specific IgE production in a mouse model of asthma were investigated. It was found that afzelin-treated groups suppressed eosinophil infiltration, allergic airway inflammation, airway hyperresponsiveness, OVA-specific IgE and Th2 cytokine secretion. The results of the present study suggested that the therapeutic mechanism by which afzelin effectively treats asthma is based on reduction of Th2 cytokine via inhibition of GATA-binding protein 3 transcription factor, which is the master regulator of Th2 cytokine differentiation and production.