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• Significant involvement of platelets in the late phase of immediate hypersensitivity reaction
• Functional definition of the TH17 phenotype
• Arginase I and II variants and asthma occurrence: Differential modifying effects of atopy and ozone
• IL-5–mediated eosinophil survival requires Pim-1 but not PI3K
• House dust mite–derived β-glucans mediate chemokine secretion
• Histamine 4 receptor, IL-31, and pruritus—new links discovered?
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Significant involvement of platelets in the late phase of immediate hypersensitivity reaction 

It has recently been reported that platelets play a vital role in a variety of inflammatory and immune processes, in addition to their function in hemostasis and thrombosis. The IgE-mediated immediate hypersensitivity reaction (IHR) including the late-phase reaction (LPR) is strongly associated with the pathogenesis of asthma and atopic dermatitis, but the role of platelets in the IHR remains unclear. Tamagawa-Mineoka et al (p 581) have provided the first evidence for the important role of platelets in the late phase of the IHR. Depletion of platelets in blood significantly suppressed the LPR at 24 hours after antigen challenge, but not the early-phase reaction of the IHR at 1 hour, in the skin in a mouse model (see Figure). The impaired LPR in platelet-depleted mice was restored by infusing platelets from normal mice, but not by P-selectin–deficient platelets. The authors show that platelets induce leukocyte recruitment into inflamed sites in the LPR by formation of platelet-leukocyte complexes via P-selectin in blood and release of chemokines from platelets in the inflamed sites. They also demonstrate that systemic administration of anti-platelet drugs significantly reduces the LPR. These results suggest that suppression of platelet activity may offer a novel strategy for treatment of allergic disorders.

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• Skin histology of platelet-depleted (D and H) and normal (B and F) mice 1 hour (B and D) and 24 hours (F and H) after challenge.

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Functional definition of the T_H17 phenotype 

The ability of the immune system to memorize antigens protects us from various pathogens but can also lead to long-lasting remittent disease against harmless environmental antigens, such as hay fever or asthma. This immunologic memory is generated by T cells, which differentiate into long-lived memory T cells on initial activation with the antigen or allergen. The presence of TGF-β during the differentiation sets the cells on the knife's edge between pro- and anti-inflammatory commitment. Burgler and colleagues (p 588) show that the presence of IL-1 during T-cell differentiation is essential for the development of T_H17 cells, which evoke a proinflammatory IL-6 response in epithelial cells (see Figure) whereas regulatory T cells, differentiated in the absence of IL-1, do not. The annotation of single biomarker genes to identify T-cell subsets, however, is not sufficient to define a T-cell subset, and the study shows that the transcription factor RORC2 is demonstrated to be TGF-β–dependently induced not only in T_H17 cells but also in Treg or in natural killer T cells. Cellular immunology is now progressing toward a functional definition of T-cell subsets, which will facilitate the association of disease pathology with T-cell subsets with a greater impact on translational medicine.

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• T_H17 cells induce IL-6 production (green) in bronchial epithelial cells.

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Arginase I and II variants and asthma occurrence: Differential modifying effects of atopy and ozone 

Arginase has emerged as a candidate gene in murine models of asthma; however, the role of variants in arginase genes (arginase I [ARG1] and arginase II [ARG2]) on asthma in children has not been clearly established. In addition, a large body of evidence indicates that atopy and exposure to ambient ozone that imparts oxidant stress in the airways are associated with asthma occurrence and exacerbations and could also influence arginase expression. In this issue of the Journal, Salam et al (p 596) report the results from a study that was conducted among nearly 3000 non-Hispanic and Hispanic white children who had participated in the Southern California Children's Health Study. The authors found that common haplotypes at both ARG1 and ARG2 loci affect the occurrence of asthma in children. Importantly, exposure to ambient ozone and child's atopy status jointly influenced the relationship of a haplotype in ARG1 and asthma but not the effects of any ARG2 variants. The authors conclude that their results provide robust evidence that arginase variants are associated with asthma in children and suggested that atopy and ambient ozone could differentially influence asthma susceptibility associated with arginase haplotypes.

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IL-5–mediated eosinophil survival requires Pim-1 but not PI3K 

Eosinophil differentiation, activation, and survival are largely regulated by IL-5. Eosinophils are both effector and immunoregulatory cells in many chronic allergic disorders. To provide hints as to how the process of increased eosinophil survival under inflammatory conditions is regulated, Andina et al (p 603) investigated signaling pathways in human eosinophils. They found that the kinase proviral integration site for Moloney murine leukemia virus 1 (Pim-1) is rapidly induced in IL-5–stimulated eosinophils in vitro and present in eosinophils under inflammatory in vivo conditions (see Figure). To understand Pim-1 function in eosinophils, the authors used, in addition to classical pharmacologic approaches, HIV-transactivator of transcription (TAT) fusion proteins containing wild-type Pim-1 or a dominant-negative form of Pim-1 to specifically investigate the role of this serine/threonine kinase. Although pharmacologic inhibition of phosphatidylinositol-3 kinase (PI3K) by LY294002, wortmannin, or the selective PI3K p110δ isoform inhibitor IC87114 was successful in each case, only LY294002, but not the other 2 PI3K inhibitors, blocked increased IL-5–mediated eosinophil survival. This suggested that LY294002 inhibited, in addition to PI3K, another kinase, which turned out to be Pim-1, is crucially involved in this process. Taken together, Pim-1, but not PI3K, plays a major role in IL-5–mediated antiapoptotic signaling in eosinophils and represents a potential new anti-eosinophil drug target.

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• Pim-1 expression by eosinophils in nasal polyp tissue.

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House dust mite–derived β-glucans mediate chemokine secretion 

House dust mite (HDM) is a potent, common aeroallergen strongly associated with asthma, but the mechanisms by which respiratory epithelium recognizes and reacts to HDM remain elusive. In this issue, Nathan et al (p 612) demonstrate that β-glucan structures within the HDM extract are responsible for epithelial release of the dendritic cell (DC)–attractant chemokine CCL20. Recruitment of DC to the lung is a crucial event in allergic airway responses, and release of CCL20 is rapid in both primary and immortalized human bronchial epithelium after HDM exposure. Mechanistic studies demonstrated that HDM-induced CCL20 release was protease- and Toll-like receptor–independent. As HDM is known to contain fungal components, the authors hypothesized that a β-glucan receptor was involved in the response to HDM. They show here that HDM-induced CCL20 secretion is abrogated by pretreatment of the HDM with a β-glucanase and by competitive inhibition by other β-glucans, such as laminarin, zymosan, and curdlan (see Figure). This work describes a novel pattern recognition pathway in which recognition of HDM-derived β-glucan structures by the airway epithelium initiates innate immune responses, independent of adaptive immunity. A better understanding of this pathway and the specific components of HDM responsible for allergic airway responses may help to direct future therapies.

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• HDM-induced CCL20 (A) competitively inhibited by other β-glucans (B) inhibited by pretreatment of HDM with β-glucanase.

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Histamine 4 receptor, IL-31, and pruritus—new links discovered? 

The recently discovered histamine 4 receptor (H4R) is receiving increasing attention in allergy research because it is expressed predominately on cells of the immune system. Gutzmer et al (p 619) investigated in detail the expression and function of the H4R on human T helper (T_H) cells. They show for the first time that the H4R is upregulated under T_H2 conditions and that stimulation of PBMC and T_H2 cells with the H4R-specific ligand 4-methylhistamine (4MH) leads to upregulation of IL-31 mRNA. The T_H2 cytokine IL-31 has been associated with pruritus; thus, the study provides a new link between histamine, the T_H2 environment, and pruritus. This might be particularly important for the pathogenesis of atopic dermatitis, which is characterized by chronic inflammation initiated by a T_H2 environment and pruritus. Indeed, the authors show that expression of H4R on T_H cells and induction of IL-31 by H4R stimulation is pronounced in patients with atopic dermatitis (see Figure). These findings provide further evidence for the pathogenetic role of the H4R in allergic inflammation and encourage the development of H4R-based therapeutic strategies.

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• The H4R ligand 4MH induces IL-31, particularly in atopic dermatitis.