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Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal; thus, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with two distinct forms of anaphylaxis: i) immediate onset anaphylaxis during first exposure to intravenous cetuximab, and ii) delayed onset anaphylaxis 3–6 hours after ingestion of mammalian food products (e.g., beef and pork). Results of our studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern and central United States, Europe, Australia and parts of Asia. Typical immune responses to carbohydrates are considered to be T cell-independent, while IgE antibody production is thought to involve sequential class-switching that requires input from T cells. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues.

Background The relevance of allergic sensitization, judged by titers of serum IgE antibodies, to the risk of an asthma exacerbation caused by rhinovirus is unclear. Objective To examine the prevalence of rhinovirus infections in relation to the atopic status of children treated for wheezing in Costa Rica, a country with an increased asthma burden. Methods The children enrolled (n=287) were 7 through 12 years old. They included 96 with acute wheezing, 65 with stable asthma, and 126 non-asthmatic controls. PCR methods, including gene sequencing to identify rhinovirus strains, were used to identify viral pathogens in nasal washes. Results were examined in relation to wheezing, total IgE, allergen-specific IgE antibody, and levels of expired nitric oxide (FENO). Results Sixty-four percent of wheezing children compared to 13% of children with stable asthma and 17% of the non-asthmatic controls tested positive for rhinovirus (p<0.001 for both comparisons). Among wheezing subjects, 75% of the rhinoviruses detected were Group C strains. High titers of IgE antibodies to dust mite allergen (especially Dermatophagoides sp) were common and correlated significantly with levels of total IgE and FENO. The greatest risk for wheezing was observed among children with titers of IgE antibodies to dust mite ≥17.5 IU/ml who tested positive for rhinovirus (odds ratio for wheezing: 31.5; 95% CI 8.3–108, p<0.001). Conclusions High titers of IgE antibody to dust mite allergen were common and significantly increased the risk for acute wheezing provoked by rhinovirus among asthmatic children.

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Objective/Hypothesis To evaluate the histology, RNA and protein signatures of nasal polyps in order to demonstrate specific subtypes of disease and differentiate “idiopathic” NPs based on tissue eosinophilia. Study Design Prospective laboratory based study Methods NP tissue was obtained from patients referred to the University of Virginia Health System for sinus surgery. Histology analyses included hematoxylin-eosin, Gomori's trichrome, toluidine blue, and chloroacetate staining. RNA and protein were extracted from tissue and cytokine transcript or protein concentrations determined. Results Idiopathic NPs can be divided into distinct subsets characterized by absence (NE) and presence (E) of prominent eosinophilia. The validity of this distinction is supported by the demonstration that NE polyps are further distinguished by glandular hypertrophy, dense collagen deposition, and mononuclear cellular infiltrate. In contrast, E-NP display edema, rare glandularity, and minimal collagen deposition except within the basement membrane. Total mast cell numbers were reduced in E-NP, whereas connective tissue mast cells were increased in NE-NP. Consistent with the distinctive pattern of increased fibrosis, NE-NP displayed increased transforming growth factor (TGF)-ß and vascular endothelial growth factor transcripts. Similarly, NE-NPs had higher concentrations of TGF-ß, fibroblast growth factor-ß, and platelet-derived growth factor protein. Conclusion Idiopathic NPs can be distinguished by their presence or absence of eosinophilia and is supported by the observations that these display distinct histological, gene and protein expression patterns. The findings suggest that as unique diseases, idiopathic NPs will require distinct therapeutic interventions.

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FEV 1 = forced expiratory volume in 1 second; GCR = glucocorticoid receptor; IL = interleukin; IL-4R = interleukin-4 receptor; IRS = insulin receptor substrate; rhuIL-4R = soluble recombinant human interleukin-4 receptor; Stat = signal transducer and activator of transcription; VCAM = vascular cell adhesion molecule.Available online http://respiratory-research.com/content/2/2/066 Introduction Interleukin (IL)-4 is a key cytokine in the development of allergic inflammation. It is associated with induction of the ε isotype switch and secretion of IgE by B lymphocytes [1]. IgE-mediated immune responses are further enhanced by IL-4 through its ability to upregulate IgE receptors on the cell surface: the low-affinity IgE receptor (FcεRII; CD23) on B lymphocytes and mononuclear phagocytic cells and the high-affinity IgE receptor (FcεRI) on mast cells and basophils [2]. IgE-dependent mast cell activation induced by IL-4 has a pivotal role in the development of immediate allergic reactions. An additional mechanism by which IL-4 contributes to airway obstruction in asthma is through the induction of mucin gene expression and the hypersecretion of mucus [3]. IL-4 increases the expression of eotaxin and other inflammatory cytokines from fibroblasts that might contribute to inflammation and lung remodelling in chronic asthma [4].An important activity of IL-4 in promoting cellular inflammation in the asthmatic lung is the induction of vascular cell adhesion molecule (VCAM)-1 on vascular endothelium [5]. Through the interaction of VCAM-1, IL-4 is able to direct the migration of T lymphocytes, monocytes, basophils, and eosinophils to inflammatory loci. In addition, IL-4 inhibits eosinophil apoptosis and promotes eosinophilic inflammation by inducing eosinophil chemotaxis and activation through the increased expression of eotaxin [6].An essential biological activity of IL-4 in the development of allergic inflammation is the ability to drive the differentiation of naive T helper type 0 (T H 0) lymphocytes into T H 2 lymphocytes [7,8]. These T H 2 cells are able to secrete IL-4, IL-5, IL-9 and IL-13 but lose the ability to produce interferon-γ AbstractInterleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma is a complex genetic disorder that has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. We report the results of initial clinical trials, which demonstrate clinical efficacy of this naturally occurring IL-4 antagonist as a therapeutic agent in asthma.