News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2010)

Chronic rhinosinusitis (CRS) with and without nasal polyps is frequently comorbid with asthma diagnosis. Plager et al (PLoS ONE 5:e11450, doi:10.1371/journal.pone.0011450) decided to look at whether nasomucosal tissue from asthmatic patients with CRS was characterized by differential transcription of eosinophil-associated genes compared with tissue from nonasthmatic patients with CRS with nasal polyps. Microarray analysis of excised inflamed mucosa and adjacent polyps from asthmatic patients with CRS, patients with rhinitis, and healthy patients with nasal polyps revealed upregulation of eosinophil chemokine genes in asthmatic patients with CRS compared with that seen in patients with rhinitis and healthy patients. Importantly, the genes with increased expression were associated with the 17q11.2 gene cluster, a chemokine locus previously implicated in allergic responses. The authors' results corroborated findings from a study on asthmatic patients with CRS in patients with aspirin-sensitive asthma with polyps.Differential transcription of eosinophil-associated genesLead author, Douglas Plager, PhD, told us about their study: “Our genome-wide screening for transcriptional abnormalities in nasosinus tissue from asthmatic patients with chronic rhinosinusitis identified several genes and gene networks … important in eosinophilic inflammation of human airways. These microarray data also provide the opportunity to compare with other eosinophilic epithelial diseases … to identify transcriptional abnormalities … common to eosinophilic epithelial inflammation in general or … eosinophilic inflammation of a given epithelial surface (eg, lung vs skin) in particular. Ultimately, the goal is to determine whether inhibiting or augmenting … the most integral proinflammatory or anti-inflammatory gene networks, respectively, can control or reverse eosinophilic epithelial inflammation in a more effective and targeted manner. Differential transcription of eosinophil-associated genes Murphy and colleagues (Thorax, doi:10.1136/thx.2009.124941) reported results from comparisons of pregnant women who smoked and had asthma, who smoked but did not have asthma, and who never smoked and exsmokers. They found that asthma exacerbations were more frequent and more severe in pregnant women who smoked than in the never-smoked group. Interestingly, the rate of smoking was higher in pregnant women with asthma than in former and never smokers.Asthma exacerbations were … more severe in pregnant women who smoked Asthma exacerbations were … more severe in pregnant women who smoked A collection of genes called TIMs (T-cell, immunoglobulin, mucin) are known to be linked to allergic asthma susceptibility. In particular, TIM-1 receptor is associated with TH2 cytokine release in atopic disease models in mice. From this basis, Sonar et al (J Clin Invest, doi:10.1182/JCI39543) generated an mAb designed to bind to a structural cleft in TIM-1. Using a humanized murine model of asthma, they demonstrated that the human TIM-1 mAb significantly reduced TH2 effector responses, minimized lung inflammation, and prevented airway hyperreactivity. Interestingly, Sonar and colleagues discovered increased therapeutic benefit of TIM-1 mAb over anti–IL-13 mAb therapy in their model.Human TIM-1 mAb significantly reduced TH2 effector responsesSenior author Paul Rennert, PhD, had this comment: “I see this work as a compelling and encouraging example of pure translational medicine moving from a genetic hypothesis to functional validation and developing a novel therapeutic antibody along the way. Furthermore, the mechanism of action of the anti–TIM-1 mAb, specifically targeting pathogenic T cells, is very distinct from anticytokine therapies and might provide exceptional potency. We are currently testing anti–TIM-1 antibodies in a variety of autoimmune and inflammatory models.” Human TIM-1 mAb significantly reduced TH2 effector responses In an article in Nature Medicine, Charles et al (2010;16:701-7) identified basophils as a major operator in lupus nephritis, which is caused by excessive deposition of immunoglobulins in the kidney. They found that circulating complexes of self-reactive IgE activated basophils, and that basophils amplified autoantibody production in an IL-4– and IgE-dependent way. Depletion of basophils in Lyn− mice not only reduced autoantibody production but also decreased circulating amounts of IL-4, IL-13, and INF-γ, both of which resulted in protection of the kidney. The authors suggested that currently available anti-IgE therapy might be effective in patients with lupus with increased IgE levels.Juan Rivera, National Institutes of HealthView Large Image Figure ViewerDownload Hi-res image Download (PPT)Basophils amplified autoantibody production in an IL-4– and IgE-dependent wayWe asked senior author, Juan Rivera, PhD, for a comment: “The findings of this study implicate basophils in the pathophysiology of diseases beyond allergies. The discovery that the autoreactive IgE (which is found both in patients with lupus and in the Lyn−/− murine model of spontaneous lupus) is linked to basophil activation, autoantibody production, and active lupus nephritis provides exciting new avenues of exploration for treatment of this disease.” Basophils amplified autoantibody production in an IL-4– and IgE-dependent way Interesting findings by Doulatov et al (Nat Immunol 2010;11:585-93) have changed our thinking about progenitor lineages, which are thought to give rise to lymphoid-restricted and myeloid-restricted lineages. The authors identified 7 basic classes of human hematopoetic progenitors, screening cord blood and bone marrow stem cells with 7 markers. The most important finding reported by Doulatov et al was the discovery that multilymphoid progenitors gave rise to lymphoid and myeloid cell lineages, including B cells, T cells, macrophages, and dendritic cells, and are, in fact, the primary source of dendritic cells. The authors confirmed the classical concept that myeloid lineage commitment required loss of lymphoid potential but revised the lymphoid lineage commitment concept to be characterized by MLP lineage production of both lymphoid and myeloid progenitors (B–natural killer cell progenitors and macrophage–dendritic cell progenitors). Contrary to the conventional model of hematopoiesis, Doulatov et al demonstrated that early lineage commitment splits off myeloid-restricted progenitors and MLPs from pluripotential stem cells, suggesting that innate immune lineages could represent the primitive state.Multilymphoid progenitors gave rise to lymphoid and myeloid cell lineages Multilymphoid progenitors gave rise to lymphoid and myeloid cell lineages News items are written by Sherri Gabbert, PhD. News items are written by Sherri Gabbert, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.