Damian Tworek

IL-25 Receptor Expression on Airway Dendritic Cells after Allergen Challenge in Subjects with Asthma

RATIONALE IL-25 is an epithelial-derived cytokine, whose effects are mediated by the IL-25 receptor (IL-17RB), and that has been implicated in the pathogenesis of allergic disease and airway viral responses. Airway myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) are professional antigen-presenting cells. pDCs may play a protective role in asthma and are key players in the innate immune response through recognition of microbial products via Toll-like receptors (TLRs). The effects of inhaled allergens on the expression of IL-17RB by mDCs and pDCs, and the effects of IL-25 on pDCs, are unknown. OBJECTIVES To evaluate allergen-induced changes in IL-17RB expression by mDCs and pDCs and to investigate the effects of IL-25 on pDCs. METHODS Patients with mild atopic asthma (n = 13) were challenged with inhaled allergen. Blood and sputum DCs were enumerated and IL-17RB expression was determined by flow cytometry before and 7 and 24 hours after allergen challenge. The effects of IL-25 on pDCs in vitro were also assessed. MEASUREMENTS AND MAIN RESULTS Inhaled allergen significantly increased mDC and pDC numbers in sputum but not in blood. The percentage of IL-17RB(+) mDCs and pDCs was significantly increased in blood and sputum 24 hours after challenge. IL-25 up-regulated TLR9 expression by pDCs and orchestrated the responses to TLR9 ligation. CONCLUSIONS IL-17RB is up-regulated on blood and sputum mDCs and pDCs after allergen inhalation. IL-25 modulates pDC function through an effect on TLR9 expression.

Glucagon‐like peptide‐1 receptor expression on human eosinophils and its regulation of eosinophil activation

Glucagon‐like peptide‐1 (GLP‐1) and its receptor are part of the incretin family of hormones that regulate glucose metabolism. GLP‐1 also has immune modulatory roles.

Toll‐like receptor‐induced expression of epithelial cytokine receptors on haemopoietic progenitors is altered in allergic asthma

Haemopoietic progenitor cells (HPC) migrate to sites of allergic inflammation where, upon stimulation with epithelial cytokines, they produce Th2 cytokines and differentiate into mature eosinophils and basophils. They also express Toll‐like receptors (TLR) involved in antimicrobial responses.

Expression of activation markers in circulating basophils and the relationship to allergen-induced bronchoconstriction in subjects with mild allergic asthma

Society (lecture) and has received research support from the NIH (U54 Grant PCORI Grant). M. E. Rothenberg has received research support from the NIH and from CURED, the Buckeye Foundation, and Food Allergy Research and Education (FARE); is a board member for the International Eosinophil Society, the Medical Advisory Panel, and the American Partnership for Eosinophilic Disorders; has received consultancy fees from Immune Pharmaceuticals, Receptos, Celsus Therapeutics, Genetech/Roche, and NKT Therapeutics; is an inventor of patents submitted and owned by Cincinnati Children’s Hospital Medical Center; has received royalties from Teva Pharmaceuticals; and has stock/stock options in Immune Pharmaceuticals, Receptos, Celsus Therapeutics, and NKT Therapeutics. The rest of the authors declare that they have no relevant conflicts of interest.

Timing is everything: Targeting IgE to reduce asthma exacerbation risk

exacerbation in the previous year, and a higher need for inhaled corticosteroids (ICS) were associated with greater seasonal exacerbation risk. Many of the available asthma treatment options reduce severe asthma exacerbation risk. This has been best described for ICS, for which even low once-daily doses can reduce severe asthma events, including emergency room visits and hospitalizations. 9 The combinations of ICS and long-acting inhaled b2-agonist (LABA) provide further benefit over and above ICS alone and using an ICS/LABA combination that contains formoterol as the LABA used as a maintenance and reliever is even more beneficial. 10 Biologic therapies are now used for the management of more severe asthma. The initial biologic approved for asthma was omalizumab, which binds to IgE and prevents engagement to its receptor. Omalizumab has been shown to be effective in severe allergic asthma, and an important part of this benefit is the reduction in severe asthma exacerbation risk. The investigators at the Inner-city Asthma Consortium had previously reported the benefit of omalizumab in children with asthma, most of whom had moderate to severe disease, while being managed with guideline-based asthma treatment. 11 Omalizumab improved asthma symptoms and reduced overall asthma exacerbations from 49% of children in the placebo arm of the study to 30% in the omalizumab arm. The most striking effect, however, was the abolition of the seasonal exacerbation peaks in spring and fall. This result had 2 important implications; first, pretreatment of children with asthma with omalizumab, on top of guidelinebased asthma treatment, is effective, and second IgE is involved in the pathogenesis of the seasonal asthma exacerbation peaks. The fact that these seasonal peaks are caused by URTIs suggests that IgE modifies the airways’ responses to respiratory viruses to allow an exaggerated immunological response leading to exacerbations. This is consistent with other studies that have shown an association between allergen exposure and enhanced risk from URTIs in those with asthma. 2