Asthma is a complex inflammatory disease thought to reflect a dysregulated Immune state established at the epithelial interface in the lung. Although subgroups of patients with different types of Inflammation have been described, allergic asthma, as represented by increased numbers of innate and adaptive IL-4/IL-13- expressing cells, remains highly prevalent. Despite this Insight, understanding the process(es) by which allergic asthma is Initiated will require studies in mice, where recent findings Implicate crosstalk between the lung epithelia and innate immune cells. An innate non-B, non-T, non-NK lymphocyte population present in mice and humans has gained attention through the capacity to respond to epithelial cytokines IL-25 and IL- 33 by release of large amounts of IL-13 and IL-5. Using cytokine reporter mice that accurately function-mark immune cells, we have succeeded in tracking and deleting these cells, which we designate innate helper type-2 or iH2 cells, through their capacity to generate either of these cytokines. Given the central role of IL- 13 and IL-5 In mediating tissue alterations important in asthma and allergic immunity, we propose two specific alms to study the function ofthese cells in allergic lung Inflammation.
Specific Aim 1. To establish lineage and function marking of iH2 cells In order to reveal their quantitative contributions to allergic lung immunity during physiologic challenges and to compare this with cytokine- mediated activation.
Specific Aim 2. To assess the functional requirements for IH2 cells during allergic challenges and In immune homeostasis, and to examine the physical positioning ofthese cells in lung tissues In situ. Insights from these two Specific Alms will be used to guide the choices of probes and profiles that will enable the study ofthese cells In bronchoaiveolar lavage and airway samples collected from patients with allergic asthma. (LAY SUMMARY). Asthma remains the most prevalent chronic debilitating disease of childhood and a major contributor to health care costs in the United States. These studies seek to understand the early steps required to generate an inflammatory lung response resembling asthma using model systems In mice.

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Mohapatra, A; Van Dyken, S J; Schneider, C et al. (2016) Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal Immunol 9:275-86
Gordon, Erin D; Locksley, Richard M; Fahy, John V (2016) Cross-Talk between Epithelial Cells and Type 2 Immune Signaling. The Role of IL-25. Am J Respir Crit Care Med 193:935-6
von Moltke, Jakob; Ji, Ming; Liang, Hong-Erh et al. (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529:221-5
Fahy, John V (2016) Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have Slowed Treatment Progress. Ann Am Thorac Soc 13 Suppl 1:S78-82
Pua, Heather H; Steiner, David F; Patel, Sana et al. (2016) MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production. Immunity 44:821-32
Wesolowska-Andersen, Agata; Seibold, Max A (2016) Is the Road to Precision Medicine in Chronic Lung Disease Paved with Degraded Chitin? Am J Respir Crit Care Med 193:107-8
Gordon, Erin D; Simpson, Laura J; Rios, Cydney L et al. (2016) Alternative splicing of interleukin-33 and type 2 inflammation in asthma. Proc Natl Acad Sci U S A 113:8765-70
Gordon, Erin D; Palandra, Joe; Wesolowska-Andersen, Agata et al. (2016) IL1RL1 asthma risk variants regulate airway type 2 inflammation. JCI Insight 1:e87871
Reber, Laurent L; Fahy, John V (2016) Mast cells in asthma: biomarker and therapeutic target. Eur Respir J 47:1040-2
Ramstein, Joris; Broos, Caroline E; Simpson, Laura J et al. (2016) IFN-γ-Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells. Am J Respir Crit Care Med 193:1281-91

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