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overview Dr. Sperling is Professor of Medicine, Associate Vice Chair for Research of the Dept of Medicine, Director of the Respiratory Biology Training Grant, and Director of the Cytometry and Antibody Technology Core Facility. She has served as a regular member of the NIH Hypersensitivity, Autoimmunity, and Immune-mediated Diseases (HAI) Study Section, and the Lung Cellular and Molecular Immunology (LCMI) Study Section. Dr. Sperling's research program focuses on the role of the immune system in lung diseases in humans and mouse models. She has made significant contributions to understanding how T cell costimulatory molecules influence inflammation and disease, and the regulation of inflammation resolution in allergic asthma. Recently, her group has been expanding its focus to address translational and basic questions in human lung diseases such as asthma, idiopathic pulmonary fibrosis, and sarcoidosis. Research Statement: The focus of my laboratory is to elucidate on the immune response characteristic of lung diseases such as atopic asthma and idiopathic pulmonary fibrosis. While in the past we focused highly on the resolution of airway inflammation (Tong et al JEM 2006 and Tong et al AJRCMB 2010), the current research is focused on the initial steps in the development of Th2 inflammation. Our goal is to determine how specific allergic stimuli signals the immune response to drive type 2 inflammation and Th2 differentiation. We have recently made three important discoveries that elucidate mechanisms involved in sensitization to allergens in the lungs. Our first finding is that allergen specific IgG in immune complexes with allergen, can directly induce dendritic cells to produce the Th2 promoting cytokine, IL-33 (Tjota et al JCI 2013). Through recent GWAS studies, IL-33 and its receptor have recently been found to be in the top five genes involved in asthma. We have found that a major source of IL-33 in various Th2 inflammatory models is the respiratory DC. Further, we have now found that this IL-33 production is essential for Th2 mediated inflammation in our models. Second, we have made the exciting discovery that the transcription factor, Interferon Regulatory Factor 4 (IRF4) directs dendritic cells to promote TH2 responses (Williams et al Nature Comm 2013). Respiratory dendritic cells (DC) are the primary initiator of T cells during lung allergic responses. DCs process inhaled allergen, traffic to draining lymph nodes, present antigen-peptides to T cells, and guide the type of T-helper response initiated. However, the mechanisms involved in priming a DC to direct Th2 helper cell differentiation have not yet been elucidated. We now believe that we have identified a key transcription factor that when expressed in DCs, confers the ability of the DC to drive Th2 immunity in the lungs. Using microarray analsysis, we identified this transcription factor as being expressed in the Th2 driving DCs, but not in other DC populations. Additionally, mice with a conditional deletion of IRF4 in DCs produce a much reduced Th2 responses after allergic challenge, while DCs with overexpression of IRF4 drive naïve CD4 T lymphocytes toward a Th2 phenotype. Thus, these data identify IRF4 as a key transcriptional regulator in DCs necessary for the development of Th2 responses. Third, we have discovered that two distinct Th2 stimuli, Immune Complexes and HDM, both utilize FcR-gamma associated receptors, Fc-gammaRIII and Dectin-2 respectively, to promote Th2-mediated lung inflammation (Tjota et al. JACI 2014). We have demonstrated that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of Th2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcR-gamma, toll-like receptor 4 (TLR4), and phosphoinositide 3 (PI3)-kinase. Exogenous IL-33 is sufficient to restore development of Th2 responses in FcR-gamma-deficient mice. Finally, adoptive transfer of allergen-pulsed FcR-gamma+/- BMDCs restores development of Th2-type inflammation in FcR-gamma-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation. Together, these data identify a mechanism whereby Th2 stimuli signal through FcR-gamma-associated receptors on DCs to induce IRF4 expression and upregulation of IL-33 production. These DCs cells are central to the induction of Th2-differentiation and type 2 allergic airway inflammation. Dr. Sperling's NIH Commons ID is ASPERLING

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