The incidence and mortality of allergic diseases, such as anaphylaxis, allergic rhinitis, atopic dermatitis and asthma, have increased at an alarming rate in the Western countries in the past several decades. In the United States alone, over 50 million people suffer from allergic diseases. The economic burden of allergic diseases is staggering;it is estimated to cost $4 billion in 2006. Recent work has implied important roles for basophils in initiating, augmenting Th2-type immune responses to allergen challenges as well as maintaining B cell memory responses. Molecules, including IL-4, IL-6, and TSLP, have been demonstrated to be essential in mediating these novel basophil functions. However, due to the difficulty in obtaining sufficient numbers of basophils, how these key molecules are regulated at molecular levels is not understood. We have established an in vivo method to expand basophils rapidly and specifically. Based on our preliminary analyses, we hypothesize that STAT5 might form a transcription network with GATA2 and C/EBPa to regulate newly discovered basophil functions. We propose three aims to test our hypothesis.
In Aim 1, we will analyze mechanisms by which C/EBPa regulates the Il4 gene.
In Aim 2, we propose to determine how GATA2 regulate the Il4 gene in basophils.
In Aim 3, we will determine how STAT5 forms a transcription network to regulate newly discovered basophil functions. Our proposal, if successfully accomplished, will significantly advance our understanding of how basophils mediate allergic immune responses at molecular levels. The knowledge gained will facilitate the development of treatments for allergic diseases and asthma.
This proposal aims to study how a regulatory network, consisting of STAT5, GATA2 and C/EBP1, regulates novel basophil functions during allergic immune responses.
|Li, Yapeng; Liu, Bing; Harmacek, Laura et al. (2018) The transcription factors GATA2 and microphthalmia-associated transcription factor regulate Hdc gene expression in mast cells and are required for IgE/mast cell-mediated anaphylaxis. J Allergy Clin Immunol 142:1173-1184|
|Huang, Hua; Li, Yapeng; Liu, Bing (2016) Transcriptional regulation of mast cell and basophil lineage commitment. Semin Immunopathol 38:539-48|
|Li, Yapeng; Qi, Xiaopeng; Liu, Bing et al. (2015) The STAT5-GATA2 pathway is critical in basophil and mast cell differentiation and maintenance. J Immunol 194:4328-38|
|Huang, Hua; Li, Yapeng (2014) Mechanisms controlling mast cell and basophil lineage decisions. Curr Allergy Asthma Rep 14:457|
|Chen, Zhihong; Wang, Shanze; Erekosima, Nkiruka et al. (2013) IL-4 confers resistance to IL-27-mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling. J Allergy Clin Immunol 132:912-21.e1-5|
|Huang, Hua; Qi, Xiaopeng (2013) Differentiation of innate type-2 effector cells. Immunol Res 55:173-7|
|Nishida, Jun; Li, Yapeng; Zhuang, Yonghua et al. (2013) IFN-? suppresses permissive chromatin remodeling in the regulatory region of the Il4 gene. Cytokine 62:91-5|
|Qi, Xiaopeng; Hong, Jessie; Chaves, Lee et al. (2013) Antagonistic regulation by the transcription factors C/EBP? and MITF specifies basophil and mast cell fates. Immunity 39:97-110|
|Huang, Hua (2011) Suppressing allergic immune responses. Front Biosci (Elite Ed) 3:864-70|
|Ohmori, Keitaro; Luo, Yuchun; Jia, Yi et al. (2009) IL-3 induces basophil expansion in vivo by directing granulocyte-monocyte progenitors to differentiate into basophil lineage-restricted progenitors in the bone marrow and by increasing the number of basophil/mast cell progenitors in the spleen. J Immunol 182:2835-41|