Allergic diseases represent a major burden to human health and well-being. However, the mechanisms whereby allergens induce the pathogenic Th2 immune responses remain largely unknown. Similarly, the mechanisms of induction of protective Th2 responses against multi-cellular parasites are poorly defined. Using a protease allergen papain as a model system, we have recently demonstrated that basophils play an essential role in allergen-induced Th2 responses, by functioning as antigen-presenting cells and as a source of Th2 polarizing cytokines. The goal of this proposal is to characterize the mechanism of action of protease allergens and to elucidate key features of basophils that enable their function as initiators of Th2 responses. We will investigate signaling pathways and transcription factors activated by protease allergens in basophils. We will examine the phenotype of allergen-activated basophils and compare it to the FceRI and IL-3 receptor activated basophils. We will examine how basophil activation is negatively regulated by a variety of anti-inflammatory and immunoregulatory signals. Finally, we will investigate the mechanisms of basophil recruitment to the lymph nodes in response to allergen challenge. These studies should provide important insights into very important but poorly understood mechanisms of allergenicity and the function of basophils in allergic responses.

Public Health Relevance

Despite the tremendous progress in understanding the mechanisms of induction of host defense from infection, there is almost nothing known about how allergens trigger the pathogenic type2 immune responses. We recently found that a poorly characterize cell type called basophil, play a key role in initiating Th2 immune responses following challenge with an allergen. In this application we propose to investigate the mechanism of basophil activation by protease allergens and to provide new insights into basophil function in initiating Th2 immune responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Dong, Gang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Okabe, Yasutaka; Medzhitov, Ruslan (2016) Tissue biology perspective on macrophages. Nat Immunol 17:9-17
Okin, Daniel; Medzhitov, Ruslan (2016) The Effect of Sustained Inflammation on Hepatic Mevalonate Pathway Results in Hyperglycemia. Cell 165:343-56
Wang, Andrew; Huen, Sarah C; Luan, Harding H et al. (2016) Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation. Cell 166:1512-1525.e12
Florsheim, Esther; Yu, Shuang; Bragatto, Ivan et al. (2015) Integrated innate mechanisms involved in airway allergic inflammation to the serine protease subtilisin. J Immunol 194:4621-30
Iwasaki, Akiko; Medzhitov, Ruslan (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343-53
Kotas, Maya E; Medzhitov, Ruslan (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160:816-827
Bezbradica, Jelena S; Rosenstein, Rachel K; DeMarco, Richard A et al. (2014) A role for the ITAM signaling module in specifying cytokine-receptor functions. Nat Immunol 15:333-42
Colegio, Oscar R; Chu, Ngoc-Quynh; Szabo, Alison L et al. (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559-63
Okabe, Yasutaka; Medzhitov, Ruslan (2014) Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157:832-44
Palm, Noah W; Medzhitov, Ruslan (2013) Role of the inflammasome in defense against venoms. Proc Natl Acad Sci U S A 110:1809-14

Showing the most recent 10 out of 14 publications