Allergic diseases, including asthma, allergic rhinitis, and food allergy, have been steadily increasing in incidence and disproportionately affect children. Allergic responses can be triggered rapidly upon exposure to an allergen that binds to IgE antibodies on mast cells and basophils; these cells then degranulate and release potent pro-inflammatory mediators. If this response occurs systemically, known as anaphylaxis, it can be life- threatening. However, despite the importance of IgE in allergic disease, the intrinsic mechanisms that regulate IgE-expressing B cells remain unclear. Recent technical advances have made it possible to directly detect and visualize IgE+ B cells in mice, revealing that IgE+ B cells undergo an abortive germinal center phase and are predisposed to differentiate into short-lived plasma cells. These properties of IgE+ B cells restrain IgE responses and therefore may help protect against allergy and anaphylaxis in healthy individuals. Recent studies have demonstrated that the distinct features of mouse IgE+ B cells are largely due to the expression of the membrane IgE B cell receptor, which has weak, chronic signaling activity compared with other isotypes. The overall objective of this study is to determine how B cell receptor signaling regulates IgE+ B cell responses in mice and whether these findings are applicable to human B cells. The specific goals of this study are to 1) elucidate the mechanisms by which B cell receptor signaling regulates IgE plasma cell responses, 2) to characterize the role of B cell receptor signaling in the dynamics of IgE+ B cells in germinal centers, and 3) to determine whether human IgE B cell receptors regulate IgE responses in a similar fashion to mouse IgE B cell receptors. The results from these studies will help us understand how potent IgE-mediated allergic responses are controlled at a molecular level. .

Public Health Relevance

Allergic diseases are growing in prevalence worldwide and represent a major public health burden. IgE antibodies play a key role in triggering allergic responses, yet the mechanisms controlling IgE production remain poorly understood. In this project, we will study how molecular signals regulate the fate of the B cells that produce IgE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI130470-02
Application #
9603699
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Davidson, Wendy F
Project Start
2017-11-20
Project End
2022-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118