The Origin and Memory of Human IgE Responses

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Project Summary IgE antibodies play a central role in allergic diseases due to their ability to bind to high-affinity receptors on mast cells and induce degranulation upon allergen crosslinking1, 2. In spite of its powerful inflammatory effects, IgE is the antibody with the lowest serum concentration and the shortest half-life, and IgE-producing B lymphocytes are extremely rare in humans and mice, suggesting that IgE production is strongly regulated. The increased incidence of allergic diseases and its detrimental effects on public health brought renewed interest in understanding the regulation of IgE production. Furthermore, the positive effect of anti-IgE treatment on allergic asthma and other chronic allergic diseases validated IgE as a therapeutic target3. Studies from mouse models uncovered several mechanisms that restrain IgE production4, 5. The germinal center (GC) phase of IgE cells is prematurely terminated, and IgE GC cells do not generate IgE memory cells or long-lived IgE plasma cells6. Instead, the sequential switching of IgG cells to IgE originates most antigen-specific high affinity IgE plasma cells6, 7, 8. These findings have brought about a new understanding on the memory of IgE response, that is, that IgE memory is contained within IgG cells that under appropriate activation, can give rise to IgE plasma cells. Based on this novel model, we hypothesize that the potential for pathogenic IgE production resides in allergen- specific “permissive” IgG memory cells that can be activated by “permissive” CD4 memory T cells to switch to IgE. We propose to determine phenotypic, transcriptional, epigenetic and functional differences between total and antigen-specific IgG memory cells and CD4 memory T cells from atopic and non-atopic individuals. Through these studies we hope to identify “permissive” memory B and T cells, and determine the risk of individuals producing pathogenic IgE. Understanding the regulation of IgE production in human subjects is of great importance to developing new therapies for allergic diseases.