PhD Student Kangwon National University, Kangwon-do, Republic of Korea
Disclosure(s):
Yu Jin Lee, M.S.: No financial relationships to disclose
Introduction/Rationale: Immunoglobulin E (IgE) mediates rapid protective immune responses but also contributes to the development of allergic diseases. Thus, stringent regulation of IgE production is essential for maintaining immune homeostasis. Recent studies have revealed that IgE-mediated immune responses are dysregulated in the absence of the gut microbiome. Although secondary bile acids (SBAs) have been documented to directly regulate T cell functions, their role in IgE homeostasis remains unclear. We therefore hypothesized that specific SBAs regulate IgE production through B cell intrinsic manner.
Methods: We investigated the role of immune modulatory SBAs in IgE antibody production using in vitro B cell differentiation system and in vivo food allergy mouse model. To evaluate contribution of SBAs in IgE homeostasis, IgE germinal center (GC) B cell responses were analyzed by flow cytometry, and antigen-specific IgE antibody levels were measured using ELISA-based assays. In addition, molecular docking analyses and transcriptomic profiling were conducted to identify putative molecular targets of SBAs and underlying molecular mechanisms.
Results: We identified isoalloLCA as a negative regulator of IgE production through inhibition of sequential class switching from IgG1 to IgE. IsoalloLCA treatment significantly reduced the accumulation of IgE GC B cells and the generation of high-affinity antigen-specific IgE antibodies in a food allergy mouse model. We identified NR4A1 as a potential target of isoalloLCA in B cells. Mechanistically, we found that efficient sequential class switching from IgG1 to IgE required robust proliferation of IgG1 GC B cells, and isoalloLCA constrained this proliferative expansion specifically.
Conclusion: We identify that isoalloLCA as a key regulator of IgE homeostasis that constrains the emergence of IgE effector B cells from IgG1 GC B cells. Our study uncovers a previously unrecognized proliferation dependent checkpoint governing sequential class switch from IgG1 to IgE during GC reactions.
