Abstract
IgE mediates allergic responses by coating mast cell or basophil surfaces and inducing degranulation upon binding a specific allergen. IgE can also be spontaneously produced in the absence of foreign allergens; yet the origin, regulation, and functions of such “natural” IgE still remain largely unknown. Here, we find that glucocorticoids enhance the production of IgE in B cells both in vivo and ex vivo without antigenic challenge. Such IgE production is promoted by B cell–intrinsic glucocorticoid receptor signaling that reinforces CD40 signaling and synergizes with the IL-4/STAT6 pathway. In addition, we found that rare B cells in the mesenteric lymph nodes are responsible for the production of glucocorticoid-inducible IgE. Furthermore, locally produced glucocorticoids in the gut may induce natural IgE during perturbations of gut homeostasis, such as dysbiosis. Notably, mice preemptively treated with glucocorticoids were protected from subsequent pathogenic anaphylaxis. Together, our results suggest that glucocorticoids, classically considered to be broadly immunosuppressive, have a selective immunostimulatory role in B cells.
| Original language | English |
|---|---|
| Article number | e20220903 |
| Journal | Journal of Experimental Medicine |
| Volume | 219 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2022 Oct 3 |
Bibliographical note
Funding Information:This research is supported by the Howard Hughes Medical Institute, Blavatnik Family Foundation, Food Allergy Science Initiative, a grant from the National Institutes of Health (AI144152 to R. Medzhitov), Yonsei Research Fund (2021-22-0049), Yonsei Signature Research Cluster Program of 2022 (2022-22-0013), and the National Research Foundation of Korea, Ministry of Science, Information and Communication Technology (ICT) and Future Planning NRF-2022R1C1C1007283. J. Lim is supported by postdoctoral fellowships from the International Human Frontier Science Program Organization (LT000037/ 2018-L) and Jane Coffin Childs Memorial Fund. R. Medzhitov is an investigator of the Howard Hughes Medical Institute.
Funding Information:
We are grateful to the members of the Medzhitov lab for in-sightful discussions and help, especially Cuiling Zhang, Shuang Yu, and Jaime Cullen for mouse colonies and in vivo experi-ments. We thank Dr. Christopher Allen (University of California, San Francisco) for the IgE reporter mice. We thank Dr. Hans C. Oettgen (Boston Children’s Hospital) for the IgE KO Balb/cJ mice. We thank Dr. Joao Pereira (Yale) for the Mb1-Cre mice. We also thank Yale Flow Cytometry for their assistance with FACS ser-vice and YCGA for 10× Immune Profiling. Images were created with BioRender.com. This research is supported by the Howard Hughes Medical Institute, Blavatnik Family Foundation, Food Allergy Science Initiative, a grant from the National Institutes of Health (AI144152 to R. Medzhitov), Yonsei Research Fund (2021-22-0049), Yonsei Signature Research Cluster Program of 2022 (2022-22-0013), and the National Research Foundation of Korea, Ministry of Science, Information and Communication Technology (ICT) and Future Planning NRF-2022R1C1C1007283. J. Lim is supported by postdoctoral fellowships from the International Human Frontier Science Program Organization (LT000037/ 2018-L) and Jane Coffin Childs Memorial Fund. R. Medzhitov is an investigator of the Howard Hughes Medical Institute. Author contributions: J. Lim, B. Vaidyanathan, and R. Medzhitov conceived the study. J. Lim, E.V. Lin, and J.Y. Hong planned, performed experiments, and analyzed the data with assistance from B. Vaidyanathan, S.A. Erickson, and C. Annicelli. J. Lim, E.V. Lin, J.Y. Hong, and R. Medzhitov wrote the manu-script with input from the other coauthors.
Publisher Copyright:
© 2022 Lim et al.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Immunology