Year: 2024
Type: preprint
Abstract: SUMMARY In response to antigens, B cells undergo antibody diversification, including affinity maturation and class switching, mediated by activation-induced cytidine deaminase (AID) in secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of antibody diversification is of fundamental importance, though the mechanisms underlying these pathways are not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in germinal center (GC) B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans . These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.
Authors: Jordan Z. Zhou, Bo Pei, Guang Wen Sun, Michael D. Pawlitz, Wei Zhang, Xinyang Li, Fayi Yao, Kati C. Hokynar, Chun-Xiao Li, Madusha L. W. Perera, Shanqiao Wei, Simin Zheng, Lisa A. Polin, Janet M. Poulik, Annamari Ranki, Kai Krohn, Charlotte Cunningham-Rundles, Andrea Cerutti, Naibo Yang, Ashok S. Bhagwat, Kefei Yu, Pärt Peterson, Kai Kisand, Bao Q. Vuong, Bihui Huang, Kang Chen
Institutions: Wayne State University, Weill Cornell Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Republic Polytechnic, Central South University, BGI Group (China), Henan University of Urban Construction, University of Helsinki, Nanyang Technological University, The Barbara Ann Karmanos Cancer Institute, Children's Hospital of Michigan, Helsinki University Hospital, Icahn School of Medicine at Mount Sinai, Complete Genomics (United States), Hospital del Mar Research Institute, Michigan State University, University of Tartu, City College of New York, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Sun Yat-sen University, Sun Yat-sen Memorial Hospital
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Wayne State University, American Congress of Obstetricians and Gynecologists, Barbara Ann Karmanos Cancer Institute, National University of Singapore, Government of Jiangsu Province, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W4390787461