A Germinal Center Checkpoint of AIRE in B Cells Limits Antibody Diversification.

Autor: Zhou JZ; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.; These authors contributed equally., Huang B; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.; The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong 518107, China.; These authors contributed equally., Pei B; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA., Sun GW; School of Applied Science, Republic Polytechnic, Singapore 738984, Singapore., Pawlitz MD; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA., Zhang W; Beijing Genomics Institute (BGI)-Shenzhen, Guangdong 518083, China., Li X; Beijing Genomics Institute (BGI)-Shenzhen, Guangdong 518083, China., Hokynar KC; Department of Virology, University of Helsinki, Helsinki 00029, Finland., Yao F; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA., Perera MLW; Department of Chemistry, Wayne State University, Detroit, MI 48202, USA., Wei S; Department of Chemistry, Wayne State University, Detroit, MI 48202, USA., Zheng S; School of Biological Sciences, Nanyang Technological University, Singapore 636921, Singapore., Polin LA; Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA., Poulik JM; Department of Pathology, Children's Hospital of Michigan, Detroit, MI 48201, USA., Ranki A; Department of Dermatology and Allergic Diseases, University of Helsinki and Helsinki University Hospital, Helsinki 00250, Finland., Krohn K; Helsinki University Hospital Research Institute, Biomedicum, Helsinki 00290, Finland., Cunningham-Rundles C; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Yang N; Beijing Genomics Institute (BGI)-Shenzhen, Guangdong 518083, China.; Complete Genomics Inc., Mountain View, California 94043, USA., Bhagwat AS; Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.; Department of Biochemistry, Microbiology and Immunology, Wayne State University, Detroit, MI 48201, USA., Yu K; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA., Peterson P; Department of Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia., Kisand K; Department of Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia., Vuong BQ; Department of Biology, City College of New York, New York, NY 10031, USA., Cerutti A; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Maryland 20892, USA., Chen K; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA.; School of Biological Sciences, Nanyang Technological University, Singapore 636921, Singapore.; Lead Contact.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 12. Date of Electronic Publication: 2024 Jan 12.
DOI: 10.1101/2024.01.10.574926
Abstrakt: In response to antigens, B cells undergo affinity maturation and class switching mediated by activation-induced cytidine deaminase (AID) in germinal centers (GCs) of secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of GC antibody diversification is of fundamental importance but not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in 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.
Databáze: MEDLINE