title: A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies.
abstract: A20/TNFAIP3 is an ubiquitin-editing enzyme, important for the regulation of the NF-κB pathway. Mutations in the TNFAIP3 gene have been linked to different human autoimmune disorders. In human B-cell lymphomas, the inactivation of A20 results in constitutive NF-κB activation. Recent studies demonstrate that in mice the germline inactivation of A20 leads to early lethality, due to inflammation in multiple organs of the body. In this report, we describe a new mouse strain allowing for the tissue-specific deletion of A20. We show that B-cell-specific deletion of A20 results in a dramatic reduction in marginal zone B cells. Furthermore, A20-deficient B cells display a hyperactive phenotype represented by enhanced proliferation upon activation. Finally, these mice develop higher levels of serum immunoglobulins, resulting in an excessive production of self-reactive autoantibodies.
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany. hoevelme@uni-mainz.de
authors.forename: Nadine
authors.initials: N
authors.lastname: Hövelmeyer
authors.forename: Sonja
authors.initials: S
authors.lastname: Reissig
authors.forename: Nguyen Thi
authors.initials: NT
authors.lastname: Xuan
authors.forename: Petra
authors.initials: P
authors.lastname: Adams-Quack
authors.forename: Dominika
authors.initials: D
authors.lastname: Lukas
authors.forename: Alexei
authors.initials: A
authors.lastname: Nikolaev
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D016328:NF-kappa B / Q000276:immunology; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D001323:Autoantibodies; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse