title: B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice.
abstract: The ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor-κB transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-κB activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose-dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin-6, A20-deficient B cells trigger a progressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of class-switched, tissue-specific autoantibodies.
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chu
authors.forename: J Christoph
authors.initials: JC
authors.lastname: Vahl
authors.forename: Dilip
authors.initials: D
authors.lastname: Kumar
authors.forename: Klaus
authors.initials: K
authors.lastname: Heger
authors.forename: Arianna
authors.initials: A
authors.lastname: Bertossi
authors.forename: Edyta
authors.initials: E
authors.lastname: Wójtowicz
authors.forename: Valeria
authors.initials: V
authors.lastname: Soberon
authors.forename: Dominik
authors.initials: D
authors.lastname: Schenten
authors.forename: Brigitte
authors.initials: B
authors.lastname: Mack
authors.forename: Miriam
authors.initials: M
authors.lastname: Reutelshöfer
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
mesh_terms: D000375:Aging / Q000276:immunology / Q000473:pathology; D000818:Animals; D015551:Autoimmunity; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D002454:Cell Differentiation; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D018628:Gene Dosage; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse