B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice

• Published in: Blood Vol. 117; no. 7; pp. 2227 - 2236
• Main Authors: Chu, Yuanyuan, Vahl, J. Christoph, Kumar, Dilip, Heger, Klaus, Bertossi, Arianna, Wójtowicz, Edyta, Soberon, Valeria, Schenten, Dominik, Mack, Brigitte, Reutelshöfer, Miriam, Beyaert, Rudi, Amann, Kerstin, van Loo, Geert, Schmidt-Supprian, Marc
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 17.02.2011; Americain Society of Hematology
• Subjects: Aging - immunology; Aging - pathology; Animals; Autoimmunity; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - pathology; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological and medical sciences; Cell Differentiation; Cysteine Endopeptidases - deficiency; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - immunology; Gene Dosage; Hematologic and hematopoietic diseases; Humans; In Vitro Techniques; Inflammation - etiology; Inflammation - immunology; Inflammation - pathology; Interleukin-6 - biosynthesis; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - immunology; Lymphocyte Activation; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells - immunology; Myeloid Cells - pathology; NF-kappa B - metabolism; Signal Transduction - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Tumor Necrosis Factor alpha-Induced Protein 3; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - immunology; Autoimmunity; Vertebrata; Mammalia; Hematology; Mouse; Animal; Rodentia; Suppressive cell; Inflammation; B-Lymphocyte; Cell differentiation; Tumor cell
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-09-306019

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.