PMID- 31151831 OWN - NLM STAT- MEDLINE DCOM- 20200722 LR - 20200722 IS - 1095-9157 (Electronic) IS - 0896-8411 (Linking) VI - 102 DP - 2019 Aug TI - DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology. PG - 167-178 LID - S0896-8411(19)30002-2 [pii] LID - 10.1016/j.jaut.2019.05.007 [doi] AB - Dendritic cells (DCs) are central regulators of tolerance versus immunity. The outcome depends amongst others on DC subset and activation status. Whereas CD11b(+) type 2 conventional DCs (cDC2s) initiate proinflammatory helper T (Th)-cell responses, CD103(+) cDC1s are crucial for regulatory T-cell (Treg) induction and CD8(+) T-cell activation. DC activation is controlled by the transcription factor NF-kappaB. Ablation of A20/Tnfaip3, a critical regulator of NF-kappaB activation, in DCs leads to constitutive DC activation and development of systemic autoimmunity. We hypothesized that the activation status of cDCs controls the development of autoimmunity. To target cDCs, DNGR1(Clec9a)-cre-mediated excision of A20/Tnfaip3 was used through generation of Tnfaip3(fl/fl)xClec9a(+/cre) (Tnfaip3(DNGR1-KO)) mice. Immune cell activation was evaluated at 31-weeks of age. We found that DNGR1-cre-mediated deletion of A20/Tnfaip3 resulted in liver pathology characterized by inflammatory infiltrates adjacent to the portal triads. Both cDC subsets as well as monocyte-derived DCs (moDCs) in Tnfaip3(DNGR1-KO) livers harbored an activated phenotype. Specifically, the costimulatory molecule CD40 in liver cDCs and moDCs was regulated by A20/Tnfaip3 expression. Livers from Tnfaip3(DNGR1-KO) mice had augmented proportions of Th1, Th17, Treg, and follicular Th (Tfh)-cells compared to control mice, accompanied by an increase in IgA-producing plasma cells. Serum IgA from Tnfaip3(DNGR1-KO) mice recognized self-proteins, specifically cytoplasmic proteins in liver periportal regions. These data show that enhanced activation of cDCs and moDCs, due to A20/Tnfaip3 ablation, promotes the development of organ-specific autoimmunity but not systemic autoimmunity. This model could be useful to examine the pathobiological processes contributing to autoimmune liver diseases. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Das, Tridib AU - Das T AD - Department of Pulmonary Medicine, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Electronic address: t.das@erasmusmc.nl. FAU - Bergen, Ingrid M AU - Bergen IM AD - Department of Pulmonary Medicine, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Electronic address: i.bergen@erasmusmc.nl. FAU - Koudstaal, Thomas AU - Koudstaal T AD - Department of Pulmonary Medicine, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Electronic address: t.koudstaal.1@erasmusm.nl. FAU - van Hulst, Jennifer A C AU - van Hulst JAC AD - Department of Pulmonary Medicine, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Electronic address: j.vanhulst@erasmusmc.nl. FAU - van Loo, Geert AU - van Loo G AD - VIB Center for Inflammation Research, VIB, Technologiepark 71, 9052, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 71, 9052, Ghent, Belgium. Electronic address: geert.vanloo@irc.vib-ugent.be. FAU - Boonstra, Andre AU - Boonstra A AD - Department of Gastroenterology and Hepatology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Electronic address: p.a.boonstra@erasmusmc.nl. FAU - Vanwolleghem, Thomas AU - Vanwolleghem T AD - Department of Gastroenterology and Hepatology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands; Department of Gastroenterology and Hepatology, University Hospital Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium. Electronic address: t.vanwolleghem@erasmusmc.nl. FAU - Leung, Patrick S C AU - Leung PSC AD - Division of Rheumatology/Allergy and Clinical Immunology, University of California, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA. Electronic address: psleung@ucdavis.edu. FAU - Gershwin, M Eric AU - Gershwin ME AD - Division of Rheumatology/Allergy and Clinical Immunology, University of California, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA. Electronic address: megershwin@ucdavis.edu. FAU - Hendriks, Rudi W AU - Hendriks RW AD - Department of Pulmonary Medicine, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Electronic address: r.hendriks@erasmusmc.nl. FAU - Kool, Mirjam AU - Kool M AD - Department of Pulmonary Medicine, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands. Electronic address: m.kool@erasmusmc.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190709 PL - England TA - J Autoimmun JT - Journal of autoimmunity JID - 8812164 RN - 0 (Clec9a protein, mouse) RN - 0 (Immunoglobulin A) RN - 0 (Lectins, C-Type) RN - 0 (NF-kappa B) RN - 0 (Receptors, Immunologic) RN - EC 3.4.19.12 (Tumor Necrosis Factor alpha-Induced Protein 3) RN - EC 3.4.22.- (Tnfaip3 protein, mouse) SB - IM MH - Animals MH - Autoimmune Diseases/*genetics/immunology/pathology MH - Autoimmunity/*genetics/immunology MH - B-Lymphocytes/immunology MH - CD8-Positive T-Lymphocytes/immunology MH - Dendritic Cells/cytology/*immunology MH - Female MH - Immune Tolerance/immunology MH - Immunoglobulin A/blood MH - Lectins, C-Type/*genetics MH - Liver/immunology/pathology MH - Liver Diseases/immunology/pathology MH - Male MH - Mice MH - Mice, Knockout MH - NF-kappa B/metabolism MH - Receptors, Immunologic/*genetics MH - T-Lymphocytes, Helper-Inducer/immunology MH - T-Lymphocytes, Regulatory/immunology MH - Tumor Necrosis Factor alpha-Induced Protein 3/*genetics EDAT- 2019/06/04 06:00 MHDA- 2020/07/23 06:00 CRDT- 2019/06/02 06:00 PHST- 2019/01/02 00:00 [received] PHST- 2019/04/27 00:00 [revised] PHST- 2019/05/05 00:00 [accepted] PHST- 2019/06/04 06:00 [pubmed] PHST- 2020/07/23 06:00 [medline] PHST- 2019/06/02 06:00 [entrez] AID - S0896-8411(19)30002-2 [pii] AID - 10.1016/j.jaut.2019.05.007 [doi] PST - ppublish SO - J Autoimmun. 2019 Aug;102:167-178. doi: 10.1016/j.jaut.2019.05.007. Epub 2019 Jul 9.