Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus.

Autor:	Odqvist L; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Jevnikar Z; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Riise R; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Öberg L; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Rhedin M; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Leonard D; Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala, Sweden., Yrlid L; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Jackson S; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Mattsson J; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Nanda S; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Cohen P; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Knebel A; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK., Arthur S; Division of Immunology and Cell Signaling, School of Life Sciences, University of Dundee, Dundee, UK., Thörn K; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Svenungsson E; Department of Medicine, Rheumatology Unit, Karolinska Institute, Stockholm, Sweden., Jönsen A; Skåne University Hospital, Department of Clinical Science Lund, Rheumatology, Lund University, Lund, Sweden., Gunnarsson I; Department of Medicine, Rheumatology Unit, Karolinska Institute, Stockholm, Sweden., Tandre K; Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala, Sweden., Alexsson A; Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala, Sweden., Kastbom A; Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, Linkoping, Sweden., Rantapää-Dahlqvist S; Department of Public Health and Clinical Medicine/Rheumatology, Umeå Universitet Medicinska fakulteten, Umea, Sweden., Eloranta ML; Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala, Sweden., Syvänen AC; Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala, Sweden., Bengtsson A; Skåne University Hospital, Department of Clinical Science Lund, Rheumatology, Lund University, Lund, Sweden., Johansson P; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Sandling JK; Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala, Sweden., Sjöwall C; Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, Linkoping, Sweden., Rönnblom L; Department of Medical Sciences, Science for Life Laboratories, Uppsala University, Uppsala, Sweden., Collins B; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden., Vaarala O; Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca R&D Gothenburg, Mölndal, Sweden vaaralao@medimmune.com.; Respiratory, Inflammation and Autoimmunity Department, MedImmune LLC, Gaithersburg, Maryland, USA.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2019 Oct; Vol. 78 (10), pp. 1363-1370. Date of Electronic Publication: 2019 Jul 12.
DOI:	10.1136/annrheumdis-2019-215434
Abstrakt:	Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4 , an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation. Competing Interests: Competing interests: LO, ZR, RR, LÖ, MR, LFY, SJ, JM, KT, PJ, BC and OV were employees at AstraZeneca Group while performing this study and may have stock/stock options in AstraZeneca. AB received research grant from DISSECT, partly funded by AstraZeneca. LR reports grants and personal fees from Astra Zeneca during the conduct of the study and personal fees from Biogen outside the submitted work. AstraZeneca provided funding to DISSECT for the conduct of this study. The remaining authors declare that they have no competing interests. There are no patents involved. (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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