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Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.ORCID iD: 0000-0002-0721-6395
AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 10, p. 1363-1370Article in journal (Refereed) Published
Abstract [en]

Objectives

Genetic variations in TNFAIP3 (A20) deubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-kappa B 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-kappa B 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.

Place, publisher, year, edition, pages
2019. Vol. 78, no 10, p. 1363-1370
National Category
Rheumatology and Autoimmunity Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-396653DOI: 10.1136/annrheumdis-2019-215434ISI: 000487465000024PubMedID: 31300459OAI: oai:DiVA.org:uu-396653DiVA, id: diva2:1370191
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2019-11-14 Created: 2019-11-14 Last updated: 2019-11-14Bibliographically approved

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Riise, RebeccaLeonard, DagTandre, KarolinaAlexsson, AndreiEloranta, Maija-LeenaSyvänen, Ann-ChristineSandling, Johanna K.Sjowall, ChristopherRönnblom, Lars
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