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

Lina Odqvist, Zala Jevnikar, Rebecca Riise, Lisa Öberg, Magdalena Rhedin, Dag Leonard, Linda Yrlid, Sonya Jackson, Johan Mattsson, Sambit Nanda, Philip Cohen, Axel Knebel, Simon Arthur, Kristofer Thörn, Elisabet Svenungsson, Andreas Jönsen, Iva Gunnarsson, Karolina Tandre, Andrei Alexsson, Alf KastbomSolbritt Rantapää-Dahlqvist, Maija-Leena Eloranta, Ann-Christine Syvänen, Anders Bengtsson, Patrik Johansson, Johanna K. Sandling, Christopher Sjöwall, Lars Rönnblom, Barry Collins, Outi Vaarala (Lead / Corresponding author)

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53 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1363-1370
Number of pages8
JournalAnnals of the Rheumatic Diseases
Issue number10
Early online date12 Jul 2019
Publication statusPublished - 1 Oct 2019


  • NET
  • PAD4
  • PADI4
  • peptidyl arginine deiminase
  • rs2230926

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • General Biochemistry,Genetics and Molecular Biology


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