PT  - JOURNAL ARTICLE
AU  - Odqvist, Lina
AU  - Jevnikar, Zala
AU  - Riise, Rebecca
AU  - Öberg, Lisa
AU  - Rhedin, Magdalena
AU  - Leonard, Dag
AU  - Yrlid, Linda
AU  - Jackson, Sonya
AU  - Mattsson, Johan
AU  - Nanda, Sambit
AU  - Cohen, Philip
AU  - Knebel, Axel
AU  - Arthur, Simon
AU  - Thörn, Kristofer
AU  - Svenungsson, Elisabet
AU  - Jönsen, Andreas
AU  - Gunnarsson, Iva
AU  - Tandre, Karolina
AU  - Alexsson, Andrei
AU  - Kastbom, Alf
AU  - Rantapää-Dahlqvist, Solbritt
AU  - Eloranta, Maija-Leena
AU  - Syvänen, Ann-Christine
AU  - Bengtsson, Anders
AU  - Johansson, Patrik
AU  - Sandling, Johanna K
AU  - Sjöwall, Christopher
AU  - Rönnblom, Lars
AU  - Collins, Barry
AU  - Vaarala, Outi
TI  - Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
AID  - 10.1136/annrheumdis-2019-215434
DP  - 2019 Oct 01
TA  - Annals of the Rheumatic Diseases
PG  - 1363--1370
VI  - 78
IP  - 10
4099  - http://ard.bmj.com/content/78/10/1363.short
4100  - http://ard.bmj.com/content/78/10/1363.full
SO  - Ann Rheum Dis2019 Oct 01; 78
AB  - 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.