RT Journal Article
SR Electronic
T1 Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1363
OP 1370
DO 10.1136/annrheumdis-2019-215434
VO 78
IS 10
A1 Odqvist, Lina
A1 Jevnikar, Zala
A1 Riise, Rebecca
A1 Öberg, Lisa
A1 Rhedin, Magdalena
A1 Leonard, Dag
A1 Yrlid, Linda
A1 Jackson, Sonya
A1 Mattsson, Johan
A1 Nanda, Sambit
A1 Cohen, Philip
A1 Knebel, Axel
A1 Arthur, Simon
A1 Thörn, Kristofer
A1 Svenungsson, Elisabet
A1 Jönsen, Andreas
A1 Gunnarsson, Iva
A1 Tandre, Karolina
A1 Alexsson, Andrei
A1 Kastbom, Alf
A1 Rantapää-Dahlqvist, Solbritt
A1 Eloranta, Maija-Leena
A1 Syvänen, Ann-Christine
A1 Bengtsson, Anders
A1 Johansson, Patrik
A1 Sandling, Johanna K
A1 Sjöwall, Christopher
A1 Rönnblom, Lars
A1 Collins, Barry
A1 Vaarala, Outi
YR 2019
UL http://ard.bmj.com/content/78/10/1363.abstract
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.