TY - JOUR T1 - NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 342 LP - 349 DO - 10.1136/annrheumdis-2018-213764 VL - 78 IS - 3 AU - Susan Schlenner AU - Emanuela Pasciuto AU - Vasiliki Lagou AU - Oliver Burton AU - Teresa Prezzemolo AU - Steffie Junius AU - Carlos P Roca AU - Cyril Seillet AU - Cynthia Louis AU - James Dooley AU - Kylie Luong AU - Erika Van Nieuwenhove AU - Ian P Wicks AU - Gabrielle Belz AU - Stéphanie Humblet-Baron AU - Carine Wouters AU - Adrian Liston Y1 - 2019/03/01 UR - http://ard.bmj.com/content/78/3/342.abstract N2 - Objectives NFIL3 is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans.Methods Here, we characterised a kindred of two monozygotic twin girls with juvenile idiopathic arthritis at the genetic and immunological level, using whole exome sequencing, single cell sequencing and flow cytometry. Parallel studies were performed in a mouse model.Results The patients inherited a novel p.M170I in NFIL3 from each of the parents. The mutant form of NFIL3 demonstrated reduced stability in vitro. The potential contribution of this mutation to arthritis susceptibility was demonstrated through a preclinical model, where Nfil3-deficient mice upregulated IL-1β production, with more severe arthritis symptoms on disease induction. Single cell sequencing of patient blood quantified the transcriptional dysfunctions present across the peripheral immune system, converging on IL-1β as a pivotal cytokine.Conclusions NFIL3 mutation can sensitise for arthritis development, in mice and humans, and rewires the innate immune system for IL-1β over-production. ER -