RT Journal Article
SR Electronic
T1 NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 342
OP 349
DO 10.1136/annrheumdis-2018-213764
VO 78
IS 3
A1 Susan Schlenner
A1 Emanuela Pasciuto
A1 Vasiliki Lagou
A1 Oliver Burton
A1 Teresa Prezzemolo
A1 Steffie Junius
A1 Carlos P Roca
A1 Cyril Seillet
A1 Cynthia Louis
A1 James Dooley
A1 Kylie Luong
A1 Erika Van Nieuwenhove
A1 Ian P Wicks
A1 Gabrielle Belz
A1 Stéphanie Humblet-Baron
A1 Carine Wouters
A1 Adrian Liston
YR 2019
UL http://ard.bmj.com/content/78/3/342.abstract
AB 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.