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Ann Rheum Dis. 2018 Dec 14. pii: annrheumdis-2018-213764. doi: 10.1136/annrheumdis-2018-213764. [Epub ahead of print]

NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology.

Author information

1
Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium.
2
VIB Center for Brain and Disease Research, Leuven, Belgium.
3
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
4
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
5
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
6
Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium adrian.liston@vib.be.

Abstract

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.

KEYWORDS:

IL-1β; NFIL3; genetic; juvenile idiopathic arthritis; macrophages

PMID:
30552177
DOI:
10.1136/annrheumdis-2018-213764
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Conflict of interest statement

Competing interests: None declared.

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