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NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology
  1. Susan Schlenner1,2,
  2. Emanuela Pasciuto1,2,
  3. Vasiliki Lagou1,2,
  4. Oliver Burton1,2,
  5. Teresa Prezzemolo1,2,
  6. Steffie Junius1,2,
  7. Carlos P Roca1,2,
  8. Cyril Seillet3,4,
  9. Cynthia Louis3,
  10. James Dooley1,2,
  11. Kylie Luong3,4,
  12. Erika Van Nieuwenhove1,2,5,
  13. Ian P Wicks3,4,
  14. Gabrielle Belz3,4,
  15. Stéphanie Humblet-Baron1,2,
  16. Carine Wouters1,5,
  17. Adrian Liston1,2
  1. 1 Department of Microbiology and Immunology, KUL - University of Leuven, Leuven, Belgium
  2. 2 VIB Center for Brain and Disease Research, Leuven, Belgium
  3. 3 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  4. 4 Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
  5. 5 Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
  1. Correspondence to Dr Adrian Liston, Department of Microbiology and Immunology, KUL - University of Leuven, Leuven 3000, Belgium; adrian.liston{at}; Professor Carine Wouters, Department of Microbiology and Immunology, KUL - University of Leuven, Leuven 3000, Belgium; carine.wouters{at}; Dr Stéphanie Humblet-Baron, Department of Microbiology and Immunology, KUL - University of Leuven, Leuven 3000, Belgium; stephanie.humbletbaron{at}


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.

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

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  • Handling editor Josef S Smolen

  • Correction notice This article has been corrected since it published Online First. The corresponding author's details have been updated.

  • Contributors SS, EP, OB, TP, CS, CL, JD, SJ and KL performed experiments. SS, VL, CPR, IPW, GB and AL analysed data. EVN, SH-B and CW provided clinical information. SH-B, CW and AL designed and led the study.

  • Funding This work was supported by the ERC grant IMMUNO and the VIB Grand Challenges Program. SH-B, EP, VL, SJ and EVN are FWO fellows. This work was supported by the Reid Charitable Trusts, National Health and Medical Research Council of Australia Clinical Practitioner Fellowship (1023407), Senior Principal Research Fellowship (1135898), RD Wright Career Development Fellowship (1123000), Program Grants (1016647, 1054925) and Victorian Government Operational Infrastructure Support.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval UZ Leuven Ethical Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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