Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Rheumatology, TRANSCRIPTION FACTOR E4BP4, CELL, ASSOCIATION, PATHWAYS, DISEASES, IL-1β, NFIL3, genetic, juvenile idiopathic arthritis, macrophages, Animals, Arthritis, Juvenile, Basic-Leucine Zipper Transcription Factors, Child, Disease Models, Animal, Female, Humans, Immunity, Innate, Interleukin-1beta, Mice, Mutation, Twins, Monozygotic, Exome Sequencing, 1103 Clinical Sciences, 1107 Immunology, 1117 Public Health and Health Services, Arthritis & Rheumatology, 3202 Clinical sciences, 3204 Immunology

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.