Genetic association of ankylosing spondylitis with TBX21 influences T-bet and pro-inflammatory cytokine expression in humans and SKG mice as a model of spondyloarthritis

Max C Lau, Patricia Keith, Mary-Ellen Costello, Linda A Bradbury, Kelly A Hollis, Ranjeny Thomas, Gethin P Thomas, Matthew A Brown, Tony J Kenna

    Research output: Contribution to journalArticlepeer-review

    20 Citations (Scopus)

    Abstract

    Objectives: Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthropathy. Inflammation in AS is poorly understood. TBX21 encodes T-bet, a transcription factor, lying within a locus with genome-wide significant association with AS. T-bet is implicated in innate and adaptive immunity. However, the role of T-bet in AS pathogenesis is unclear.

    Methods: We assessed the importance of T-bet in disease development and progression in peripheral blood mononuclear cells from 172 AS cases and 83 healthy controls carrying either risk or protective alleles of the peak AS-associated TBX21 single nucleotide polymorphism. Kinetics and localisation of T-bet expression in the SKG mouse model of spondyloarthropathy was examined, along with the impact of Tbx21 knockout on arthritis development in SKG mice.

    Results: Patients with AS had higher T-bet expression than healthy individuals, driven predominantly by natural killer and CD8+ T cells, with expression levels in CD8+ T cells completely distinguishing AS cases from healthy controls. T-bet expression was increased in AS cases carrying risk compared with protective alleles of rs11657479. In curdlan-treated SKG mice, T-bet expression increased early after disease initiation and persisted throughout the course of disease. There was marked reduction in gut and peripheral joint inflammation, and less IFNγ-producing and IL-17-producing CD8+ T cells, in Tbx21−/− compared with wild-type SKG mice.

    Conclusions: AS-associated variants in TBX21 influence T-bet expression. T-bet+ innate and adaptive immune cells have altered IL-17 and IFNγ, and early activation marker CD69 expression than T-bet cells. This indicates that T-bet is a major component of inflammatory pathways of spondyloarthropathy in humans and mice.
    Original languageEnglish
    Pages (from-to)261-269
    Number of pages9
    JournalAnnals of the Rheumatic Diseases
    Volume76
    Issue number1
    Early online dateDec 2016
    DOIs
    Publication statusPublished - Jan 2017

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