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

Lau, Max C., Keith, Patricia, Costello, Mary-Ellen, Bradbury, Linda A., Hollis, Kelly A., Thomas, Ranjeny, Thomas, Gethin P., Brown, Matthew A. and Kenna, Tony J. (2016) 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. Annals of the Rheumatic Diseases, . doi:10.1136/annrheumdis-2015-208677


Author Lau, Max C.
Keith, Patricia
Costello, Mary-Ellen
Bradbury, Linda A.
Hollis, Kelly A.
Thomas, Ranjeny
Thomas, Gethin P.
Brown, Matthew A.
Kenna, Tony J.
Title 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
Formatted title
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
Journal name Annals of the Rheumatic Diseases   Check publisher's open access policy
ISSN 1468-2060
0003-4967
Publication date 2016-04-28
Year available 2016
Sub-type Article (original research)
DOI 10.1136/annrheumdis-2015-208677
Open Access Status Not Open Access
Total pages 9
Place of publication London, United Kingdom
Publisher B M J Group
Collection year 2017
Language eng
Formatted 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 genomewide 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 IFN?-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 IFN?, 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.
Keyword Ankylosing spondylitis
AS
T-bet
TBX21
Spondyloarthropathy
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute - Open Access Collection
 
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