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.
- Gene Polymorphism
- Ankylosing Spondylitis
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Handling editor Tore K Kvien
MAB and TJK contributed equally.
Contributors MCL designed and conducted experiments, analysed data, wrote manuscript. PK and MEC conducted experiments, analysed data and edited manuscript. LAB, KAH and RT: provided samples, designed experiments and edited manuscript. GPT: designed experiments, analysed data and edited manuscript. MAB and TJK: designed study, analysed data, wrote and edited manuscript.
Funding Department of Health, Australian Government. National Health and Medical Research Council. Senior Principal Research Fellowship APP1024879.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Princess Alexandra Hospital and University of Queensland Ethics Committees (ethics no. Metro South HREC/05/QPAH/221 and UQ 2006000102).
Provenance and peer review Not commissioned; externally peer reviewed.