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 and Alters Host Microbiome and Response to Microbial Stimuli

Max Lau¹, Patricia Keith¹, Madeline McCready¹, Mary-Ellen Costello¹, Linda Bradbury¹, Kelly Holiis¹, Ranjeny Thomas², Gethin P. Thomas³, Matthew A. Brown¹ and Tony J. Kenna¹, ¹Translational Research Institute, Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia, ²Translational Research Institute, The University of Queensland Diamantina Institute, Brisbane, Australia, ³Translational Reserch Institute, The University of Queensland Diamantina Institute, Brisbane, Australia

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Ankylosing spondylitis (AS), Immune Dysregulation, microbiome and transcription factor

Session Information

Date: Tuesday, November 15, 2016

Title: Spondylarthropathies Psoriatic Arthritis – Pathogenesis, Etiology - Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: TBX21 encodes the transcription factor T-bet and is genome-wide significant associated with ankylosing spondylitis (AS). T-bet is implicated in innate and adaptive immunity. However, the role of T-bet in AS pathogenesis is unclear. We recently demonstrated that T-bet expression is enhanced in AS patients and that T-bet controls IFN-gamma+IL-17+ NK cells and CD8 T cells. In the SKG model of spondyloarthropathy (SpA) mice lacking the Tbx21 gene were protected from peripheral arthritis and gut inflammation. We hypothesized that enhanced T-bet expression in AS alters mucosal immunity in the gut and contributes to enhanced reactivity to microbial challenge. Furthermore we hypothesized that the enhanced T-bet expression seen in AS is antigen-driven and that T-bet+ cells express markers of prior antigen encounter.

Methods: We used 16S RNA sequencing to assess the impact of Tbx21 on the gut microbiome in fecal samples from wildtype SKG mice or Tbx21-/- littermate controls. AS patient PBMC samples were used to investigate the response of T-bet+ cells to in vitro challenge with bacterial stimuli. Finally we looked for evidence of antigen-experience on T-bet+ NK cells and CD8 T cells from AS cases and healthy controls to determine whether these cells are being stimulated in vivo in AS patients.

Results: Tbx21 influenced the intestinal microbial composition with decreased abundance of inflammatory species such as Bacteroidaceae, Prevotellaceae, Rikenellaceae, Lachnospiraceae observed in Tbx21-/- compared with Tbx21+/+ littermate control SKG mice. T-bet+ NK cells and CD8 T cells secreted IL-17 and IFN-gamma following in vitro challenge with a range of TLR agonists. In the periphery of AS cases T-bet+ NK cells and CD8 T cells displayed phenotypic markers of recent antigen exposure but the frequnecy of circulating memory T cells was profoundly reduced compared with healthy controls.

Conclusion: AS-associated variants in TBX21 influence T-bet expression and numbers of IL-17 and IFN-gamma secreting NK and CD8+ T cells. T-bet is a major component of inflammatory pathways of spondyloarthropathy in humans and mice and may contribute to inflammation by influencing the gut microbiome and/or through influences on immune cell function in response to microbial challenge.

Disclosure: M. Lau, None; P. Keith, None; M. McCready, None; M. E. Costello, None; L. Bradbury, None; K. Holiis, None; R. Thomas, None; G. P. Thomas, None; M. A. Brown, None; T. J. Kenna, None.

To cite this abstract in AMA style:

Lau M, Keith P, McCready M, Costello ME, Bradbury L, Holiis K, Thomas R, Thomas GP, Brown MA, Kenna TJ. 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 and Alters Host Microbiome and Response to Microbial Stimuli [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/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-and-alters-host-microbiome-and/. Accessed .

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