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.
abstract: OBJECTIVE
  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.
authors.affiliation: Queensland University of Technology, Institute for Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Max C
authors.initials: MC
authors.lastname: Lau
authors.affiliation: Queensland University of Technology, Institute for Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Keith
authors.affiliation: Queensland University of Technology, Institute for Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Costello
authors.affiliation: Queensland University of Technology, Institute for Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Bradbury
authors.affiliation: Queensland University of Technology, Institute for Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Hollis
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Gethin P
authors.initials: GP
authors.lastname: Thomas
authors.affiliation: Queensland University of Technology, Institute for Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Queensland University of Technology, Institute for Health and Biomedical Innovation, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Kenna
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
keywords: Ankylosing Spondylitis; Gene Polymorphism; Inflammation; Spondyloarthritis