Enhanced Expression of the Transcription Factor T-Bet Alters Pro-Inflammatory Cytokine Profile in Ankylosing Spondylitis

Max C. Lau¹, Patricia Keith¹, Mary-Ellen Costello¹, Linda A. Bradbury¹, Kelly A. Hollis¹, Gethin P. Thomas², Matthew A. Brown^1,3 and Tony J. Kenna¹, ¹The University of Queensland Diamantina Institute, Brisbane, Australia, ²Translational Reserch Institute, The University of Queensland Diamantina Institute, Brisbane, Australia, ³Translational Research Institute, Brisbane, Australia

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Ankylosing spondylitis (AS), Immune Dysregulation, innate immunity and mouse model, T cells

Session Information

Date: Tuesday, November 10, 2015

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

Session Type: ACR Poster Session C

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

Background/Purpose: TBX21 encodes T-bet, a T-box transcription factor, and lies within a locus with genome-wide significant association with AS (rs11657479, odds ratio=1.13, P=6.16×10^-10). T-bet is implicated in both innate and adaptive arms of immunity. However, the role of T-bet in AS pathogenesis is unclear

Methods:

We examined the role of T-bet in disease development and progression in peripheral blood mononuclear cells (PBMCs) from 172 AS cases and 83 healthy control (HC) carrying either risk or protective alleles of rs11657479, the peak AS-associated Tbx21 SNP, by qPCR and flow cytometry. We also examined kinetics and localization of T-bet expression in the SKG mouse model of spondyloarthropathy, and the impact of Tbx21 knockout on arthritis development in SKG mice.

Results:

T-bet expression by qPCR was increased in AS cases compared with HC (P=3.6×10^-5), and was associated with rs11657479 genotypes in AS cases (P=0.0017), with risk genotype carriers having higher expression (ΔΔCt=0.064±0.074) than protective (ΔΔCt=0.022±0.020, P=0.0003) genotypes. The proportion of cells expressing T-bet was increased in both CD3-positive and -negative PBMCs in AS vs HC (CD3- 1.3x increase, P=0.0012; CD3+ 3.9x increase, P<10^-4). A marked expansion of T-bet CD3+ CD4- CD8+ T cells was seen in AS cases (31.47±8.45%) compared with healthy controls (3.00±2.54%)(P<0.0001), with all AS cases studied having higher proportions of these T-bet expressing cells than all controls studied. This increase in AS case T-bet expression was particularly prominent in interleukin-17- (IL-17) producing NK cells (3.4x increase % cells expressing T-bet, P=0.0005) and cytotoxic T (T_C17.1) cells (5.6x increase % cells expressing T-bet, P<10^-4). In curdlan-treated SKG mice, T-bet expression increased early after disease initiation and persisted, from 7 days onward, throughout the course of AS-like disease. In Tbx21-/- compared with wild-type SKG mice, there was marked reduction in both gut and peripheral joint inflammation, and reduced numbers of T_C17.1 cells.

Conclusion: Tbx21 genetic variants operate to increase the risk of AS through effects on T-bet expression. T-bet, through influences on the function of innate and adaptive immune cells, plays a major role in the pathogenesis of spondyloarthropathy in humans and mice.

Disclosure: M. C. Lau, None; P. Keith, None; M. E. Costello, None; L. A. Bradbury, None; K. A. Hollis, None; G. P. Thomas, None; M. A. Brown, Abbvie, Pfizer, UCB, Wyeth, Leo Pharma, NIAMS, NHMRC, Arthritis Australia, Qld Government, 2,Pfizer, Abbvie, UCB, 5,Pfizer, Abbvie, UCB, 8; T. J. Kenna, None.

To cite this abstract in AMA style:

Lau MC, Keith P, Costello ME, Bradbury LA, Hollis KA, Thomas GP, Brown MA, Kenna TJ. Enhanced Expression of the Transcription Factor T-Bet Alters Pro-Inflammatory Cytokine Profile in Ankylosing Spondylitis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/enhanced-expression-of-the-transcription-factor-t-bet-alters-pro-inflammatory-cytokine-profile-in-ankylosing-spondylitis/. Accessed .

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-expression-of-the-transcription-factor-t-bet-alters-pro-inflammatory-cytokine-profile-in-ankylosing-spondylitis/