RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis-Novel Targets for Therapy?

Abstract

Susceptibility to ankylosing spondylitis (AS) is polygenic with more than 100 genes identified to date. These include HLA-B27 and the aminopeptidases (ERAP1, ERAP2, and LNPEPS), which are involved in antigen processing and presentation to T-cells, and several genes (IL23R, IL6R, STAT3, JAK2, IL1R1/2, IL12B, and IL7R) involved in IL23 driven pathways of inflammation. AS is also strongly associated with polymorphisms in two transcription factors, RUNX3 and T-bet (encoded by TBX21), which are important in T-cell development and function. The influence of these genes on the pathogenesis of AS and their potential for identifying drug targets is discussed here.

Keywords: ankylosing spondylitis; autoimmunity; functional genomics; inflammation; therapy.

Figure 1

Epigenetic regulation at the RUNX3 AS-associated locus. In CD8+ T-cells the regulatory region upstream the promoter of RUNX3 is characterized by binding of several TFs, included p300 and IRF4, and enhancer histone marks (H3K4Me1). RUNX3 AS-risk allele has an epigenetic effect to reduce RUNX3 expression that might affect CD8+ T-cell numbers and function. The contribution of other genes associated with AS, like T-bet, Eomes and IL7R strengthen the involvement of CD8+ T-cells development pathway in AS pathogenesis.

Figure 2

Microbial dysbiosis or viral infection drives IL-23 production. T-bet expression in T cells promotes IL-23R expression licensing IL-23-mediated inflammation. Carriage of rs11657479 enhances T-bet expression in CD8 T cells and NK cells and enhances pro-inflammatory functions in those cell types.