RUNX3 in autoimmune rheumatic diseases: cell-specific mechanisms and translational implications

Runt-related transcription factor 3 (RUNX3) regulates immune-cell differentiation, effector function and tolerance. Studies of autoimmune rheumatic diseases have reported changes in its methylation and expression, but the findings differ between cell types and tissues. This review examines RUNX3 in systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis (SSc), psoriasis and psoriatic arthritis, drawing on patient studies and experimental work. Genetic associations near RUNX3 implicate this region in susceptibility to ankylosing spondylitis and psoriatic arthritis, although the mechanisms linking these variants to disease remain unclear. Patient studies have also identified epigenetic and transcriptional changes. In lupus, increased RUNX3 methylation has been reported in blood-derived samples without matched measurements of transcript or protein abundance. SSc illustrates the importance of examining individual cell populations: RUNX3 expression is lower in circulating plasmacytoid dendritic cells, whereas RUNX3 transcript abundance is higher in dermal fibroblasts. Experiments in human CD4 + T cells in psoriasis studies show that manipulating RUNX3 alters cytokine production. In mouse models, deletion of Runx3 in CD11c-expressing cells worsens fibrosis. These experiments demonstrate functions of RUNX3 in specific cells and models, but their relationship to the molecular changes observed in patients requires further study. Linking patient observations to functional experiments in the corresponding cell populations will help determine how RUNX3 contributes to disease and whether these findings have therapeutic relevance.