Our recent data showed that naïve CD4+ T cells in lupus undergo an epigenetic pro-inflammatory shift implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without expression changes of corresponding genes, and poises naïve CD4+ T cells for Th2, Th17, and Tfh immune responses, and opposes inhibitory TGF-β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might be playing an important role in shifting the epigenetic landscape with increased disease activity in lupus naïve CD4+ T cells. In fact, we also show that the expression of miR26a and miR101, which are sensitive to glucose availability and target EZH2, negatively correlated with disease activity in lupus patients. Recent data from other groups suggest that glycolysis in increased in lupus T cells. More recently we confirmed that EZH2 is overexpressed in naïve CD4+ T cells from lupus patients compared to controls, and that miR26a and miR101 are downregulated. We also show that inhibiting glycolysis in naïve CD4+ T cells from healthy people restores higher expression levels of miR26a and miR101. We believe that EZH2 upregulated, possibly induced by increased glycolysis in lupus resulting in downregulation of miR26a and miR101, induces an epigenetic landscape shift in naïve CD4+ T cells that favors T cell activation and non-Th1 immune responses, which predates transcriptional activity and correlates with disease flares in lupus. The proposed T cell epigenetic model of disease flare in lupus patients is depicted in the figure below. We are working to more comprehensively understand the role of EZH2 dysregulation in lupus, and whether inhibiting EZH2 is a potential therapeutic target in lupus.
T cell epigenetic model of disease flares in lupus (Based on findings from Coit el al. Arthritis and Rheumatology 2016)