Background Systemic lupus erythematosus is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus, however, early T cell events triggering disease flares are incompletely understood. We studied DNA methylation in naïve CD4+ T cells from lupus patients to determine if epigenetic remodelling in CD4+ T cells is an early event in lupus flares.
Materials and methods A total of 74 lupus patients with disease activity ranging from 0–18 as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were included in this study. Naïve CD4+ T cells were isolated from peripheral blood samples and DNA extracted for genome-wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcriptional activity using RNA sequencing and microRNA arrays.
Results We demonstrate 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 signalling. 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. Further, the expression of miR26a and miR101, which are sensitive to glucose availability and target EZH2, negatively correlated with disease activity in lupus patients.
Conclusion An epigenetic landscape shift in naïve CD4+ T cells that favours T cell activation and non-Th1 immune responses predates transcriptional activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation. The proposed T cell epigenetic model of disease flare in lupus patients is depicted in Figure 1.
Acknowledgements This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI097134.
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