GG-02 Epigenetic reprogramming in NAïVE CD4+ T cells favouring T cell activation and NON-TH1 effector T cell immune response as an early event in lupus flares. (31st August 2016)

• Record Type: Journal Article
• Authors: Coit, Patrick; Dozmorov, Mikhail G; Merrill, Joan T; McCune, W Joseph; Maksimowicz-McKinnon, Kathleen; Wren, Jonathan D; Sawalha, Amr H
• Is Part Of: Lupus science & medicine. Volume 3(2016)Supplement 1
• Page Start: A28
• Page End: A28
• Publication Date: 2016-08-31
• Subjects: Systemic lupus erythematosus -- Periodicals; 616.772005
• DOI: 10.1136/lupus-2016-000179.54
• Languages: English
• ISSNs: 2398-8851

Abstract

Abstract : 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.