Epigenetic Reprogramming in Naive CD4+ T Cells Favoring T Cell Activation and Non‐Th1 Effector T Cell Immune Response as an Early Event in Lupus Flares. Issue 9 (September 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: Arthritis & rheumatology. Volume 68:Issue 9(2016)
• Page Start: 2200
• Page End: 2209
• Publication Date: 2016-09
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.39720
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: Systemic lupus erythematosus (SLE) 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. This study was undertaken to examine DNA methylation in naive CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares. Methods: A total of 74 lupus patients with an SLE Disease Activity Index score of 0–18 were included. Naive CD4+ T cells were isolated from peripheral blood samples, and DNA was extracted for genome‐wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcription activity using RNA sequencing and microRNA arrays. Results: We demonstrated that naive CD4+ T cells in lupus undergo an epigenetic proinflammatory shift, implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without changes in expression of the corresponding genes, poises naive CD4+ T cells for Th2, Th17, and follicular helper T cell immune responses, and opposes inhibitory transforming growth factor β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might play an important role in shifting the epigenetic landscape, with increased disease activity in lupus naive CD4+ T cells. Further, the expression of microRNA‐26a, which is sensitive to glucose availability and targets EZH2, was negatively correlated with disease activity in lupus patients. Conclusion: An epigenetic landscape shift in naive CD4+ T cells that favors T cell activation and non‐Th1 immune responses predates transcription activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.