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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
Author(s) -
Coit Patrick,
Dozmorov Mikhail G.,
Merrill Joan T.,
McCune W. Joseph,
MaksimowiczMcKin Kathleen,
Wren Jonathan D.,
Sawalha Amr H.
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39720
Subject(s) - epigenetics , systemic lupus erythematosus , biology , immunology , dna methylation , immune system , t cell , disease , gene expression , medicine , genetics , gene
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.