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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
#MMPMID27111767
Coit P
; Dozmorov MG
; Merrill JT
; McCune WJ
; Maksimowicz-McKinnon K
; Wren JD
; Sawalha AH
Arthritis Rheumatol
2016[Sep]; 68
(9
): 2200-9
PMID27111767
show ga
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
? 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.
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