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.
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.



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.



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.



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.
University of Michigan, Ann Arbor.
Patrick
P
Coit
Virginia Commonwealth University, Richmond.
Mikhail G
MG
Dozmorov
Oklahoma Medical Research Foundation, Oklahoma City.
Joan T
JT
Merrill
University of Michigan, Ann Arbor.
W Joseph
WJ
McCune
Henry Ford Health System, Detroit, Michigan.
Kathleen
K
Maksimowicz-McKinnon
Oklahoma Medical Research Foundation and University of Oklahoma, Oklahoma City.
Jonathan D
JD
Wren
University of Michigan, Ann Arbor.
Amr H
AH
Sawalha
D000293:Adolescent; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics*; D008875:Middle Aged; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D013997:Time Factors; D055815:Young Adult