Disease chronicity in juvenile dermatomyositis (JDM): Epigenetic clues
Principal Investigator: Lauren Pachman
Affiliation: Northwestern University
Abstract: Juvenile dermatomyositis (JDM) is the most common pediatric inflammatory myopathy and occurs in young children (mean age at onset of symptoms, 6.7 years;girl: boy ratio=2.3:1) with 1-2% mortality and increased morbidity secondary to dystrophic calcifications and secondary contractures. The children have a decreased quality of life, but the role of chronic inflammation has not been evaluated. The duration of time of the untreated inflammation is a critical factor: untreated symptoms of greater than two months are associated with a chronic rash and upregulation of vascular remodeling genes on gene expression profile studies. The chronic rash is also associated with loss of nailfold capillary end row loops, impaired absorption of medications, and as young adults, the patients appear prone to premature cardiovascular damage. Damage to endothelial cells is mediated by IFN- 1 and TNF-1, and both cytokines are increased in JDM sera and tissue. Increased TNF-1 levels are associated with a polymorphism in the promoter region of TNF-1-308. We also found a complex gene-gene-gender interaction between the OPN and TNF-1 promoter regions in JDM children. This defined a high serum IFN-1 subgroup within JDM, which may contribute to the increased incidence of JDM in girls. In treating JDM, the accepted guide to therapy is serum levels of muscle enzymes, which normalize rapidly, leaving a void. A major barrier to providing effective therapy in JDM is the lack of biomarkers of inflammation as well as prognostic indicators of disease severity. The purpose of this study is to identify epigenetic mechanisms - differences in global methylation and miRNA expression - critical in dissecting the impact of chronic inflammation and gender on JDM microvasculopathy. We hypothesize: 1) Decreased quality of life in chronic JDM is related less to weakness than to the chronic skin involvement, associated with long untreated disease, and, 2) identification of epigenetic regulatory mechanisms and specific miRNAs in JDM muscle and in endothelial precursor cells (EPCs) will disclose novel pathogenetic mechanisms that will guide the development of more effective therapy. To accomplish this goal, well-characterized muscle biopsies from untreated children with JDM will be compared: 1) short duration (<2 month) vs. long (e 2 months) duration, and 2) age-matched boys compared with girls, also matched for disease duration. In Specific Aim 1, global methylation studies, comparing JDM with controls will identify areas of hypomethylation, such as the WT1 and HOX genes, and test their relation to intensity levels of miRNA expression. Specific Aim 2 will determine the association of levels of miRNA expression with the child's quality of life, disease activity scores (DAS), and their TNF-1-308 AA/AG vs GG status. For example, we found that miR-34a, upregulated in JDM GG with short disease duration modulates the expression of the transcriptional activator Bcl12, important in the apoptotic pathway. In Specific Aim 3, endothelial precursor cells (EPCs) will be isolated from the blood of JDM and age-gender matched controls and their epigenetic features characterized. In addition, their function will be studied in vitro and compared with the extent of the child's structural loss of nailfold capillary end row loops. The isolated EPCs will then be tested in gain/loss of function experiments, with the goal of restoration of normality. It is anticipated that the scientific knowledge gained from the proposed work will inform our future decision making and lead to more rational and effective interventions. PUBLIC HEALTH RELEVANCE: Juvenile dermatomyositis (JDM) is an autoimmune disease of children, in which there is damage to the small blood vessels;chronic inflammation is associated with persistent rash, loss of range of motion, deposits of calcifications and even the ability to perform tasks like climbing stairs or lifting objects and, therefore, affects the child's quality of life. In this study, the quality of life of the children with JDM will be determined and correlated with their epigenetic status - inherited changes in phenotype (individual's observable traits) determined by genes and the environment - by testing diagnostic muscle biopsies from untreated children with JDM with long (>2 months) compared with short disease duration (d 2 months) and boys compared with girls (matched for disease duration) and age-, gender-matched healthy controls. The goal is to identify specific markers, like microRNA, or "turned on genes" that may be key to repair the vascular damage and to identify more effective medical interventions.
Funding Period: ----------------2010 - ---------------2014-
more information: NIH RePORT