Untreated DQA1*0501+JDM:Clinical and Genetic Profiles

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DESCRIPTION (provided by applicant): Juvenile dermatomyositis (JDM), a frequently devastating disease affecting young children, is often preceded by an upper respiratory infection. In JDM, 85% are DQA1*0501+ and the TNFalpha-308A allele is associated with increased TNFalpha production and a prolonged disease course. Study of muscle biopsy (MBx) from untreated DQA1*0501+ children with JDM, compared with MBx from normal children or from a pediatric necrotizing myopathy showed a striking increase in interferon (IFN)-inducible genes, compatible with an anti-microbial response. The purpose of this study is to determine the gene expression profiles that are 1) specific to JDM regardless of race or gender, and 2) distinguish the JDM child with remittent as opposed to nonremittent disease. Specific Aim 1A will compare the gene expression profiles of 5 DQA1*0501+ untreated white girls with JDM + TNFA; in Specific Aim 1B, 5DQA1*0501 - white girls + the TNFa-308 A allele will be studied; in Specific Aim 1C, Hispanic, African-American and Native American children with 3DM will be tested, and in Specific Aim 1D the genes expressed in boys will compared with girls. Cells from the JDM MBx will be isolated by laser capture microdissection to determine the origin of the gene expression and peripheral blood lymphocytes (PBL) enriched for a specific lymphocyte phenotype (e.g. CD4, CD8) will be tested as well. Selected genes expressed in the expression profiles will be confirmed by qRT-PCR, and their proteins identified by immunohistochemistry, western blot, and ELISA. Specific Aim 2 will characterize the gene expression profiles in MBx at diagnosis compared with selected genes in PBL, and at greater than or equal to 6 months of follow-up (needle MBx and PBL) of JDM responsive to immunosuppressive therapy. Specific Aim 3 will characterize the gene expression profiles in JDM as well as children with myositis related antibodies, who have nonremittent disease. In this aim, the expression profiles in MBx and PBL at diagnosis will be compared with needle MBx and PBL at obtained greater than or equal to 36 months. In Specific Aim 3d, an anti-TNFalpha biologic agent, such as Etanercept, will be administered to children with nonremittent disease, and the expressed genes compared before and after therapy. We speculate that 1) the gene expression profile in DQA1*0501+ JDM will differ from DQA1*0501- JDM, confirming a difference in disease pathogenesis, and that boys and girls may also differ, suggesting a gender effect; and 2) increased production of TNFalpha (and the TNFalpha-308 A allele) will be associated with persisting gene expression profiles displaying INF-inducible genes in children with myositis who have nonremittent disease. Understanding the function of these expressed genes should lead to novel therapies specific for JDM.