Untreated DQA1*0501+JDM:Clinical and Genetic Profiles

描述（由申请人提供）：青少年皮肌炎（JDM）是一种影响幼儿的常见破坏性疾病，通常发生在上呼吸道感染之前。在JDM中，85%是DQA1*0501+，而TNFalpha- 308a等位基因与TNFalpha产生增加和病程延长有关。未经治疗的DQA1*0501+ JDM儿童的肌肉活检（MBx）与正常儿童或儿童坏死性肌病的MBx相比，显示干扰素（IFN）诱导基因显著增加，与抗微生物反应相兼容。本研究的目的是确定1)与种族或性别无关的JDM特异性基因表达谱，以及2)区分JDM儿童与非JDM疾病的相关性。特异性Aim 1A将比较5例DQA1*0501+未经治疗的JDM + TNFA白人女孩的基因表达谱；在Specific Aim 1B中，研究5DQA1*0501 -白人女孩+ TNFa-308 A等位基因；在特异性Aim 1C中，西班牙裔、非裔美国人和印第安人患有3DM的儿童将被检测，在特异性Aim 1D中，男孩和女孩的基因表达将被比较。来自JDM MBx的细胞将通过激光捕获显微解剖分离，以确定基因表达的起源，并且还将测试为特定淋巴细胞表型（例如CD4， CD8）富集的外周血淋巴细胞（PBL）。在表达谱中表达的选定基因将通过qRT-PCR确认，并通过免疫组织化学，western blot和ELISA鉴定其蛋白。特异性目标2将表征MBx在诊断时与PBL中选定基因的基因表达谱，以及对免疫抑制治疗有反应的JDM进行大于或等于6个月的随访（针MBx和PBL）。特异性Aim 3将表征JDM以及患有非缓解性疾病的肌炎相关抗体儿童的基因表达谱。为此，将诊断时MBx和PBL的表达谱与大于或等于36个月时的针头MBx和PBL进行比较。在特异性Aim 3d中，一种抗tnfalpha生物制剂，如依那西普，将被用于患有非缓解性疾病的儿童，并比较治疗前后的表达基因。我们推测1)DQA1*0501+ JDM与DQA1*0501- JDM的基因表达谱存在差异，证实了疾病发病机制的差异，并且男孩和女孩也可能存在差异，提示性别效应；2) TNFalpha（和TNFalpha-308 A等位基因）的增加将与持续性基因表达谱相关，在患有非缓解性疾病的肌炎儿童中显示inf诱导基因。了解这些表达基因的功能有助于开发针对JDM的新疗法。

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.