Untreated DQA1*0501+JDM:Clinical and Genetic Profiles

描述（由申请人提供）：青少年皮肌炎（JDM），一种经常影响幼儿的破坏性疾病，通常在上呼吸道感染之前发生。在JDM中，85%为DQA 1 *0501+，TNF α-308 A等位基因与TNF α产生增加和病程延长相关。对来自未经治疗的DQA 1 *0501+ JDM儿童的肌肉活检（MBx）与来自正常儿童或儿科坏死性肌病的MBx进行比较的研究显示，干扰素（IFN）诱导基因显著增加，与抗微生物反应一致。本研究的目的是确定基因表达谱，1）JDM的特异性，无论种族或性别，2）区分JDM儿童与缓解性疾病，而不是非缓解性疾病。具体目标1A将比较5名DQA 1 *0501+未治疗白色女孩与JDM + TNFA的基因表达谱;在具体目标1B中，将研究5名DQA 1 *0501 -白色女孩+TNFa-308 A等位基因;在特定目标1C中，将对西班牙裔、非洲裔美国人和美洲土著3型糖尿病儿童进行检测，在特定目标1D中，将男孩中表达的基因与女孩中表达的基因进行比较。将通过激光捕获显微切割分离JDM MBx中的细胞，以确定基因表达的来源，还将检测富集特定淋巴细胞表型（例如CD 4、CD 8）的外周血淋巴细胞（PBL）。将通过qRT-PCR确认表达谱中表达的选定基因，并通过免疫组织化学、蛋白质印迹和ELISA鉴定其蛋白质。具体目标2将描述与PBL中选定基因相比，诊断时MBx中的基因表达谱，以及免疫抑制治疗应答的JDM随访时间大于或等于6个月时（针MBx和PBL）。特异性目标3将表征JDM以及患有非缓解性疾病的肌炎相关抗体的儿童的基因表达谱。为此，将在诊断时MBx和PBL中的表达谱与在大于或等于36个月时获得的针MBx和PBL中的表达谱进行比较。在Specific Aim 3d中，将对患有非缓解性疾病的儿童给予抗TNF α生物制剂，如依那西普，并比较治疗前后的表达基因。我们推测：1）DQA 1 *0501+ JDM的基因表达谱与DQA 1 *0501- JDM不同，证实了疾病发病机制的差异，男孩和女孩也可能不同，表明性别效应;和2）增加TNF α的产生（和TNF α-308 A等位基因）将与持续的基因表达谱相关，显示INF-α，非缓解性肌炎患儿中的诱导基因了解这些表达基因的功能应该会导致JDM特异性的新疗法。

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.