Untreated DQA1*0501+JDM:Clinical and Genetic Profiles

未经处理的 DQA1*0501 JDM：临床和遗传概况

• 批准号: 6924544
• 负责人: LAUREN M. PACHMAN
• 金额: $ 26.41万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924544
• 关键词: African American; Hispanic Americans; MHC class II antigen; Native Americans; adolescence (12-20); artificial immunosuppression; caucasian American; child (0-11); clinical research; dermatomyositis; enzyme linked immunosorbent assay; gender difference; gene expression; human subject; human therapy evaluation; immunocytochemistry; immunogenetics; interferons; laser capture microdissection; lymphocyte; patient oriented research; polymerase chain reaction; racial /ethnic difference; relapse /recurrence; tumor necrosis factor alpha; western blottings

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.

描述（由申请人提供）：少年皮肌炎（JDM）是一种经常影响幼儿的灾难性疾病，通常是在上呼吸道感染之前。在JDM中，85％为DQA1*0501+，TNFALPHA-308A等位基因与TNFalpha产生增加和疾病延长有关。与正常儿童或小儿坏死性肌病的MBX相比，未经治疗的DQA1*0501+儿童的肌肉活检（MBX）研究表明，干扰素（IFN）可诱导的基因伴随着抗生细胞反应兼容。这项研究的目的是确定1）与JDM相关的基因表达谱，而不论种族或性别如何，以及2）与非重要性疾病相反的JDM儿童区分JDM儿童。特定的目标1a将比较5 dqa1*0501 +未经治疗的白人女孩的基因表达谱和JDM + TNFA；在特定的目标1B，5DQA1*0501 -White Girls + TNFA -308 A等位基因将被研究；在特定的AIM 1C中，将测试西班牙裔，非裔美国人和美国原住民儿童，并且在特定的目标1D中，男孩中表达的基因将与女孩相比。通过激光捕获显微解剖来分离JDM MBX的细胞，以确定富含特定淋巴细胞表型（例如CD4，CD4）的基因表达和外周血血液淋巴细胞（PBL）的起源。在表达谱中表达的选定基因将由QRT-PCR确认，其蛋白质通过免疫组织化学，蛋白质印迹和ELISA鉴定。与PBL中选定的基因相比，特定的目标2将表征MBX中MBX中的基因表达谱，并且在响应免疫抑制治疗的JDM的随访（针MBX和PBL）的6个月后期（针MBX和PBL）。特定的目标3将表征JDM中的基因表达谱以及患有肌炎的儿童患有非发病疾病的儿童。在此目标中，将在诊断时与MBX和PBL中的表达曲线与针头MBX和PBL进行比较，并获得大于或等于36个月。在特定的AIM 3D中，将向患有非重要性疾病的儿童进行抗TNFALPHA生物学剂，例如依那耐酸copt，并且在治疗前后进行了比较。我们推测1）DQA1*0501+ JDM中的基因表达谱将与DQA1*0501- JDM不同，确认了疾病发病机理的差异，男孩和女孩也可能有所不同，表明性别作用； 2）tnfalpha（以及Tnfalpha-308 A等位基因）的产生与持续存在的基因表达谱有关，这些基因表达谱显示出患有非发病疾病的肌炎儿童中表现出可诱导的基因。了解这些表达基因的功能应导致针对JDM的新型疗法。