VASCULOPATHY OF JUVENILE DERMATOMYOSITIS

描述(摘自申请表)：青少年皮肌炎 (JDMS)，影响最常见的儿科炎症性肌病 3/100万儿童/年的死亡率超过2%，是一种遗传学上的 相关(DQAI*0501)影响毛细血管和 微动脉，其中没有疾病的实验室预测因素 进程或严重程度。这项提议的假设是病态的 血管结构的损伤涉及细胞免疫的激活。 系统、T细胞和巨噬细胞，并与升高的 反映环境变化的循环介质浓度 血管生成和止血。这项提议将提供一个全面的 评估三个层次的结构发现--体检、 甲皱毛细血管形态和肌肉活检--这将使 与实验室证据的介体特征的比较 特异性T细胞亚群(Th1、Th2)与循环反应因子 血栓形成和止血的变化。第一个具体目标是 制定疾病活动性和慢性化评分(ACSS) 40例甲皱患者1)临床表现2)甲皱的断层研究 3)肌肉活检和组织学检查的组织学改变。 用皮尔逊相关法确定它们之间的关系 系数。在特定目标2中，纵向研究，诊断 肌肉活检将评估Th1(IL2， 和Th2细胞(IL-4、IL-10)及其定位 产物经免疫组织化学染色。Th1与Th2的关系 相关的细胞因子可能与JDMS的疾病进展和 将在6个月后通过针刺活组织检查对20例新发病的JDMS进行重新评估 使用方差分析开始治疗。浓缩物 循环巨噬细胞(IL-8、肿瘤坏死因子-α)或淋巴细胞源(bFGF、 将测量影响血管生成和止血的因素 在特定的目标#3，以及凝血标志物，d-二聚体纤维蛋白 切割产物，凝血酶原激活肽，F 1.2，vWF：Ag和 血栓调节蛋白，使用配对t检验的样本在发病和后续- 升高，并与三种ACs水平相关。在具体目标4中， 循环因子--血浆衍生血清，普通外周血 血单个核细胞和分离的CD4+和CD8+T细胞--及其 组织培养上清液将在体外模型上进行测试 血管内皮细胞的增殖、迁移、管腔形成与平滑肌 扩散和迁徙。《特殊目标5》将比较这些孩子 有无LI类抗原DQAI*0501，有ACSS和水平 使用2个样本t检验对特定的血管活性物质进行比较。

DESCRIPTION (Taken from the application): Juvenile dermatomyositis (JDMS), the most common pediatric inflammatory myopathy affecting 3/1,000,000 children/year with a mortality of over 2%, is a genetically associated (DQAI *0501) systemic vasculopathy affecting capillaries and arterioles, in which there are no laboratory predictors of disease course or severity. The hypothesis of this proposal is that pathological damage to vascular structures involves activation of the cellular immune system, T cells and macrophages, and is correlated with elevated concentrations of circulating mediators reflecting alterations of angiogenesis and hemostasis. This proposal will provide a comprehensive assessment of structural findings at three levels-physical examination, nailfold capillary morphology, and muscle biopsy--which will allow comparisons with laboratory evidence of mediators characteristic of specific T cells subsets (Thl, Th2) and circulating factors reflecting alterations in thrombosis and hemostasis. The first Specific Aim is to develop disease activity and chronicity scores (ACSs) in a cross- sectional study of 40 JDMS of 1 ) clinical findings, 2) nailfold capillaroscopy, and 3) histological change on muscle biopsy and determine the relationship between them using Pearson correlation coefficients. In Specific Aim #2, a longitudinal study, the diagnostic muscle biopsy will be assessed for mRNA characteristic of Th1 (IL2, INFgamma) and Th2 cells (IL-4, IL-1O) as well as localization of these products by immunohistochemistry. The relationship of Th1 to Th2 associated cytokines may be relative to disease progression in JDMS and will be reevaluated in 20 new onset JDMS by needle biopsy 6 months after initiation of therapy using analysis of variance. The concentration of circulating macrophage (IL-8, TNF-alpha) or lymphocyte derived (bFGF, TGFbeta) factors affecting angiogenesis and hemostasis will be measured in Specific Aim #3, as well markers of coagulation, d-dimer fibrin cleavage product, prothrombin activation peptide, F 1.2, vWF:Ag and thrombomodulin, using a paired t-test for samples at onset and follow- up, and the levels correlated with the three ACSs. In Specific Aim #4, circulating factors--plasma derived serum, unfractionated peripheral blood mononuclear cells, and isolated CD4+ and CD8+ T cells--and their tissue culture supernatant will be tested on in vitro models of endothelial proliferation, migration, tube formation and smooth muscle proliferation and migration. Specific Aim #5 will compare those children with and without the Class lI antigen, DQAI *0501, with ACSs and levels of the specific vasoactive mediators using 2 sample t-tests.