Macrophage Activation Syndrome Biomarkers in Systemic Juvenile Idiopathic Art

全身性青少年特发性艺术中的巨噬细胞激活综合征生物标志物

• 批准号: 8382402
• 负责人: ALEXEI A GROM
• 金额: $ 24.42万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382402
• 关键词: Acute; Adolescent; Alleles; Animals; Apoptotic; Arts; Biological Markers; CD8B1 gene; Cell physiology; Chronic Childhood Arthritis; Clinical; Clinical Research; Clinical assessments; Complication; Consensus; Control Groups; Cross-Sectional Studies; Cytoplasmic Granules; DNA; DNA Library; Data; Depressed mood; Development; Diagnosis; Diagnostic; Disease; Down-Regulation; Early Diagnosis; Enrollment; Evaluation; Ferritin; Flare; Frequencies; Gene Frequency; Genes; Genetic Polymorphism; Goals; Guidelines; Haplotypes; Hereditary Disease; Human; Immune response; Immunologics; Incidence; Individual; Inflammatory; Inherited; Interleukin 2 Receptor; Intracellular Transport; Life; Link; Literature; Macrophage Activation; Modification; Monitor; Mutation; Natural Killer Cells; Outcome; Parents; Pathway interactions; Patients; Population; Predisposition; Prevalence; Principal Investigator; Reaction; Recording of previous events; Research; Risk; Sampling; Secondary to; Serum; Signal Transduction; Single Nucleotide Polymorphism; Specificity; Staging; Study of serum; Subgroup; Syndrome; T-Lymphocyte; Testing; Time; UNC13B gene; base; clinical phenotype; cohort; cytokine; cytopenia; disorder subtype; familial hemophagocytic lymphohistiocytosis; follow-up; genetic analysis; killings; macrophage; meetings; multidisciplinary; perforin; prognostic; programs; prospective; uncontrolled T lymphocyte proliferation

PROJECT SUMMARY. Macrophage activation syndrome (MAS) is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. MAS has been strongly associated with systemic Juvenile Idiopathic Arthritis (sJIA). It is a potentially fatal condition, but the diagnosis is difficult due to the lack of diagnostic criteria. In clinically similar genetic diseases, the exaggerated immune response has been linked to defective cytolytic function. We have preliminary data indicating the presence of single-nucleotide polymorphisms (SNP) in the MUNC13-4 gene whose product is involved in the secretion of cytolytic granules. These SNP alleles appear to be inherited as an extended haplotype in the majority of MAS patients. Therefore, the main question in Specific Aim 1 is whether genetic polymorphisms in the MUNC 13-4 gene are associated with MAS in sJIA and thus, may help identify patients at a long-term risk for MAS. In this part of the study, banked DMA samples from a large cohort of sJIA patients (including those with MAS) and controls will be examined for the presence of the MUNC13-4 haplotype by targeted genetic analysis of a limited number of SNPs. The SNP data will then be linked to the clinical phenotypes of the patients determined in Specific Aims 2 and 3. We have preliminary evidence that serum levels of soluble IL2 receptor a chain (slL2Ra) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages in MAS, and thus serve as early diagnostic markers. The main question in Specific Aim 2 is whether elevated levels of slL2Ra and sCD163 will distinguish patients with overt and subclinical MAS from patients with conventional sJIA flare. The main question in Specific Aim 3 is whether sJIA patients at risk for MAS represent a distinct subtype of sJIA with a distinct course, and these patients can be distinguished at onset of sJIA. The longterm goal of this proposal is to understand the pathways leading to the increased incidence of MAS in sJIA, define the MAS risk group, and to develop guidelines for monitoring and treatment of such patients.

项目摘要。巨噬细胞激活综合征（MAS）的特征是压倒性的 由T细胞和嗜雄性巨噬细胞的过度扩张驱动的炎症反应。马斯 与全身少年特发性关节炎（SJIA）密切相关。这可能是致命的 条件，但是由于缺乏诊断标准，诊断很困难。在临床上相似的遗传中 疾病，夸张的免疫反应已与缺陷的细胞溶解功能有关。我们有 初步数据，表明在Munc13-4基因中存在单核苷酸多态性（SNP） 其产物参与细胞溶剂颗粒的分泌。这些SNP等位基因似乎是继承的 作为大多数MAS患者的扩展单倍型。因此，特定目的1中的主要问题是 MUNC 13-4基因中的遗传多态性是否与SJIA中的MAS相关，因此可以 帮助识别长期MAS风险的患者。在研究的这一部分中，从一个 将检查大量的SJIA患者（包括具有MAS的患者）和对照组是否存在 通过有限数量的SNP的靶向遗传分析，MUNC13-4单倍型。 SNP数据将 然后与在特定目标2和3中确定的患者的临床表型相关。我们有 初步证据表明血清可溶性IL2受体A链（SLL2RA）和可溶性CD163的水平 （SCD163）可以反映MAS中T细胞和巨噬细胞的激活和扩展的程度，因此 用作早期诊断标记。特定目标2中的主要问题是升高的水平是否升高 SLL2RA和SCD163将与常规患者区分开公开和亚临床MAS患者 SJIA FLARE。特定目的3中的主要问题是，有MAS风险的SJIA患者是否代表了独特的 SJIA的亚型具有不同的过程，可以在SJIA发作时区分这些患者。长期 该建议的目标是了解导致MAS在SJIA发病率增加的途径， 定义MAS风险组，并制定监测和治疗此类患者的准则。