Macrophage Activation Syndrome Biomarkers in Systemic Juvenile Idiopathic Art

项目摘要。巨噬细胞活化综合征（MAS）的特点是压倒性的 由T细胞和噬血细胞巨噬细胞过度扩增驱动的炎症反应。MAS 与全身性幼年特发性关节炎（sJIA）密切相关。这是一个潜在的致命 条件，但由于缺乏诊断标准，诊断困难。在临床上类似的遗传 在疾病中，夸大的免疫应答与细胞溶解功能缺陷有关。我们有 初步数据表明MUNC 13 -4基因中存在单核苷酸多态性（SNP） 其产物参与溶细胞颗粒的分泌。这些SNP等位基因似乎是遗传的 在大多数MAS患者中作为扩展单倍型。因此，具体目标1的主要问题是 MSP 13-4基因的遗传多态性是否与sJIA中的MAS相关，因此， 帮助识别有MAS长期风险的患者。在研究的这一部分中， 将检查sJIA患者（包括MAS患者）和对照的大队列是否存在以下情况： MUNC 13 -4单倍型通过有限数量的SNPs的靶向遗传分析。SNP数据将 然后与特定目的2和3中确定的患者的临床表型相关联。我们有 初步证据表明，可溶性IL 2受体α链（sIL 2 Ra）和可溶性CD 163 （sCD 163）可反映MAS中T细胞和巨噬细胞的活化和扩增程度， 作为早期诊断指标。具体目标2的主要问题是， sIL 2 Ra和sCD 163将区分具有明显和亚临床MAS的患者与具有常规MAS的患者。 sJIA耀斑。具体目标3中的主要问题是，有MAS风险的sJIA患者是否代表了一种独特的 sJIA的亚型具有不同的过程，并且这些患者可以在sJIA发作时被区分。的长期 该提案的目的是了解导致sJIA中MAS发病率增加的途径， 确定MAS风险组，并制定监测和治疗此类患者的指南。

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.