Macrophage Activation Syndrome Biomarkers in Systemic Juvenile Idiopathic Art

项目总结。巨噬细胞激活综合征(MAS)的特征是 T细胞和嗜血巨噬细胞过度膨胀引起的炎症反应。Mas 与系统性青少年特发性关节炎(SJIA)密切相关。这是一种潜在的致命 但由于缺乏诊断标准，诊断很困难。在临床上相似的遗传 在疾病方面，过度的免疫反应被认为与细胞溶解功能缺陷有关。我们有 初步数据表明Munc13-4基因存在单核苷酸多态(SNP) 其产物参与细胞溶解颗粒的分泌。这些SNP等位基因似乎是遗传的 在大多数MAS患者中作为一种延伸的单倍型。因此，具体目标1的主要问题是 MUNC 13-4基因的遗传多态是否与sJIA的MAS相关，从而可能 帮助识别MAS的长期风险患者。在研究的这一部分中，将来自 将对大量sJIA患者(包括患有MAS的患者)和对照组进行检查，以确定是否存在 通过对有限数量的SNP进行靶向遗传分析，获得Munc13-4单倍型。苏格兰民族党的数据将 然后与特定目标2和3中确定的患者的临床表型联系起来。我们有 血清可溶性IL-2受体a链(SL2Ra)和可溶性CD163水平的初步研究 (SCD163)可能反映了MAS中T细胞和巨噬细胞的活化和扩张程度，从而 可作为早期诊断标记物。具体目标2中的主要问题是，升高的 SL2Ra和sCD163将区分显性和亚临床MAS患者与常规MAS患者 SJIA照明弹。具体目标3中的主要问题是sJIA患者是否有MAS的风险代表着一个独特的 病程不同的sJIA亚型，发病时可区分。从长远来看 这项提案的目标是了解导致sJIA中MAS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.