Pathobiology of the Monomyelocytoid Cell Gene Expression Signature in SystemicJIA

项目总结(见说明)： 系统性幼年特发性关节炎(SJIA)患者约占JIA总人口的10%，是儿童关节炎最明显的亚型。大多数区别于其他JIA亚型的外周血液基因表达特征反映了单核细胞样细胞中天然免疫途径的激活。SJIA的一个令人困惑的特征是与巨噬细胞激活综合征(MAS)密切相关，MAS是一种威胁生命的疾病，其特征是由T细胞和吞噬血细胞的过度激活和扩张引发的压倒性炎症反应。而显式MAS是 相对罕见的、轻微的亚临床MAS可能发生在30-50%的活动期SJIA患者中。我们的基因表达研究表明，这些患者的基因表达模式结合了红细胞生成的强烈特征(最可能反映了对亚临床吞噬血细胞反应的红细胞周转率增加)和巨噬细胞分化的替代途径的强烈特征。鉴于SJIA的高度炎症性质和干扰素-γ的存在，通常驱动巨噬细胞分化(Ml)的经典促炎途径的细胞因子-γ的存在，在这种情况下缺乏干扰素诱导的特征和出现选择性激活的M2巨噬细胞的特征是令人惊讶的。初步证据表明，SJIA中的巨噬细胞对干扰素-γ的反应性可能发生改变，使其分化倾向于M2途径。因此，这些巨噬细胞可能有一种独特的表型，不符合M1/M2范式。由于MAS中的巨噬细胞强烈表达M2标志物GDI63，我们推测与巨噬细胞分化的M2通路有关的偏向途径也可能与SJIA中MAS的易感性有关。为了进一步探索这一点，首先我们将确认巨噬细胞分化的替代途径的强烈信号的存在确实识别出更有可能发展为MAS的患者(Sp。目标1)。然后，我们将进一步根据M1/M2极化(Sp.目标2)。最后，在特定的目标3中，我们将检测临床前期和完全成熟的MAS患者骨髓中巨噬细胞的表型，并评估其与SJIA活动期SJIA患者循环单核/巨噬细胞表型重叠的程度。目的2.本项目的长期目标是确定导致SJIA患者MAS易感性的途径，并开发生物标记物用于这种危及生命的疾病的早期诊断。

PROJECT SUMMARY (See instructions): Systemic Juvenile Idiopathic Arthritis (SJIA) patients constitute about 10% of all JIA population and represent the most distinct subtype of childhood arthritis. Most peripheral blood gene expression signatures that distinguish SJIA from other JIA subtypes reflect activation of the innate immune pathways in monomyelocytoid cells. A perplexing feature of SJIA is a strong association with macrophage activation syndrome (MAS), a life-threatening condition characterized by an overwhelming inflammatory reaction driven by excessive activation and expansion of T cells and hemophagocytic macrophages. While overt MAS is relatively rare, mild subclinical MAS may be occurring in 30-50% of patients with active SJIA. Our gene expression studies suggest that these patients can be distinguished by a gene expression pattern that combines a strong signature of erythropoiesis (most likely reflecting an increased red blood cell turnover in response to subclinical hemophagocytosis) and a strong signature of the alternative pathway of macrophage differentiation. Given the highly inflammatory nature of SJIA and the presence of IFN-y, a cytokine that normally drives the classic pro-inflammatory pathway of macrophage differentiation (Ml), the absence of the IFN-induced signature and emergence of the features of alternatively activated M2 macrophages in this setting are surprising. Preliminary evidence suggests that macrophages in SJIA may show altered responsiveness to IFN-y skewing their differentiation towards the M2 pathway. As a result, these macrophages may have a unique phenotype that does not fit the M1/M2 paradigm. Since hemophagocytic macrophages in MAS strongly express GDI 63, an M2 marker, we hypothesize that the pathways associated with skewing towards the M2 pathway of macrophage differentiation may also contribute to predisposition to MAS in SJIA. To explore this further first we will confirm that the presence of a strong signature of the alternative pathway of macrophage differentiation indeed identifies patients who are more likely to develop MAS (Sp. Aim 1). We will then further characterize the phenotype of circulating monocytes/macrophages in SJIA in terms of M1/M2 polarization (Sp. Aim 2). Finally, in Specific Aim 3, we will determine the phenotype of the macrophages in the bone marrow in pre-clinical and full blown MAS and assess the extent of it's overlap with the phenotype of circulating monocytes/macrophages in active SJIA as determined in Sp. Aim 2. The long-term goal of this project is to identify pathways responsible for the development of MAS predisposition in SJIA and develop biomarkers for early diagnosis of this life-threatening condition.