Pathobiology of the Monomyelocytoid Cell Gene Expression Signature in SystemicJIA

项目总结（见说明）： 全身性幼年特发性关节炎（SJIA）患者约占所有JIA人群的10%，是儿童关节炎最独特的亚型。大多数区分SJIA与其他JIA亚型的外周血基因表达特征反映了单核细胞样细胞中先天免疫途径的激活。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，巨噬细胞激活综合征是一种危及生命的疾病，其特征是T细胞和噬血细胞巨噬细胞的过度激活和扩张导致压倒性的炎症反应。虽然公开的MAS是 30-50%的活动性SJIA患者可能发生相对罕见的轻度亚临床MAS。我们的基因表达研究表明，这些患者可以通过结合红细胞生成的强烈特征（最有可能反映了红细胞周转增加，以应对亚临床噬血细胞）和巨噬细胞分化的替代途径的强烈特征的基因表达模式来区分。考虑到SJIA的高度炎症性质和IFN-γ（一种通常驱动巨噬细胞分化（Ml）的经典促炎途径的细胞因子）的存在，在这种情况下IFN诱导的特征的缺失和交替活化的M2巨噬细胞的特征的出现是令人惊讶的。初步证据表明，SJIA中的巨噬细胞可能显示出对IFN-γ的反应性改变，使其分化偏向M2途径。因此，这些巨噬细胞可能具有不符合M1/M2范式的独特表型。由于MAS中的噬血细胞巨噬细胞强烈表达M2标记物GDI 63，我们假设与巨噬细胞分化的M2途径相关的途径也可能有助于SJIA中MAS的易感性。为了进一步探索这一点，我们将首先确认巨噬细胞分化的替代途径的强签名的存在确实鉴定了更有可能发展MAS的患者（Sp. Aim 1）。然后，我们将根据M1/M2极化进一步表征SJIA中循环单核细胞/巨噬细胞的表型（Sp. Aim 2）。最后，在特定目标3中，我们将确定临床前和成熟MAS中骨髓中巨噬细胞的表型，并评估其与特定目标2中确定的活性SJIA中循环单核细胞/巨噬细胞表型的重叠程度。该项目的长期目标是确定负责SJIA中MAS易感性发展的途径，并开发用于早期诊断这种危及生命的疾病的生物标志物。

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.