Pathobiology of PBMC Gene Expression Signatures in Polyarticular and Oligoarticul

我们在人的外周血单个核细胞(PBMC)中发现了三个基因表达特征。 儿童新近发病的多关节和少关节幼年特发性关节炎(JIA) 病理生物学和临床结果有明显差异的患者亚群。这些签名 包括：1)主要由年龄较大(6岁)的患者表达的“单核细胞特征” 多发性关节炎，与更严重的疾病和更频繁的抗肿瘤坏死因子治疗有关 生物学；2)也主要在老年多发性关节炎患者中表达的“T细胞签名”，包含 与T细胞暴露于TGFp和其他促凋亡影响有关的基因与 慢性活动型关节炎，并与几个可能的遗传标志物表达增加有关 JIA易感性(IGF1R、JMJD1C和PTPN2)；以及3)由Young表达的“B细胞特征” (&lt；6岁)患有少关节炎或多发性关节炎的患者，并涉及这些患者之间的相似病理 两个JIA亚型。我们最重要的假设是，这些PBMC信号检测到具有 在受到关节炎炎症环境的影响后进入循环，从而反映 关节炎部位的病理活动。具体地说，我们假设1)单核细胞签名 检测参与和/或对关节组织损伤做出反应的循环单核细胞；2)T细胞 Signature检测关节炎关节中暴露于内源性机制的循环T细胞 旨在抑制关节炎症，如调节性T细胞活动；以及3)B细胞 Signature检测在发育中的B细胞库中具有异常活性的循环B细胞 在6岁以下的儿童中。我们将在我们的特定目标中测试这些假设：1)识别孤立的 与总PBMC基因表达特征的差异表达相对应的PBMC亚群，2) 评估PBMC基因表达特征与滑液病理的关系，以及3)确定基因 外周血单核细胞标志物在全血中的表达从长远来看，我们相信 提高对与这些PBMC信号相关的病理生物学的理解将导致新的分子 用于评估和预测关节炎活动的工具，将促进少关节和 多关节JIA。 相关性(请参阅说明)： 我们已经确定了不同亚组儿童血细胞中基因表达的差异。 患有幼年关节炎。这些差异似乎反映了特定的疾病过程，只有在 患者的亚群。我们进一步假设，这些基因可以被用作评估 目前的关节炎活动，并预测结果，如对特定药物的反应，在 这最终将有助于改善青少年关节炎儿童的预后。

We have identified three gene expression signatures in peripheral blood mononuclear cells (PBMC) from children with recent-onset polyarticular and oligoarticular juvenile idiopathic arthritis (JIA) that identify subsets of patients with apparent differences in pathobiology and clinical outcomes. These signatures include: 1) a "Monocyte Signature" that is predominantly expressed by older (a6 years) patients with polyarthritis, and is associated with greater disease severity and more frequent treatment with anti-TNF biologies; 2) a "T Cell Signature" that is also predominantly expressed by older polyarthritis patients, contains genes that implicate T cell exposure to TGFp and other pro-apoptotic influences, is associated with chronically active arthritis, and is associated with increased expression of several putative genetic markers of JIA susceptibility {IGF1R, JMJD1C and PTPN2); and 3) a "B Cell Signature" that is expressed by younger (<6 years) patients with either oligoarthritis or polyarthritis, and implicates similar pathology between these two JIA subtypes. Our over-arching hypothesis is that these PBMC signatures detect cells that have entered the circulation after being influenced by arthritic inflammatory milieus, and therefore reflect pathological activity at sites of arthritis. Specifically, we hypothesize that 1) the Monocyte Signature detects circulating monocytes that have participated in and/or responded to joint tissue damage; 2) the T Cell Signature detects circulating T cells that have been exposed to endogenous mechanisms in arthritic joints that are aimed at suppressing joint inflammation, such as regulatory T cell activity; and 3) the B Cell Signature detects circulating B cells with abnormal activity in the context of the developing B cell repertoires in children under age 6. We will test these hypotheses in our Specific Aims: 1) Identify differences in isolated PBMC subsets that correspond to differential expression of total PBMC gene expression signatures, 2) assess relationships of PBMC gene expression signatures to synovial fluid pathology, and 3) identify gene expression biomarker surrogates of PBMC signatures in whole blood. In the long-term, we believe that improved understanding of pathobiology associated with these PBMC signatures will lead to novel molecular tools for assessing and predicting arthritis activity that will advance clinical management of oligoarticular and polyarticular JIA. RELEVANCE (See instructions): We have identified differences in expression of sets of genes in blood cells among sub-groups of children with juvenile arthritis. These differences appear to reflect specific disease processes that are only active in subsets of patients. We further hypothesize that these sets of genes can be used as "biomarkers" to assess arthritis activity in the present, and predict outcomes, such as response to particular medications, in the future, which ultimately will help improve the outcomes of children with juvenile arthritis.