Pathobiology of PBMC Gene Expression Signatures in Polyarticular and Oligoarticul

我们已经确定了三个基因表达的签名，在外周血单核细胞（PBMC）从 最近发生的多关节和少关节幼年特发性关节炎（JIA）的儿童， 在病理生物学和临床结果方面具有明显差异的患者亚组。这些签名 包括：1）“单核细胞标签”，其主要由患有以下疾病的老年患者（a6岁）表达： 多发性关节炎，并与更严重的疾病和更频繁的抗TNF治疗有关 生物制剂; 2）也主要由老年多关节炎患者表达的“T细胞标签”，包含 涉及T细胞暴露于TGF β和其他促凋亡影响的基因，与 慢性活动性关节炎，并与几个假定的遗传标记的表达增加有关， JIA易感性（IGF 1 R、JMJD 1C和PTPN 2）;和3）由年轻的JIA患者表达的“B细胞标签”， （<6岁）患有少关节炎或多关节炎的患者，并且这些患者之间存在相似的病理学 两种JIA亚型。我们的过度假设是，这些PBMC特征检测具有以下特征的细胞： 在受到关节炎炎性环境的影响后进入循环，因此反映了 关节炎部位的病理活动。具体来说，我们假设1）单核细胞签名 检测参与和/或响应关节组织损伤的循环单核细胞; 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细胞活性;和3）B细胞 特征检测在发育中的B细胞库的背景下具有异常活性的循环B细胞 在6岁以下的儿童中。我们将在我们的具体目标中测试这些假设：1）识别孤立的差异 对应于总PBMC基因表达特征的差异表达的PBMC亚群，2） 评估PBMC基因表达特征与滑液病理学的关系，和3）鉴定基因 全血中PBMC特征的表达生物标志物替代物。从长远来看，我们认为， 对与这些PBMC特征相关的病理生物学的更好理解将导致新的分子生物学。 评估和预测关节炎活动的工具，将促进少关节和 多关节型JIA。 相关性（参见说明）： 我们已经确定了不同儿童亚组血细胞中基因表达的差异 青少年关节炎这些差异似乎反映了特定的疾病过程，这些疾病过程只在 患者的子集。我们进一步假设这些基因组可以作为“生物标志物”来评估 关节炎活动，并预测结果，如对特定药物的反应，在 未来，这最终将有助于改善青少年关节炎儿童的结果。

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.