T Cell Transcriptomes Describe Patient Subtypes in Systemic Lupus Erythematosus

BackgroundT cells regulate the adaptive immune response and have altered function in autoimmunity. Systemic Lupus Erythematosus (SLE) has great diversity of presentation and treatment response. Peripheral blood component gene expression affords an efficient platform to investigate SLE immune dysfunction and help guide diagnostic biomarker development for patient stratification.MethodsGene expression in peripheral blood T cell samples for 14 SLE patients and 4 controls was analyzed by high depth sequencing. Unbiased clustering of genes and samples revealed novel patterns related to disease etiology. Functional annotation of these genes highlights pathways and protein domains involved in SLE manifestation.ResultsWe found transcripts for hundreds of genes consistently altered in SLE T cell samples, for which DAVID analysis highlights induction of pathways related to mitochondria, nucleotide metabolism and DNA replication. Fewer genes had reduced mRNA expression, and these were linked to signaling, splicing and transcriptional activity. Gene signatures associated with the presence of dsDNA antibodies, low complement levels and nephritis were detected. T cell gene expression also indicates the presence of several patient subtypes, such as having only a minimal expression phenotype, male type, or severe with or without induction of genes related to membrane protein production.ConclusionsUnbiased transcriptome analysis of a peripheral blood component provides insight on autoimmune pathophysiology and patient variability. We present an open source workflow and richly annotated dataset to support investigation of T cell biology, develop biomarkers for patient stratification and perhaps help indicate a source of SLE immune dysfunction.背景 T细胞可调控适应性免疫应答，且在自身免疫病中功能发生改变。系统性红斑狼疮（Systemic Lupus Erythematosus，SLE）的临床表现与治疗应答具有高度异质性。外周血基因表达谱为研究SLE免疫功能异常提供了高效平台，有助于指导用于患者分层的诊断生物标志物开发。 方法 采用高深度测序技术对14例SLE患者及4例健康对照的外周血T细胞样本的基因表达水平进行分析。对基因与样本进行无偏聚类后，发现了与疾病病因学相关的新型表达模式。对这些基因进行功能注释后，明确了参与SLE发病的通路与蛋白质结构域。 结果 我们在SLE患者的T细胞样本中发现数百个基因的转录本表达水平发生持续性改变，通过DAVID分析显示这些基因富集于线粒体、核苷酸代谢及DNA复制相关通路。表达水平下调的基因数量较少，这些基因主要与信号转导、RNA剪接及转录活性相关。同时检测到与抗双链DNA（dsDNA）抗体阳性、补体水平降低及肾炎相关的基因特征。T细胞基因表达谱还提示存在多种患者亚型，例如仅表现为轻微表达表型、男性型，或严重型（伴或不伴膜蛋白生成相关基因的诱导表达）。 结论 对外周血组分进行无偏转录组分析，可为自身免疫病理生理学机制及患者异质性研究提供新视角。本研究提供了一套开源分析流程与注释丰富的数据集，可用于支持T细胞生物学研究、开发用于患者分层的生物标志物，或有助于阐明SLE免疫功能异常的潜在诱因。