Neutrophils in Lupus Pathogenesis

中性粒细胞在狼疮发病机制中的作用

• 批准号: 7663883
• 负责人: Maria Virginia Pascual
• 金额: $ 34.18万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663883
• 关键词: Apoptosis; Autoantigens; Autoimmune Responses; Child; Data; Dendritic Cells; Development; Disease; Disease Marker; Gene Expression; Genes; Goals; Hypergammaglobulinemia; Interferon-alpha; Kidney; Kidney Diseases; Lupus; Lupus Nephritis; Medical; Myelogenous; Pathogenesis; Pathology; Patients; Play; Proteins; Role; Serum; Source; System; Systemic Lupus Erythematosus; T-Lymphocyte; Transcript; density; neutrophil; plasma cell differentiation; response

SLE is a particularly aggressive disease in children, and represents an unmet medical need. We have found that SLE is characterized by major alterations in the dendritic cell system where uncontrolled IFN alpha release drives unabated activation/maturation of myeloid DCs. We have also found that IFN-alpha is a powerful inducer of plasma cell differentiation and survival possibly contributing to the hypergammaglobulinemia observed in SLE patients. Finally, using global gene expression analyses of SLE PBMCs we have identified clusters of differentially expressed genes i) induced by IFN-alpha. ii) expressed by low density immature and mature neutrophils. We have determined that the expression of neutrophil-specific genes 1) correlates with SLE disease activity, 2) allows to discriminate patients with and without lupus nephritis (LN), and 3) predicts the development of LN. These data support that neutrophils play an important role in the pathogenesis of SLE and in the induction of renal disease. Therefore, the goals of the present application are to i) further define the role of neutrophil-encoded transcripts and proteins as markers of disease activity and predictors of response to therapy, ii) to identify the serum factors responsible for the activation/apoptosis of SLE neutrophils, iii) to determine whether neutrophils represent a source of self-antigens for dendritic cells to be presented to T cells and drive autoimmune responses, and iv) to establish the direct role of neutrophils in kidney pathology. Ultimately these studies will further our understanding of SLE pathogenesis and help us develop better therapies to treat SLE patients.

SLE是儿童特别侵略性疾病，代表了未满足的医疗需求。我们有 发现SLE的特征是在树突状细胞系统中发生了重大变化，而IFN不受控制 Alpha释放驱动髓样DC的不减弱/成熟。我们还发现IFN-Alpha是 浆细胞分化和生存的强大诱导剂可能有助于 在SLE患者中观察到高γ-球素血症。最后，使用SLE的全局基因表达分析 PBMC我们已经确定了由IFN-α引起的差异表达基因的簇。 ii）表示 通过低密度不成熟和成熟的中性粒细胞。我们已经确定中性粒细胞特异性的表达 基因1）与SLE疾病活动相关，2）允许区分有或没有的患者 狼疮肾炎（LN）和3）预测LN的发展。这些数据支持中性粒细胞发挥 在SLE的发病机理和肾脏疾病的诱导中的重要作用。 因此，本应用的目标是i）进一步定义中性粒细胞编码的作用 成绩单和蛋白质作为疾病活动的标志物和对治疗反应的预测指标，ii）确定 负责SLE中性粒细胞激活/凋亡的血清因子，iii）是否确定是否是否 中性粒细胞代表了将树突状细胞呈现给T细胞的自我抗原来源，并驱动 自身免疫反应，以及iv），以确定中性粒细胞在肾脏病理学中的直接作用。最终 这些研究将进一步了解SLE发病机理，并帮助我们开发更好的疗法 治疗SLE患者。