OK COBRE: FC RECEPTOR B LYMPHOCYTE SIGNALING IN LUPUS

OK COBRE：狼疮中 FC 受体 B 淋巴细胞信号传导

• 批准号: 6972160
• 负责人: Joel Marvin Guthridge
• 金额: $ 44.44万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972160
• 关键词: B lymphocyte; CD antigens; antibody receptor; autoimmunity; biological signal transduction; clinical research; disease /disorder etiology; female; gene expression; genetic polymorphism; genetic susceptibility; genotype; human data; human genetic material tag; immunogenetics; leukocyte activation /transformation; linkage mapping; microarray technology; patient oriented research; protein structure function; receptor expression; systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease. A strong genetic linkage at 1q23 and association results with lupus reveal the importance of the low-affinity Fc receptor family as genes for lupus susceptibility. Fc-gammaRIIb knock-out mouse studies and two separate, unpublished genetic association studies have implicated the Fc-gammaRIIb as a susceptibility gene for lupus. A polymorphism in the transmembrane domain of Fc-gammaRIIb alters lipid raft association and influences intracellular calcium and CD19 phosphorylation following B cell activation. Two promoter polymorphisms increased Fc-gammaRIIb expression and caused decreased intracellular calcium levels and decreased apoptosis. The effect of the Fc-gammaRIIb knockout in the mouse and the incompletely described enhancing effects of the human Fc-gammaRIIb polymorphisms strongly suggest possible involvement of Fc-gammaRIIb in lupus development by a yet to be described mechanism that we suspect involves the receptor activation pathway. The previous studies relied upon in vitro assays of recombinant Fc-gammaRIIb molecules transfected into model cell systems for characterization of Fc receptor functions. Although informative, these data do not allow us to fully appreciate the functional differences of these polymorphic Fc-gammaRIIb molecules in cells from actual lupus patients or matched normal controls. We will approach these important issues by utilizing the genetic and cellular resources from the OMRF lupus genetics group to directly assess the functional differences in Fc-gammaRIIb in B cells derived from lupus patients and normal matched controls. We propose that polymorphisms in both the Fc-gammaRIIb protein and the Fc-gammaRIIb promoter that alter Fc-gammaRIIb expression will result in functional differences in signaling through this receptor. We anticipate that these differences will be reflected in differences in B cell signaling responses upon engagement of the Fc-gammaRIIb, of the B cell receptor, or of co-engagement of both receptors. We will analyze B cell responses associated with Fc-gammaRIIb related signaling pathways in lupus cases and controls selected by strong 1q23 linkage and group them into signaling classes by type of B cell signaling responses resulting from Fc-gammaRIIb engagement. Genotypes of the signaling classes will be analyzed to determine if there is increased association with lupus. Gene expression or biochemical pathways associated with each signaling class will be assessed and used to identify genes that contribute to lupus susceptibility through epistatic or additive gene effects. Understanding the role of Fc-gammaRIIb in B cell activation will allow us to better explain lupus development and uncover novel therapeutic targets for this devastating disease.

系统性红斑狼疮 (SLE) 是一种复杂的多基因自身免疫性疾病。 1q23 处的强遗传连锁以及与狼疮的关联结果揭示了低亲和力 Fc 受体家族作为狼疮易感性基因的重要性。 Fc-gammaRIIb 敲除小鼠研究和两项独立的、未发表的遗传关联研究表明 Fc-gammaRIIb 是狼疮的易感基因。 Fc-gammaRIIb 跨膜结构域的多态性改变脂筏关联并影响细胞内钙和 CD19 B 细胞激活后磷酸化。两个启动子多态性增加了 Fc-gammaRIIb 表达，导致细胞内钙水平降低和细胞凋亡减少。 Fc-gammaRIIb 敲除对小鼠的影响以及未完全描述的人 Fc-gammaRIIb 多态性的增强作用强烈表明 Fc-gammaRIIb 可能通过尚未描述的机制参与狼疮发展 我们怀疑涉及受体激活途径。先前的研究依赖于转染至模型细胞系统中的重组 Fc-gammaRIIb 分子的体外测定，以表征 Fc 受体功能。尽管信息丰富，但这些数据并不能让我们充分了解这些多态性 Fc-gammaRIIb 分子在来自实际狼疮患者或匹配的正常对照细胞中的功能差异。我们将利用 OMRF 狼疮遗传学小组的遗传和细胞资源来直接评估狼疮患者 B 细胞中 Fc-gammaRIIb 的功能差异，从而解决这些重要问题 和正常匹配对照。我们认为，Fc-gammaRIIb 蛋白和 Fc-gammaRIIb 启动子中改变 Fc-gammaRIIb 表达的多态性将导致通过该受体的信号传导的功能差异。我们预计这些差异将反映在 Fc-gammaRIIb 接合、B 细胞受体接合或两种受体共同接合时 B 细胞信号传导反应的差异上。我们将分析狼疮病例和通过强 1q23 连接选择的对照中与 Fc-gammaRIIb 相关信号通路相关的 B 细胞反应，并根据 Fc-gammaRIIb 参与产生的 B 细胞信号反应类型将它们分为信号传导类别。将分析信号类别的基因型以确定与狼疮的关联是否增加。将评估与每个信号传导类别相关的基因表达或生化途径，并用于识别通过上位或加性基因效应导致狼疮易感性的基因。了解 Fc-gammaRIIb 在 B 细胞激活中的作用将使我们能够更好地解释 狼疮的发展并发现这种破坏性疾病的新治疗靶点。