MOLECULAR BASIS OF B CELL DYSFUNCTION IN SYSTEMIC LUPUS ERYTHEMATOSUS

易患系统性红斑狼疮的潜在分子缺陷和 明确其临床表现是发展所必需的 治疗这种系统性自身免疫性疾病的特殊新疗法。这 SCOR应用程序将利用以下方面的专业知识和密切合作 康奈尔附属纽约医院的调查人员以及 HSS的大量患者资源，以实现这一目标。在……里面 项目2，我们将研究控制T辅助细胞(Th)的分子- 和细胞因子介导的B细胞功能，这可能导致异常 系统性红斑狼疮的免疫调节和自身抗体的产生。我们最近做了 开发新的实验系统来研究B细胞的机制 激活和发挥作用。我们将利用这些化验方法来调查 系统性红斑狼疮的免疫调节异常。我们的具体目标是：1) 描述Th细胞介导的B细胞激活和 系统性红斑狼疮的分化。替代B细胞配体、Th细胞和 细胞因子将被用来研究SLE B细胞对 激活刺激。微生物超抗原(SA)将用于指导 TH细胞向目标B细胞发出信号。融合蛋白包含 共刺激分子的配体结合域将被用来破坏 同源Th-B细胞相互作用。2)。为了分析一种细胞因子模型- 正常受试者和非受试者B细胞活化的介导下调 SLE患者。抗原和Th细胞介导的B细胞的作用 激活信号，以及由各种细胞因子介导的信号 参与B细胞增殖的细胞癌基因(c-myc)和 凋亡抵抗(Bcl2)将在正常B细胞中被定义 人群，然后扩展到SLE患者。3)。详细分析 SLE B细胞自发产生IL-6的分子机制 一种与系统性红斑狼疮患者B细胞活性升高有关的细胞因子。装订 构成和诱导转录因子对IL-6基因的影响 我们将比较SLE和正常B细胞中的启动子。分子基础 对于转录因子表达或功能的任何缺陷 调查过了。4)。Th在体外和体内的作用 系统性红斑狼疮小鼠模型中细胞介导的B细胞活化。利用SA 而SA反应性Th细胞为同源T细胞提供帮助，我们将进行分析 非自身免疫性B细胞对NZB×NZW F1、MRL/++的体外应答 和MRL-LPR/LPR狼疮小鼠。含不同成分的融合蛋白的作用 重组SCID小鼠和完整自身免疫的共刺激分子 老鼠将在体内进行分析。

Definition of the underlying molecular defects that predispose to SLE and define its clinical manifestations is required for development of specific new therapeutics for this systemic autoimmune disease. This SCOR application will draw on the expertise and close collaboration among investigators at the Cornell affiliated New York Hospitals, as well as the extensive patient resources at HSS, to achieve this objective. In Project 2, we will study the molecules that control T helper cell (Th)- and cytokine-mediated B cell function and that may contribute to abnormal immunoregulation and autoantibody production in SLE. We have recently developed new experimental systems to study the mechanisms of B cell activation and function. We will utilize these assays to investigate immunoregulatory abnormalities in SLE. Our specific aims are: 1) To characterize abnormalities in Th cell-mediated B cell activation and differentiation in SLE. Surrogate B cell ligands, Th cells, and cytokines will be used to investigate the response of SLE B cells to activating stimuli. Microbial superantigens (SA) will be used to direct Th cells signals to the target B cells. Fusion proteins containing ligand binding domains of costimulatory molecules will be used to disrupt cognate Th-B cell interactions. 2). To analyze a model of cytokine- mediated downregulation of B cell activation in normal subjects and in patients with SLE. The effect of antigen- and Th cell-mediated B cell activation signals, as well as those mediated by various cytokines, on cellular oncogenes involved in B cell proliferation (c-myc) and resistance to apoptosis (bcl-2) will be defined in normal B cell populations, and then extended to SLE patients. 3). To analyze in detail the molecular mechanism of SLE B cell "spontaneous" production of IL-6, a cytokine implicated in increased B cell activity in SLE. The binding of constitutive and inducible transcription factors to the IL-6 gene promoter will be compared in SLE and normal B cells. The molecular basis for any defects in transcription factor expression or function will be investigated. 4). To characterize in vitro and in vivo the role of Th cell-mediated B cell activation in murine models of SLE. Utilizing SA and SA-reactive Th cells to provide cognate T cell help, we will analyze the in vitro response to B cells from nonautoimmune, NZB x NZW F1, MRL/++ and MRL-lpr/lpr lupus mice. The effect of fusion proteins containing costimulatory molecules on reconstituted SCID mice and intact autoimmune mice will be analyzed in vivo.