B CELLS IN MURINE SLE

小鼠 SLE 中的 B 细胞

• 批准号: 2683290
• 负责人: ROBERT A. EISENBERG
• 金额: $ 20.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-06-30 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683290
• 关键词: B lymphocyte; CD95 molecule; T lymphocyte; antibody formation; autoantibody; autoimmunity; cell cell interaction; cell population study; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; gene expression; genetic strain; laboratory mouse; systemic lupus erythematosus; tissue mosaicism

Lpr and gld are single, recessive, autosomal genes which are non- complementary and which each induce similar syndromes of systemic autoimmunity and lymphoproliferation. The lpr gene has recently been determined to code for a defective form of the Fas apoptosis receptor, while the gld codes for a defective form of the Fas ligand. By using mixed cellular chimeras of congenic mouse strains, we have previously demonstrated that both the B cells and T cells in lpr mice express intrinsic abnormalities that are essential to the autoimmune syndrome. In parallel experiments with gld mice, we have found that in gld/+ mixed chimeras, the gld B cells do not show the striking preferential production of immunoglobulins and autoantibodies found in lpr/+ double chimeras, nor does lymphadenopathy occur. This indicates that the gld defect is extrinsic to the B cells that produce autoantibodies and the T cells that hyperaccumulate in this model. Further data have suggested that the Fas ligand may function in an autocrine manner as well. In the present application, we will determine the cellular source of the normal presumed Fas ligand that is supplied by the co-transferred +/+ bone marrow and determine the specificity of Fas/Fas ligand interaction. The Specific Aims of the current proposal are: l) Does the expression of Fas ligand by B cells suppress gld disease? Although our preliminary data suggest that the answer to this question is "no," we have reservations regarding this conclusion. The proposed experiments will clarify this important issue. 2) What specific cell types produce the Fas ligand? The phenotype of the cells will clarify this important issue. 3) What is the specificity of the cells involved in Fas/Fas ligand interactions? If direct cell-cell communication is required (rather than the release of a soluble factor), we should be able to define the antigenic or receptor specificity of the Fas ligand bearing cell. 4)What cell populations express Fas ligand protein? An antibody to Fas ligand will be produced and use to detect cell-surface expression. These studies will thus help elucidate the in vivo functional effects of Fas/Fas ligand interactions in immunoregulation and tolerance induction. This understanding of the mechanism of action of the lpr and gld genetic defects will focus future research aimed at elucidating the causal mechanisms of human SLE.

LPR和GLD是单一的，隐性的常染色体基因，是非 - 互补，每种都会引起类似的全身综合症 自身免疫性和淋巴增生。 LPR基因最近 确定为FAS凋亡受体的缺陷形式编码， 而GLD代码为FAS配体的缺陷形式。通过使用 优质小鼠菌株的混合细胞嵌合体，我们以前有 证明LPR小鼠中的B细胞和T细胞都表达 对自身免疫综合征必不可少的固有异常。 在与GLD小鼠的并行实验中，我们发现在GLD/+中 混合嵌合体，GLD B细胞没有显示出惊人的优先 LPR/+ Double中发现的免疫球蛋白和自身抗体的产生 嵌合体，也没有发生淋巴结肿大。这表明GLD 缺陷是产生自身抗体的B细胞外部的， 在此模型中超积聚的T细胞。进一步的数据提出了 FAS配体也可能以自分泌方式起作用。在 目前的应用，我们将确定 共同转移 +/ +提供的正常假定FAS配体 骨髓并确定FAS/FAS配体的特异性 相互作用。当前建议的具体目的是：l） B细胞表达FAS配体会抑制GLD疾病？虽然我们的 初步数据表明，这个问题的答案是“否”，我们 对此结论有保留。提出的实验 将澄清这个重要的问题。 2）哪些特定细胞类型产生 FAS配体？细胞的表型将阐明这一点 问题。 3）涉及FAS/FAS的细胞的特异性是什么 配体相互作用？如果需要直接的细胞通信 （而不是发布可溶性因素），我们应该能够 定义FAS配体轴承的抗原或受体特异性 细胞。 4）哪些细胞群表达FAS配体蛋白？抗体 将产生FAS配体并用于检测细胞表面 表达。 因此，这些研究将有助于阐明体内功能效应 免疫调节和公差中的FAS/FAS配体相互作用 就职。对LPR和LPR作用机制的理解 GLD遗传缺陷将集中于未来的研究，旨在阐明 人SLE的因果机制。