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是单基因，隐性，常染色体非显性遗传 互补的，每一个都引起类似的全身综合征 自身免疫和淋巴增生。lpr基因最近被 确定编码缺陷形式的Fas凋亡受体， 而gld编码Fas配体的缺陷形式。通过使用 同源小鼠品系的混合细胞嵌合体，我们以前 表明lpr小鼠的B细胞和T细胞都表达 自身免疫综合征的内在异常 在对gld小鼠的平行实验中，我们发现在gld/+ 在混合嵌合体中，gld B细胞没有显示出显著的优先性， 在lpr/+双抗体中发现的免疫球蛋白和自身抗体的产生 嵌合体，也不发生淋巴结病。这表明政府物流服务署 缺陷对于产生自身抗体的B细胞是外在的， 在这个模型中过度积累的T细胞。进一步的数据表明， Fas配体也可能以自分泌的方式发挥作用。在 在本申请中，我们将确定细胞来源。 正常的假定Fas配体，由共转移的+/+ 检测Fas/Fas配体的特异性 互动目前建议的具体目标是：1） B细胞表达Fas配体抑制gld病？虽然我们的 初步数据表明，这个问题的答案是“不”，我们 对这一结论持保留意见。拟议的实验 将澄清这一重要问题。2)哪些特定的细胞类型产生 Fas配体细胞的表型将阐明这一重要的 问题. 3)Fas/Fas参与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间通信， （而不是释放可溶性因子），我们应该能够 定义携带Fas配体的抗原或受体特异性 cell. 4)哪些细胞表达Fas配体蛋白？的抗体 Fas配体将被产生并用于检测细胞表面 表情 因此，这些研究将有助于阐明体内功能效应 Fas/Fas配体相互作用在免疫调节和免疫耐受中的作用 诱导这种对lpr作用机制的理解， gld基因缺陷将集中在未来的研究，旨在阐明 人类SLE的致病机制。