B CELLS IN MURINE SLE

LPR和GLD是单基因、隐性基因、常染色体基因，不是 相辅相成，每一种都会导致类似的全身性症状 自身免疫和淋巴组织增殖。LPR基因最近一直是 被确定为Fas凋亡受体的缺陷形式的编码， 而GLD编码有缺陷形式的Fas配体。通过使用 同种小鼠品系的混合细胞嵌合体，我们之前已经 证实LPR小鼠体内的B细胞和T细胞均表达 对自身免疫综合症至关重要的内在异常。 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细胞没有表现出明显的优势 在LPR/+双链中发现免疫球蛋白和自身抗体的产生 嵌合体，也不会发生淋巴结病。这表明，GLD 缺陷是产生自身抗体的B细胞的外在缺陷， 在这个模型中过度聚集的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 目前的应用，我们将确定细胞来源的 正常的假定Fas配体，由共转移的+/+提供 检测Fas/Fas配体的特异性 互动。目前提案的具体目的是：L)做 B细胞表达Fas配体抑制GLD疾病？虽然我们的 初步数据显示，这个问题的答案是否定的，我们 对这一结论持保留态度。拟议中的实验 将澄清这一重要问题。2)特定的细胞类型产生什么 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 配基相互作用？如果需要直接小区间通信 (而不是释放可溶性因子)，我们应该能够 确定Fas配体的抗原性或受体特异性 手机。4)哪些细胞群表达Fas配体蛋白？一种抗体 制备TO-Fas配体并用于检测细胞表面 表情。 这些研究将有助于阐明在体内的功能效应。 Fas/Fas配体相互作用在免疫调节和耐受中的作用 归纳法。这种对LPR和LPR作用机制的理解 GLD基因缺陷将成为未来研究的重点，旨在阐明 人类系统性红斑狼疮的病因机制。

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.