T CELL CYTOLYTIC ACTIVITY IN SLE

本提案考虑了以下工作模式来解释如何 多克隆T细胞刺激可促进人类SLE的发生。1)自然- 发生的环境因素可在体内触发多克隆T细胞 在所有主机中激活。2)这种多克隆T细胞正常激活 导致辅助T细胞和辅助性T细胞的多克隆激活 下调调节的T细胞。3)多克隆激活的辅助性T细胞 有能力促进激活和区分多个(如果 并非全部)B细胞，包括那些能够产生致病的B细胞 自身抗体。4)多克隆激活的下调调节T细胞 平衡这种促进自身免疫的反应，至少在一定程度上， 通过物理裂解对多克隆免疫球蛋白生产至关重要的细胞 (包括B细胞本身)。5)数值较小的CD8+56+T 细胞亚群是这种多克隆的主要效应者。 下调CTL活性。6)多克隆下调CTL活性 系统性红斑狼疮患者CD8+56+T细胞介导功能受损 对多克隆免疫球蛋白产生和增强至关重要的细胞的存活 相关B细胞产生致病作用的机会 自身抗体。7)CTL缺陷是SLE的易感因素 发病机制。 本提案将在此工作的基础上重点讨论4个具体问题 模特。1)正常CD8+56+T细胞是否能有效下调多克隆Ig 产生，这种CD8+56+T细胞介导的下调是否受损 在SLE中？2)正常的下调CD8+56+T细胞是如何产生的，以及 系统性红斑狼疮有哪些缺陷？3)正常的CD8+56+T细胞如何影响 系统性红斑狼疮的缺陷是什么？ CD8+56+T细胞缺陷是否早于临床表现？ 这些问题的答案应该对以下问题有相当大的启发 人类系统性红斑狼疮的基本致病免疫紊乱。

This proposal considers the following working model to explain how polyclonal T cell stimulation can promote human SLE. 1) Naturally- occurring environmental agents can trigger in vivo polyclonal T cell activation in all hosts. 2) Such polyclonal T cell activation normally results in polyclonal activation of both helper T cells and downregulatory T cells. 3) The polyclonally activated helper T cells have the capacity to promote activation and differentiation of many (if not all) B cells, including those capable of producing pathogenic autoantibodies. 4) The polyclonally activated downregulatory T cells counterbalance this autoimmunity-promoting response, at least in part, via physical lysis of cells crucial to polyclonal Ig production (including the B cells themselves). 5) The numerically small CD8+56+ T cell subset is the predominant effector of this polyclonal downnregulatory CTL activity. 6) Polyclonal downregulatory CTL activity mediated by CD8+56+ T cells is impaired in SLE, allowing for enhanced survival of the cells crucial to polyclonal Ig production and enhanced opportunity for the relevant B cell to produce pathogenic autoantibodies. 7) The CTL defect is a predisposing factor in SLE pathogenesis. This proposal will focus on 4 specific questions based on this working model. 1) Do normal CD8+56+ T cells potently downregulate polyclonal Ig production, and is such CD8+56+ T cell-mediated downregulation impaired in SLE? 2) How are normal downregulatory CD8+56+ T cells generated, and what are the defects in SLE? 3) How do normal CD8+56+ T cells effect their downregulation, and what is the defect in SLE? 4) Does the SLE defect in CD8+56+ T cells antedate onset of overt clinical disease? The answers to these questions should shed considerable light on fundamental pathogenetic immune disturbances in human SLE.