T CELL CYTOLYTIC ACTIVITY IN SLE

本提案考虑以下工作模型来解释如何 多克隆T细胞刺激可促进人SLE。1)当然- 发生的环境因素可以触发体内多克隆T细胞 激活所有主机。2)这种多克隆T细胞活化通常 导致辅助性T细胞的多克隆活化， 下调T细胞。3)多克隆激活的辅助性T细胞 有能力促进许多细胞的活化和分化（如果 不是所有的）B细胞，包括那些能够产生致病性 自身抗体4)多克隆激活的下调性T细胞 至少部分地抵消这种自身免疫促进反应， 通过物理裂解对多克隆IG生产至关重要的细胞 （包括B细胞本身）。5)小的CD 8 +56+ T 细胞亚群是这种多克隆的主要效应子。 下调CTL活性。6)多克隆下调CTL活性 在SLE中，由CD 8 +56+ T细胞介导的免疫应答受损， 细胞的存活对多克隆IG的产生至关重要， 相关B细胞产生致病性 自身抗体7)CTL缺陷是SLE的易感因素 发病机制 本提案将在此基础上重点讨论4个具体问题 模型1)正常的CD 8 +56+ T细胞是否有效下调多克隆IG 这种CD 8 +56+ T细胞介导的下调是否受损 在SLE？2)正常的下调CD 8 +56+ T细胞是如何产生的， SLE有哪些缺陷？3)正常的CD 8 +56+ T细胞如何影响 它们的下调，SLE的缺陷是什么？4)SLE是否 CD 8 +56+ T细胞的缺陷早于明显的临床疾病的发作？ 这些问题的答案应该能很好地说明 人类系统性红斑狼疮的基本致病性免疫紊乱。

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.