IMMUNOREGULATORY MECHANISMS IN THE RHEUMATIC DISEASES

我们的长期目标是阐明免疫机制 其在自身免疫性结缔组织的发病机制中是重要的 疾病 我们最近有了新的观察，CD8+淋巴细胞 来自SLE患者的子集矛盾地维持抗体产生。 在 在下一个项目期间，我们将确定这些CD8+细胞是否发现 在正常人身上。 我们将了解这些细胞是否为B提供帮助 细胞激活或仅限于通过完全激活细胞来扩增抗体产生。 分化的B细胞。 使用正常人的淋巴细胞，我们将 测试假设，上调对抗体产生的影响， CD8+细胞反映了这些细胞的中间成熟阶段。 这 将通过用单克隆抗体激活单个CD8+来实现 针对细胞表面受体的抗体和确定条件 这使得它们能够增强或抑制抗体的产生。 信号 参与调节活动产生的转导途径 将被记录。 我们将研究细胞内游离 钙和配体特异性激活的蛋白激酶获得的 正常淋巴细胞的研究，我们将进行比较研究的CD8 + 来自SLE患者、家庭成员、不一致双胞胎对的淋巴细胞， 正常值以确定SLE细胞是否更容易成为放大器 而不是抑制剂。 或者，我们将确定是否过度 B细胞辅助和抑制活性受损是由于缺乏 终端所需的来自其它小区的信号 CD8+细胞的分化。 阐明特定信号， 诱导抑制或增强以及导致 它们在系统性红斑狼疮中的调节作用对于我们了解以下方面最有用 其他慢性炎症性疾病的发病机制。

Our long term objective has been to elucidate the immunologic mechanisms which are important in the pathogenesis of the autoimmune connective tissue diseases. We have recently made the novel observation that CD8+ lymphocyte subsets from SLE patients paradoxically sustain antibody production. In the next project period, we will determine whether these CD8+ cells found in normal subjects. We will learn whether these cells provide help for B cell activation or are limited to amplifying antibody production by fully differentiated B cells. Using lymphocytes from normal individuals, we will test the hypothesis that up-regulatory effects on antibody production by CD8+ cells reflect an intermediate maturation phase of these cells. This will be accomplished by activating individual CD8+ with monoclonal antibodies against cell surface receptors and determining the conditions which enable them to enhance or suppress antibody production. Signal transduction pathways involved in the generation of regulatory activities will be documented. We will study mobilization of intracellular free calcium and ligand specific activation of protein kinase gained from the study of normal lymphocytes, we will perform comparative studies of CD8+ lymphocytes from SLE patients, family members, discordant twin pairs and normals to determine whether SLE cells are more prone to become amplifiers instead of suppressors. Alternatively, we will determine whether excessive B cell help and impaired suppressor activity result from a deficiency of signals from other cells which are required for the terminal differentiation of CD8+ cells. Elucidation of the specific signals which induce suppression or enhancement and the biochemical mechanisms leading to their regulatory effects in SLE will be most useful in our understanding of the pathogenesis of other chronic inflammatory diseases.