IMMUNOREGULATORY MECHANISMS IN THE RHEUMATIC DISEASES

我们的长期目标是阐明免疫机制。 它们在自身免疫结缔组织的发病机制中起重要作用 疾病。我们最近做了一项新的观察，CD8+淋巴细胞 来自SLE患者的亚群矛盾地维持着抗体的产生。在……里面 在下一个项目期，我们将确定这些CD8+细胞是否发现 在正常受试者中。我们将了解这些细胞是否为B细胞提供帮助 细胞激活或仅限于通过充分 分化的B细胞。使用正常人的淋巴细胞，我们将 检验这样一种假设，即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 将通过用单抗激活单个CD8+来实现 抗细胞表面受体抗体及其条件的测定 这使它们能够增强或抑制抗体的产生。讯号 参与调节活动产生的转导途径 都会被记录在案。我们将研究细胞内游离的动员 钙离子和配体特异性激活的蛋白激酶 正常淋巴细胞的研究，我们将进行CD8+的比较研究 来自SLE患者、家庭成员、不和谐双胞胎和 正常以确定SLE细胞是否更容易成为扩增器 而不是抑制者。或者，我们将确定是否过度 B细胞的帮助和抑制活性受损是由于缺乏 来自终端所需的其他小区的信号 CD8+细胞的分化。对特定信号的阐明 诱导抑制或增强及其导致的生化机制 它们在系统性红斑狼疮中的调节作用将对我们理解 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.