ROLE OF CD21/CD35 IN REGULATING SELF-REACTIVE B CELLS

CD21/CD35 在调节自身反应性 B 细胞中的作用

基本信息

批准号：
6632589
负责人：
THOMAS J SCHNEIDER
金额：
$ 5.01万
依托单位：
IMMUNE DISEASE INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6632589
关键词：
B lymphocyte CD antigens apoptosis autoantibody autoimmunity biological signal transduction bone marrow chimeric proteins complement receptor dendritic cells gene expression genetically modified animals immune tolerance /unresponsiveness laboratory mouse liver mutant organ culture protein structure function

项目摘要

Long known to be critical for innate immunity, the role of Cr1 and 2 in the adaptive immune response was solidified by experiments using Cr2-/- mice (which lack both receptors as they are encoded at a single locus, Cr2.) These mice showed a profound defect in response to T-dependent foreign Ag. Recent insight gained from these mice suggests that the regulation of self-reactive B cells in these mice is also perturbed. Specifically, mice lacking CRsl/2 fail to maintain tolerance to a model self-Ag, HEL (the HEL/anti-HEL Tg mouse model permits the study of B cells that are functionally inactive or anergic). In addition, breeding these animals to B6/lpr accelerated their progression to SLE-like disease. C4 null mice showed a similar phenotype as the Cr2-/-, suggesting an explanation to the long-standing paradox that C4 deficiency predisposes to SLE (in humans): normally targeting of ubiquitous complement-coated self-Ags to CRexpressing resident FDCs permits deletion or functional inactivation of self-reactive B cells. To test this hypothesis, I propose to: 1) Determine which cell type must express CR1 for the maintenance of tolerance; 2) Determine whether the co-receptor signaling capability of CR1 is necessary for the same, and; 3) Test whether developing B cells are anergized in the BM after targeting of self Ags to this tissue.

长期以来，Cr1 和 2 对先天免疫至关重要，而 Cr2-/- 小鼠（由于它们在单个位点 Cr2 上编码，因此缺乏这两种受体）的实验证实了 Cr1 和 2 在适应性免疫反应中的作用。这些小鼠显示对 T 依赖的外来 Ag 的反应存在严重缺陷。最近从这些小鼠身上获得的见解表明，这些小鼠中自身反应性 B 细胞的调节也受到干扰。具体地，缺乏CRs1/2的小鼠无法维持对模型自身Ag、HEL的耐受性（HEL/抗HEL Tg小鼠模型允许研究功能失活或无能的B细胞）。此外，将这些动物饲养到 B6/lpr 加速了它们向 SLE 样疾病的进展。 C4缺失小鼠表现出与Cr2-/-相似的表型，这对C4缺乏易患SLE（人类）这一长期存在的悖论提出了解释：通常将普遍存在的补体包被的自身抗原靶向CR表达的驻留FDC，从而允许删除或自身反应性 B 细胞的功能失活。为了检验这个假设，我建议：1）确定哪种细胞类型必须表达 CR1 以维持耐受性； 2) 确定CR1的辅助受体信号传导能力是否是必需的，并且； 3) 测试在将自身抗原靶向该组织后，BM 中发育中的 B 细胞是否被激活。