Development and Function of Natural Autoreactive B Cells

描述（由申请人提供）：尽管普遍认为B 具有自身反应性的细胞被删除或使其功能失活， 自身反应性抗体，被称为“天然自身抗体”，可以被发现 在健康动物的血清中，与克隆耐受性明显矛盾， 理论VH 36 O 9/VK 21 C编码的抗胸腺细胞/T细胞自身抗体 生殖系基因是这样一种天然抗体，来源于CD 5 + B细胞（B-1）， 小鼠，主要负责天然自身抗体的群体 分泌物ATA识别发育调节的T细胞特异性 胸腺细胞上表达的Thy-1/CD 90糖蛋白上的碳水化合物表位， 辅助性T细胞我们先前对VH 36 O 9 mu转基因小鼠（ATAmuTg）的研究 证明ATA B细胞的产生和血清ATA的分泌 需要自身抗原，因为这两者在Thy-1敲除小鼠中均不存在。在 相比之下，ATA特异性的强制表达是由骨髓B细胞引起的， VH 3609 mu/VK 29 C双转基因小鼠（ATAmuKTg）主要导致 正如我们最近的研究所表明的那样。在这里，我们建议调查 为什么会发生这种正选择和负选择通过表征 VH 36 O 9 mu/VK 29 C双转基因小鼠（ATAmuKTg），我们将鉴定 B细胞阳性/阴性选择的发育阶段（目的1）。到 研究抗原形式是否对阳性/阴性选择至关重要，我们 将建立Thy-1转基因小鼠系，表达跨膜或 分泌型Thy-1（Aim 2）在Aim 3中，我们将测试阳性选择是否是 胎儿“B-1”B细胞发育的独特特征， 自身反应特异性选择差异的可能性 将测试“B-1”与“B-2”B细胞发育之间的阈值（目标3）。 实现这些目标将有助于更全面地了解 抗原受体库的选择在B细胞的发展，并将测试我们的 假设天然自身反应性B细胞生成是先天性免疫缺陷的一部分， 免疫系统“B-1”可主动产生某些自身反应性B细胞 对免疫保护至关重要，保留重要的淋巴细胞克隆， 在免疫监测中发挥作用。

DESCRIPTION (provided by applicant): Although it is widely accepted that B cells with self-reactivity are deleted or rendered functionally inactive, self-reactive antibodies, referred to as "natural autoantibodies," can be found in the serum of healthy animals, in an apparent paradox to the clonal tolerance theory. An anti-thymocyte/T cell autoantibody (ATA) encoded by VH36O9/VK 21C germline genes is such a natural antibody, derived from CD5+ B cells (B-1) in mice, the population predominantly responsible for natural autoantibody secretion. ATA recognizes a developmentally regulated T cell specific carbohydrate epitope on the Thy-l/CD90 glycoprotein expressed on thymocytes and helper T cells. Our previous work with VH36O9mu transgenic mice (ATAmuTg) demonstrated that the generation of ATA B cells and the secretion of serum ATA required self-antigen, since both were absent from Thy-1 knockout mice. In contrast, forced expression of ATA specificity by the bone marrow B cells in VH36O9mu/VK29C double transgenic mice (ATAmuKTg) results in predominantly negative selection as our recent study suggests. Here we propose to investigate why this positive versus negative selection occurs. By characterizing VH36O9mu/VK29C double transgenic mice (ATAmuKTg), we will identify the developmental stage(s) of B cell positive/negative selection (Aim 1). To investigate if the antigen form is critical for positive/negative selection, we will establish Thy-1 transgenic mouse lines expressing either transmembrane or secreted Thy-1 (Aim 2) In Aim 3 we will test whether positive selection is a unique feature of fetal "B-1" B cell development, selecting in favor of natural autoreactive specificities. The possibility of differences in selection threshold between "B-1" versus "B-2" B cell development will be tested (Aim 3). Accomplishing these aims will help to establish a more complete picture of antigen receptor repertoire selection in B cell development and will test our hypothesis that natural autoreactive B cell generation is a part of the innate immune system. "B-1" may actively produce certain autoreactive B cells essential for immune protection, preserving important lymphocyte clones for the rest of life to serve in immunologic surveillance.