Development and Function of Natural Autoreactive B Cells

描述(由申请人提供)：虽然人们普遍认为B 具有自反应性的细胞被删除或在功能上不活动， 被称为“天然自身抗体”的自身反应性抗体 在健康动物的血清中，与克隆耐受性存在明显的矛盾 理论。VH36O9/VK 21C编码的抗胸腺细胞/T细胞自身抗体 生殖系基因就是这样一种天然抗体，来源于CD5+B细胞(B-1) 老鼠是天然自身抗体的主要来源 分泌物。ATA识别发育调节的T细胞特异性 胸腺细胞表达的Thy-L/CD90糖蛋白的糖链表位 辅助性T细胞。我们之前在VH36O9mU转基因小鼠(ATAmuTg)上的工作 证明ATA B细胞的产生和血清ATA的分泌 需要自身抗原，因为两者在Thy-1基因敲除小鼠中都不存在。在……里面 相比之下，骨髓B细胞强制表达ATA特异性 VH36O9mU/VK29C双转基因小鼠(ATAmuKTg) 正如我们最近的研究表明的那样，消极选择。在这里，我们建议调查 为什么会发生这种正面和负面的选择。通过刻画 VH36O9mU/VK29C双转基因小鼠(ATAmuKTg)，我们将鉴定 B细胞阳性/阴性选择发育期(S)(目标1)。至 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Thy-1(目标2)在目标3中，我们将测试积极选择是否是一种 胎儿“B-1”B细胞发育的独特性，偏向自然选择 自动反应特性。选择上存在差异的可能性 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建立一个更全面的 B细胞发育中的抗原受体谱系选择，并将测试我们的 假设自然自身反应性B细胞的产生是先天的一部分 免疫系统。“B-1”可能会主动产生某些自身反应性B细胞 对免疫保护至关重要，保存重要的淋巴细胞克隆以供 余生服务于免疫监测。

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.