ANTISM B CELL REGULATION

描述(改编自《调查员摘要》)：主要目标 这位研究者的目的是了解抗Sm的调节和 抗单链DNA B细胞在正常小鼠中的表达 自身免疫小鼠对这些抗原的耐受性丧失的阶段。 对Sm和ssDNA的应答是人类SLE和MRL/MP-LPR/LPR的特征 (MRL/LPR)自发发展成类SLE疾病的小鼠。我们有 利用H链基因重排获得Ig H链转基因(TG)小鼠 编码针对Sm和单链DNA的抗体。这些老鼠长得很大 脾抗Sm和抗ssDNA B细胞的数量，但不自发 分泌自身抗体。因此，它们在外围受到监管，但 这一机制似乎与迄今所描述的任何机制都不同。这个 研究人员提出，这些细胞在#年后期被消灭。 B细胞分化，在未成熟的B细胞向A细胞的转变过程中 成熟的B细胞。在目标1中，他将测试这一假设的预测，使用 双转基因小鼠，其中每个B细胞具有相同的特异性和亲和力 对于Sm.在这些Ig TG小鼠中存在功能性的抗Sm T细胞，并且 因此，在目标2中，他将确定排斥是否依赖于Fas和 T细胞介导的。在第三个目标中，他将检验这一假设 产生耐受信号的强度受响应调节器的影响 CD19和CD22。这将通过更改可用的 将抗Sm-TG小鼠与CD19-TG和CD22杂交，获得这些蛋白质 基因敲除老鼠。在第四个目标中，他将使用逆转录病毒基因转移来 在小鼠骨髓中引入SMD基因，以检验以下假设 MRL/LPR小鼠B细胞耐受缺陷仅在排斥状态下才明显 来自成熟的B细胞亚群，而不是其他形式的B细胞耐受， 中枢缺失或无能。他将导致抗Sm抗体的中心缺失 在MRL/LPR小鼠中的B细胞，并确定这是否阻止自发的 抗Sm反应的发展。

DESCRIPTION (Adapted from Investigator's abstract): The principal objective of this investigator is to understand the regulation of anti-Sm and anti-single stranded (ss) DNA B-cells in normal mice, and to identify the stage at which tolerance to these antigens is lost in autoimmune mice. Responses to Sm and ssDNA are characteristic of human SLE and MRL/Mp-lpr/lpr (MRL/lpr) mice that spontaneously develop an SLE-like disease. We have generated Ig H chain Transgenic (Tg) mice using a H chain gene rearrangement that encodes antibodies specific for Sm and ssDNA. These mice develop large numbers of splenic anti-Sm and anti-ssDNA B-cells, but do not spontaneously secrete autoantibody. Thus, they are regulated in the periphery, but the mechanism appears to be different from any so-far described. The investigator proposes that these cells are eliminated at a late stage in B-cell differentiation, during the transition from an immature B-cell to a mature B-cell. In Aim 1, he will test predictions of this hypothesis using double Tg mice in which every B-cell has the same specificity and affinity for Sm. Functional anti-Sm T-cells are present in these Ig Tg mice, and therefore in Aim 2 he will determine whether exclusion is Fas dependent and T-cell mediated. In the third aim, he will test the hypothesis that the strength of the tolerogenic signal is affected by the response modulators CD19 and CD22. This will be accomplished by altering the availability of these proteins by crossing the anti-Sm Tg mice with CD19 Tg and CD22 knockout mice. In the fourth aim, he will use retroviral gene transfer to introduce the SmD gene in mouse bone marrow to test the hypothesis that the defect in B-cell tolerance in MRL/lpr mice is manifest only in exclusion from the mature B-cell subset, not in other forms of B-cell tolerance, central deletion or anergy. He will induce central deletion of anti-Sm B-cells in MRL/lpr mice and determine whether this blocks the spontaneous development of the anti-Sm response.