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Mechanisms of B cell tolerance against peripheral antigen

B细胞对外周抗原的耐受机制

基本信息

批准号：
13557026
负责人：
KOYASU Shigeo
金额：
$ 8.06万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

It is believed that mechanisms leading self-tolerance are operative in both B and T cells. However, those for B cells are less clarified. In particular, it is largely unknown how B cells acquire tolerance against antigens that are expressed primarily in peripheral organs and tissues. In order to examine the mechanism of such B cell peripheral tolerance, we employed a newly established model mouse system where autoantibody against desmoglein 3 (Dsg3) is continuously produced Dsg3 is a cadherin type cell-to-cell adhesion molecule expressed in stratified squamous epithelia and autoantibody production against Dsg3 leads to a well characterized autoimmune disease, pemphigus vulgaris (PV). We have established a PV model mouse by adoptive transfer of Dsg3^<-/-> splenocytes immunized with recombinant mouse Dsg3 to Rag2^<-/-> recipient mice expressing Dsg3, resulting in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis … More . We established hybridoma clones producing anti-mouse Dsg3 from these model mice and isolated heavy and light chain genes from one of such hybridomas. We then generated a transgenic mouse by injecting both genes into fertilized eggs. In anti-Dsg3 antoantibody transgenic mice, B cells expressing anti-mouse Dsg3 were readily observed in the bone marrow and peripheral organs, even though Dsg3 is expressed in the stratified squamous epithelia of these mice. These mice do not show any PV phenotypes, indicating that the generation of B cells reactive with Dsg3 alone is not sufficient for the development of PV phenotypes. Our results further suggest that the tolerance against Dsg3 is not established by simple deletion of autoreactive B cells and mechanisms other than deletion are likely involved in the tolerance against Dsg3. Future studies using this model mouse system will help us to understand the molecular mechanisms of establishment of self-tolerance and breakdown of self-tolerance against peripheral antigens in B cells. Less

据认为，导致自我耐受的机制在B细胞和T细胞中都是有效的。然而，对于B细胞的这些研究还不是很清楚。特别是，B细胞如何获得对主要在外周器官和组织中表达的抗原的耐受性，在很大程度上是未知的。为了研究这种B细胞外周免疫耐受的机制，我们采用了一个新建立的模型小鼠系统，其中持续产生抗桥粒芯糖蛋白3(Dsg3)的自身抗体，Dsg3是一种在复层鳞状上皮细胞中表达的钙粘附素型细胞间黏附分子，而产生抗Dsg3的自身抗体导致一种典型的自身免疫性疾病-寻常型天疱疮(PV)。我们通过将重组小鼠Dsg3免疫的脾细胞过继转移到表达Dsg3的Rag2^&lt；-/-&gt；受体小鼠，建立了PV模型小鼠，结果稳定地产生了抗Dsg3Ig G，并发展了包括口腔糜烂和基底上棘层松解症…在内的PV表型。更多。我们从这些模型鼠中建立了产生抗鼠Dsg3的杂交瘤克隆，并从其中一个杂交瘤中分离出了重链和轻链基因。然后，我们将这两种基因都注入受精卵中，从而产生了一只转基因小鼠。在抗Dsg3自身抗体转基因小鼠中，尽管Dsg3在复层鳞状上皮中表达，但在骨髓和外周器官中很容易观察到表达抗鼠Dsg3的B细胞。这些小鼠没有表现出任何PV表型，这表明仅与Dsg3反应的B细胞的生成不足以发展成PV表型。我们的结果进一步表明，对Dsg3的耐受不是通过简单地删除自身反应性B细胞来建立的，对Dsg3的耐受可能涉及除缺失之外的其他机制。未来使用该模型小鼠系统的研究将有助于我们了解B细胞对外周抗原的自我耐受建立和破坏的分子机制。较少