Selective Presentation of Autoantigens by B Cells

B 细胞选择性呈递自身抗原

• 批准号: 6874452
• 负责人: Andrea Janine Sant
• 金额: $ 23.52万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874452
• 关键词: B lymphocyte; MHC class II antigen; NOD mouse; antigen presentation; autoantigens; autoimmunity; chemical stability; clinical research; immune tolerance /unresponsiveness; insulin dependent diabetes mellitus; major histocompatibility complex; peptides; transfection /expression vector; vesicle /vacuole

DESCRIPTION (provided by applicant): In the current application, we test the hypothesis that MHC class II-restricted antigen presentation by B cells is a critical precipitating event in the breakdown of immunological tolerance to self antigens, in particular those that are responsible for autoimmune diabetes. One key component of this hypothesis that will be tested in our experiments is that many of the peptides that initiate or propagate autoimmunity have low stability interactions with MHC class II molecules. These low stability-interactions with class II makes these peptides exceptionally sensitive to "DM editing" during endosomal loading of peptides onto class II within cells that induce central tolerance. DM editing thus precludes expression of these complexes on thymic antigen presenting cells (APC). Because of DM editing, self-reactive T cells to these low stability peptides are not deleted during T cell development. We hypothesize that in the periphery, B cells possess a selective ability to present these low stability self-peptides in association with MHC-class II molecules by virtue of B cell specific expression of the MHC-encoded DO molecule. DO expression will attenuate DM editing of these peptides within endosomal compartments of APC, allowing their de novo expression at the cell surface. Testing of the above hypothesis will be accomplished by deriving a generalized strategy for targeting of the self peptides implicated in IDDM to antigen-specific B cells. We expect that because of attenuated DM editing, B cells will be potentiated in their ability to present these low stability, cryptic self peptides and their presentation of these antigens will break tolerance in vivo. The goals of this grant will be accomplished through 4 Specific Aims: Specific Aim 1. Derive a molecular construct that targets autoantigenic T cell epitopes to antigen-specific B cells. Specific Aim 2. Determine the kinetic stability of peptides: class II complexes that are implicated in autoimmunity. Specific Aim 3. Test whether antigen-specific B cells display potentiated ability to present autoantigenic self peptides. Specific Aim 4. Test the effect of B cell antigen presentation in vivo on breaking of self tolerance to autoantigens.

描述（由申请人提供）：在本申请中，我们测试了以下假设：B 细胞的 MHC II 类限制性抗原呈递是破坏对自身抗原的免疫耐受性的关键诱发事件，特别是那些负责自身免疫的抗原糖尿病。这一假设的一个关键组成部分将在我们的实验中进行测试，即许多启动或传播自身免疫的肽与 MHC II 类分子的相互作用稳定性较低。这些与 II 类的低稳定性相互作用使得这些肽在将肽内体装载到细胞内的 II 类上时对“DM 编辑”异常敏感，从而诱导中枢耐受。因此，DM 编辑阻止了这些复合物在胸腺抗原呈递细胞 (APC) 上的表达。由于 DM 编辑，T 细胞对这些低稳定性肽的自身反应在 T 细胞发育过程中不会被删除。我们假设，在外周，B 细胞凭借 MHC 编码的 DO 分子的 B 细胞特异性表达，具有选择性地呈递这些与 MHC II 类分子相关的低稳定性自肽的能力。 DO 表达将减弱 APC 内体区室中这些肽的 DM 编辑，从而允许它们在细胞表面从头表达。对上述假设的检验将通过推导将 IDDM 中涉及的自身肽靶向抗原特异性 B 细胞的通用策略来完成。我们预计，由于 DM 编辑减弱，B 细胞呈递这些低稳定性、神秘的自肽的能力将得到增强，并且它们呈递这些抗原将打破体内的耐受性。这项资助的目标将通过 4 个具体目标来实现： 具体目标 1. 衍生出一种分子结构，将自身抗原 T 细胞表位靶向抗原特异性 B 细胞。 具体目标 2. 确定肽的动力学稳定性：与自身免疫相关的 II 类复合物。 具体目标 3. 测试抗原特异性 B 细胞是否表现出增强的呈递自身抗原性自身肽的能力。 具体目标 4. 测试体内 B 细胞抗原呈递对破坏自身抗原自身耐受性的影响。