Selective Presentation of Autoantigens by B Cells

描述（由申请人提供）：在目前的申请中，我们验证了B细胞MHC ii类限制性抗原呈递是自身抗原免疫耐受破裂的关键促成事件，特别是那些导致自身免疫性糖尿病的抗原。这一假说的一个关键组成部分将在我们的实验中得到验证，即许多启动或传播自身免疫的肽与MHC II类分子的相互作用具有低稳定性。这些与II类的低稳定性相互作用使得这些肽在细胞内将肽内体装载到II类上时对“DM编辑”异常敏感，从而诱导中枢耐受。因此，DM编辑排除了这些复合物在胸腺抗原提呈细胞（APC）上的表达。由于DM编辑，对这些低稳定性肽的自反应性T细胞在T细胞发育过程中不会被删除。我们假设，在外周，B细胞通过mhc编码DO分子的B细胞特异性表达，具有选择性地呈现这些与mhc II类分子相关的低稳定性自肽的能力。DO表达会减弱APC内体区室中这些肽的DM编辑，使其在细胞表面重新表达。上述假设的检验将通过推导一种针对IDDM中涉及抗原特异性B细胞的自身肽的通用策略来完成。我们预计，由于DM编辑的减弱，B细胞将增强其呈递这些低稳定性、隐性自身肽的能力，并且它们呈递这些抗原将在体内打破耐受性。本基金的目标将通过以下四个具体目标来实现：推导出一种靶向自身抗原T细胞表位到抗原特异性B细胞的分子结构。具体目标2。确定多肽的动力学稳定性：与自身免疫有关的II类复合物。具体目标3。检测抗原特异性B细胞呈递自身抗原自身肽的能力是否增强。具体目标试验体内B细胞抗原呈递对自身抗原自身耐受破缺的影响。

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.