Selective Presentation of Autoantigens by B Cells

描述（由申请人提供）：在本申请中，我们检验了这样的假设，即由B细胞进行的MHC II类限制性抗原呈递是对自身抗原的免疫耐受性的破坏中的关键性沉淀事件，特别是那些导致自身免疫性糖尿病的抗原。将在我们的实验中测试的这一假设的一个关键组成部分是，许多启动或传播自身免疫的肽与MHC II类分子具有低稳定性相互作用。这些与II类的低稳定性相互作用使得这些肽在内体将肽装载到诱导中枢耐受的细胞内的II类上期间对“DM编辑”格外敏感。因此，DM编辑排除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，对这些低稳定性肽的自身反应性T细胞在T细胞发育期间不会被删除。我们假设，在外周，B细胞具有选择性的能力，通过B细胞特异性表达MHC编码的DO分子，将这些低稳定性自身肽与MHC II类分子结合呈递。DO表达将减弱APC的内体区室内这些肽的DM编辑，允许它们在细胞表面重新表达。上述假设的检验将通过推导出将与IDDM有关的自身肽靶向抗原特异性B细胞的通用策略来完成。我们预期，由于减弱的DM编辑，B细胞将增强其呈递这些低稳定性、隐蔽的自身肽的能力，并且它们对这些抗原的呈递将破坏体内耐受性。该补助金的目标将通过4个具体目标来实现：具体目标1。衍生将自身抗原性T细胞表位靶向抗原特异性B细胞的分子构建体。 具体目标2。测定与自身免疫有关的肽类II类复合物的动力学稳定性。 具体目标3。检测抗原特异性B细胞是否显示出提呈自身抗原自身肽的增强能力。 具体目标4。测试体内B细胞抗原呈递对自身抗原自身耐受性破坏的影响。

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.