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.
| Menges, Paula R; Jenks, Scott A; Bikoff, Elizabeth K et al. (2008) An MHC class II restriction bias in CD4 T cell responses toward I-A is altered to I-E in DM-deficient mice. J Immunol 180:1619-33 |
