Antigen presentation in autoimmune disease
Marshall, Naomi Jane
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The aim of my project was to examine the extent to which endogenous expression of a largely renal-specific antigen influences the repertoire in adulthood of autoreactive T cells specific to that antigen. The renal-specific antigen, human α3(IV)NC1, is the target of autoimmune attack in Goodpasture’s disease. This protein was expressed and purified in recombinant (using bacterial and mammalian cell expression systems) and purified in native (extracted from human tissue) forms. Transgenic mice were generated that express HLA-DR15 (associated with Goodpasture’s disease) as their sole MHC class II molecule, and for which α3(IV)NC1 can be endogenous or exogenous. The CD4 T cell responses of these mice were then tested following immunisation with α3(IV)NC1. In mice with endogenous expression of α3(IV)NC1 there were no consistent detectable proliferative T cell responses to any α3(IV)NC1 peptides in a set of overlapping peptides representative of the entire sequence. In the mice lacking endogenous α3(IV)NC1 there were consistent responses to the peptide α3(IV)NC1 136-150. This contains part of the peptide recognised by the most abundant autoreactive T cells in patients with acute Goodpasture’s disease. Therefore, the T cell responses seen in man to an endogenous (auto)antigen have similar fine specificity to those seen in mice responding to the same protein as a foreign antigen. This is surprising as one might expect self-tolerance in man to be most secure to such dominantly presented and immunogenic (in HLA DR15 mice) self peptides. However, recent work suggests that the peptide most commonly presented in humans is normally destroyed during antigen processing, giving a possible explanation for the lack of tolerance. Future work should study why tolerance is ineffective to this particular peptide, whether tolerance can be reinforced, these questions could be addressed using a transgenic mouse model that develops Goodpasture-like pathology. In addition, how processing is defective in Goodpasture’s disease could be explored by making antigen presenting hybridomas from patient samples or from the transgenic mouse line described within this thesis.