Predicted high affinity binding of prion PRPC protein to Human Leukocyte Antigen (HLA)

Misfolding of the cellular prion protein (PRP^C) is associated with fatal neurodegenerative prion diseases for which no treatments are currently available. Although the immune system is generally non-responsive (tolerant) to self-proteins such as PRP^C, evidence of anti-prion antibodies suggests escape from self-tolerance in some individuals and supports the potential for the human immune system to be leveraged against prion disease. Human leukocyte antigen (HLA) plays a central role in rejecting endogenous non-self proteins (e.g. cancer neoantigens) by activating CD8+ cytolytic T cells via the Class I system (HLA-I) and CD4+ helper T cells via the Class II (HLA-II) system. Here we investigated the predicted binding affinity of 334 HLA molecules with all possible linear 9-mer (for HLA-I) and 15-, 18- and 22-mer (for HLA-II) PRP^C peptides to identify peptide-HLA (pHLA) complexes with strong predicted binding (IC₅₀ < 50 nM). We found that 12.4% of all prion peptides tested showed strong binding affinity to HLA molecules and that 20.2% of HLA alleles were able to bind strongly with PRP^C peptides. These findings suggest that carriers of certain HLA alleles that are capable of binding strongly to PRP^C peptides may have enhanced protection against prion disease, through reduction in the overall amount of PRP^C available for conversion to the misfolded, infectious scrapie isoform (PRP^Sc) of PRP^C and, potentially, by destroying it. These findings have implications for other disorders including common neurodegenerative diseases characterized by protein misfolding (e.g. α-synuclein, huntingtin, amyloid, tau, etc.).