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

Misfolding of the cellular prion protein (PRPC) 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 PRPC, 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) PRPC 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 PRPC peptides. These findings suggest that carriers of certain HLA alleles that are capable of binding strongly to PRPC peptides may have enhanced protection against prion disease, through reduction in the overall amount of PRPC available for conversion to the misfolded, infectious scrapie isoform (PRPSc) of PRPC 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.).