Apostolos P Georgopoulos, Lisa M James, Matthew Sanders
{"title":"Predicted high affinity binding of prion PRPC protein to Human Leukocyte Antigen (HLA).","authors":"Apostolos P Georgopoulos, Lisa M James, Matthew Sanders","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Misfolding of the cellular prion protein (PRP<sup>C</sup>) 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<sup>C</sup>, 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<sup>C</sup> peptides to identify peptide-HLA (pHLA) complexes with strong predicted binding (IC<sub>50</sub> < 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<sup>C</sup> peptides. These findings suggest that carriers of certain HLA alleles that are capable of binding strongly to PRP<sup>C</sup> peptides may have enhanced protection against prion disease, through reduction in the overall amount of PRP<sup>C</sup> available for conversion to the misfolded, infectious scrapie isoform (PRP<sup>Sc</sup>) of PRP<sup>C</sup> 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.).</p>","PeriodicalId":520421,"journal":{"name":"Journal of immunological sciences","volume":"10 1","pages":"15-36"},"PeriodicalIF":0.0,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13245592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148214224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Apostolos P Georgopoulos, Lisa M James, Phillip K Peterson
{"title":"Human Leukocyte Antigen (HLA) at the Root of Persistent Antigens and Long COVID.","authors":"Apostolos P Georgopoulos, Lisa M James, Phillip K Peterson","doi":"10.29245/2578-3009/2025/1.1257","DOIUrl":"10.29245/2578-3009/2025/1.1257","url":null,"abstract":"<p><p>Here we offer a perspective on recent findings of persistent SARS-CoV-2 antigens in Long COVID<sup>1</sup> through the lens of immunogenetic risk and protection, namely in the context of the fundamental role of Human Leukocyte Antigen (HLA) in eliminating viral infections. Specifically, we attribute the persistence of viral antigens to the lack or weak protection conferred by HLA against SARS-CoV-2 in individuals carrying HLA alleles with low binding affinities to the virus. We suggest that determining the HLA Class I and II makeup of Long COVID patients will provide valuable new information in elucidating the cause for antigen persistence underlying the development of Long COVID and pave the way for successful interventions.</p>","PeriodicalId":520421,"journal":{"name":"Journal of immunological sciences","volume":"9 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}