TY - JOUR T1 - Protective anti-prion antibodies in human immunoglobulin repertoires JF - bioRxiv DO - 10.1101/2020.02.05.933721 SP - 2020.02.05.933721 AU - Assunta Senatore AU - Karl Frontzek AU - Marc Emmenegger AU - Andra Chincisan AU - Marco Losa AU - Regina Reimann AU - Geraldine Horny AU - Jingjing Guo AU - Sylvie Fels AU - Silvia Sorce AU - Caihong Zhu AU - Nathalie George AU - Stefan Ewert AU - Thomas Pietzonka AU - Simone Hornemann AU - Adriano Aguzzi Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/02/05/2020.02.05.933721.abstract N2 - Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here we identified >6000 PrP-binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage-derived antibodies. When expressed recombinantly, these antibodies exhibited anti-PrP reactivity. Furthermore, we surveyed 48’718 samples from 37’894 hospital patients for the presence of anti-PrP IgGs, and found 21 high-titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti-PrP autoimmunity is innocuous. The existence of protective anti-prion antibodies in unbiased human immunological repertoires, combined with the reported lack of such antibodies in carriers of disease-associated PRNP mutations, suggests a link to the low incidence of spontaneous prion diseases in human populations. ER -