Downloaded from www.microbiologyresearch.org by IP: 54.70.40.11 On: Sat, 22 Dec 2018 09:19:04 Short Communication Unswitched immunoglobulin M response prolongs mouse survival in prion disease Mourad Tayebi, 1,2 John Collinge 3 and Simon Hawke 2 Correspondence Simon Hawke shawke@med.usyd.edu.au 1 Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK 2 Brain & Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia 3 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK Received 6 July 2008 Accepted 14 October 2008 Several studies have failed to demonstrate the presence of immune responses to infectious prions during the course of prion disease, reflecting the identical primary structure of normal and disease-associated isoforms and the widespread expression of the normal cellular form of prion protein, PrP C , leading to B- and/or T-cell tolerance of disease-associated isoforms and also possibly because antigen-presenting cells are unable to process the highly aggregated, detergent-insoluble, protease-resistant form, PrP Sc . Under certain circumstances, PrP Sc can be revealed to the immune system in immunogenic form, and it has been shown previously that anti- PrP antibodies can be induced to prions immunoadsorbed to Dynabeads using specific anti-PrP monoclonal antibodies, even in PrP-sufficient mice. This study demonstrated in a murine scrapie model that PrP–Dynabeads effectively stimulated the immune system to produce anti-PrP IgM antibodies over prolonged periods after repeated immunization. It was also shown that these immune responses prolonged incubation times in murine scrapie. Prions diseases, or transmissible spongiform encephalopa- thies, which include Creutzfeldt–Jakob disease in humans and bovine spongiform encephalopathy and scrapie in animals, are a group of invariably fatal diseases with a pathogenesis that involves the transformation of the mainly a-helical normal cellular prion protein, PrP C , into a disease-associated isoform, PrP Sc , that acquires increased b-sheet content, detergent insolubility and resistance to proteases. How the formation of prions induces neuro- toxicity is still poorly understood, but there is an absolute requirement for the expression of PrP C (Bueler et al., 1993). Although prions potentially adopt non-native conformations that might be recognized by the immune system during the course of natural infection, no antibody responses to prions have yet been identified, undoubtedly because of the widespread systemic expression of PrP C , rendering the adaptive immune system tolerant of it (McBride et al., 1992). Furthermore, native PrP Sc has not been considered immunogenic (Peretz et al., 1997), possibly because antigen-presenting cells are incapable of processing the highly aggregated, protease-resistant protein. Native prions have generally failed to stimulate an immune response in experimental animal models, and few antibod- ies have been produced that recognize infectious prions in native form (Tayebi & Hawke, 2006). Initially, scrapie-associated fibrils (SAFs) were used as the immunogen to generate an immune response in mice and rabbits. Although purified intact infectious SAFs in native form did not elicit detectable natural or experimental immune responses (Kascsak et al., 1987), a weakly measurable immunoreactive antibody reaction was evoked if SAFs were exposed to formic acid or SDS. So-called prion rods were also purified and then used to produce anti-PrP antibodies in rabbits (Prusiner et al., 1993) and mice (Williamson et al., 1996). Similar to the SAF preparations, prion rods also underwent substantial and stringent purification steps (Prusiner et al., 1993), which may have led to their denaturation and increased immunogenicity The immune responses induced by both the SAF preparations and the prion rods produced antibodies that bound weakly or not at all to disease- associated isoforms. Generally, the induction of anti-PrP antibodies using native or recombinant PrP has required using PrP C -null mice (Bueler et al., 1993), unless species-specific sequence variations are present in the immunogen. Nakamura et al. (2003) used native PrP to immunize PrP- null mice to generate anti-PrP antibodies. In their study, scrapie-infected cells were used as the immunogen to generate anti-PrP antibodies, demonstrating de facto that native PrP could be used as a potent immunogen without Journal of General Virology (2009), 90, 777–782 DOI 10.1099/vir.0.005041-0 005041 G 2009 SGM Printed in Great Britain 777