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Protein Conformation Significantly Influences Immune Responses to Prion Protein¹

Azadeh Khalili-Shirazi^*, Sonia Quaratino, Marco Londei, Linda Summers^*, Mourad Tayebi^*, Anthony R. Clarke^*, Simon H. Hawke^*, Graham S. Jackson^* and John Collinge^2,*

^* Medical Research Council Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, and Institute of Child Health, University College London, London, United Kingdom; and Cancer Research United Kingdom Oncology Unit, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom

In prion diseases, such as variant Creutzfeldt-Jakob disease normal cellular prion protein (PrP^C), a largely -helical structure is converted to an abnormal conformational isoform (PrP^Sc) that shows an increase in -sheet content. Similarly, the recombinant form of PrP^C (r-PrP) can be converted to a conformation dominated by -sheet (r-PrP) by reduction and mild acidification in vitro, a process that may mimic in vivo conversion following PrP^C internalization during recycling. Despite PrP^Sc accumulation and prion propagation in the lymphoreticular system before detectable neuroinvasion, no Ab response to PrP has been detected, probably due to immune tolerance. To investigate how the immune system may respond to - and -PrP, we immunized Prnp^0/0 mice that are not tolerant of PrP with r-PrP and r-PrP. In this study, we show that although T cells stimulated by these differently folded conformers PrP recognize similar immunodominant epitopes (residues 111–130 and 191–210) the cytokine profile in response to r- and r-PrP was different. Challenge with r-PrP elicited a strong response of IL-5 and IL-10, whereas r-PrP led to an early increased production of IFN-. In addition, immunization with r-PrP led to production of predominantly IgG1 isotype Ab in the sera, whereas after immunization with r-PrP, IgG2b was significantly produced. Thus, both humoral and cellular responses to these differently folded isoforms of the same protein are different, indicating a possible involvement of Th1 and Th2 pathway activation. These differences may be exploitable diagnostically and therapeutically for prion diseases, such as variant Creutzfeldt-Jakob disease.

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