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Protein Conformation Significantly Influences Immune Responses to Prion Protein

2005; American Association of Immunologists; Volume: 174; Issue: 6 Linguagem: Inglês

10.4049/jimmunol.174.6.3256

1550-6606

Azadeh Khalili-Shirazi, Sonia Quaratino, Marco Londei, L. Ebonita Summers, Mourad Tayebi, Anthony R. Clarke, Simon Hawke, Graham S. Jackson, John Collinge,

Prion Diseases and Protein Misfolding

Abstract In prion diseases, such as variant Creutzfeldt-Jakob disease normal cellular prion protein (PrPC), a largely α-helical structure is converted to an abnormal conformational isoform (PrPSc) that shows an increase in β-sheet content. Similarly, the recombinant form of PrPC (rα-PrP) can be converted to a conformation dominated by β-sheet (rβ-PrP) by reduction and mild acidification in vitro, a process that may mimic in vivo conversion following PrPC internalization during recycling. Despite PrPSc 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 α- and β-PrP, we immunized Prnp0/0 mice that are not tolerant of PrP with rα-PrP and rβ-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 rα- and rβ-PrP was different. Challenge with rα-PrP elicited a strong response of IL-5 and IL-10, whereas rβ-PrP led to an early increased production of IFN-γ. In addition, immunization with rα-PrP led to production of predominantly IgG1 isotype Ab in the sera, whereas after immunization with rβ-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.