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Protein conformation significantly influences immune responses to prion protein.

Khalili-Shirazi, A, Quarantino, S, Londei, M, Summers, L, Tayebi, M, Clarke, AR, Hawke, SH, Jackson, GS and Collinge, J (2005) Protein conformation significantly influences immune responses to prion protein. J Immunol, 174 (6), 15749856. pp. 3256-3263.

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In prion diseases, such as variant Creutzfeldt-Jakob disease normal cellular prion protein (PrPC), a largely alpha-helical structure is converted to an abnormal conformational isoform (PrPSc) that shows an increase in beta-sheet content. Similarly, the recombinant form of PrPC (ralpha-PrP) can be converted to a conformation dominated by beta-sheet (rbeta-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 alpha- and beta-PrP, we immunized Prnp(0/0) mice that are not tolerant of PrP with ralpha-PrP and rbeta-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 ralpha- and rbeta-PrP was different. Challenge with ralpha-PrP elicited a strong response of IL-5 and IL-10, whereas rbeta-PrP led to an early increased production of IFN-gamma. In addition, immunization with ralpha-PrP led to production of predominantly IgG1 isotype Ab in the sera, whereas after immunization with rbeta-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.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Khalili-Shirazi, A
Quarantino, S
Londei, M
Summers, L
Clarke, AR
Hawke, SH
Jackson, GS
Collinge, J
Date : 15 March 2005
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:15
Last Modified : 24 Jan 2020 18:49

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