Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study

Ironside, James W.; Bishop, Matthew; Connolly, K. C.; Hegazy, Doha; Lowrie, Suzanne; Grice, Margaret Le; Ritchie, Diane; McCardle, Linda; Hilton, David A.

doi:10.1136/bmj.38804.511644.55

Cited by 137 publications

(84 citation statements)

References 9 publications

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“…More than two million BSEinfected cattle have entered the human food chain during the 1980s' and 1990s'. Although mathematical modeling suggests that a huge epidemic is unlikely [195], caution must be exerted because the prevalence of the infection seems greater than the disease incidence, reflecting the strong propensity of the vCJD agent to accumulate in peripheral tissues and blood without causing any harm [4,22,93,99,123]. The risk of human-to-human transmission of the vCJD agent is undoubtedly a growing public-health concern.…”

Section: The Spectrum Of Prion Diseasesmentioning

confidence: 99%

Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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Section: The Spectrum Of Prion Diseasesmentioning

confidence: 99%

Prion agent diversity and species barrier

2008

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“…Central to this is whether the identified immuno-reactivity truly reflects authentic prion infection. Interpretation has been hampered by the inability to do confirmatory immunoblotting of formalin-fixed tissue and by the fact that two of the three positive specimens that could be analysed were from individuals with a PRNP codon 129 valine homozygous genotype [50]. Polymorphism at residue 129 of human PrP [encoding either methionine (M) or valine (V)] powerfully affects susceptibility to human prion diseases, with residue 129 acting to restrict the propagation of particular prion strains through conformational selection [6,51,52] and heterozygosity conferring resistance by inhibiting homologous protein-protein interactions [52][53][54].…”

Section: Introductionmentioning

confidence: 99%

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

Wadsworth

Dalmau-Mena

Joiner

et al. 2010

The Journal of Pathology

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Anonymous screening of lymphoreticular tissues removed during routine surgery has been applied to estimate the UK population prevalence of asymptomatic vCJD prion infection. The retrospective study of Hilton et al (J Pathol 2004; 203: 733-739) found accumulation of abnormal prion protein in three formalin-fixed appendix specimens. This led to an estimated UK prevalence of vCJD infection of ∼1 in 4000, which remains the key evidence supporting current risk reduction measures to reduce iatrogenic transmission of vCJD prions in the UK. Confirmatory testing of these positives has been hampered by the inability to perform immunoblotting of formalin-fixed tissue. Animal transmission studies offer the potential for 'gold standard' confirmatory testing but are limited by both transmission barrier effects and known effects of fixation on scrapie prion titre in experimental models. Here we report the effects of fixation on brain and lymphoreticular human vCJD prions and comparative bioassay of two of the three prevalence study formalin-fixed, paraffin-embedded (FFPE) appendix specimens using transgenic mice expressing human prion protein (PrP). While transgenic mice expressing human PrP 129M readily reported vCJD prion infection after inoculation with frozen vCJD brain or appendix, and also FFPE vCJD brain, no infectivity was detected in FFPE vCJD spleen. No prion transmission was observed from either of the FFPE appendix specimens. The absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue precludes interpreting negative transmissions from vCJD prevalence study appendix specimens. In this context, the Hilton et al study should continue to inform risk assessment pending the outcome of larger-scale studies on discarded surgical tissues and autopsy samples.

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“…One patient had received transfusion of red cells from a donor who subsequently died from vCJD, and the other patient had received treatment with plasma products from a donor who subsequently died from vCJD. In addition, a retrospective study on the prevalence of subclinical vCJD infection using appendectomy and tonsillectomy specimens in the United Kingdom found 3/12,648 positive cases, two of which were found to be the 129V/V genotype (8,9). These studies indicate that individuals with the 129M/V or 129V/V genotype may be susceptible to vCJD, including secondary vCJD infection.…”

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confidence: 99%

Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes

Takeuchi

Kobayashi

Ironside

et al. 2013

Journal of Biological Chemistry

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Background: Secondary vCJD infection may occur in all human PRNP genotypes, but its clinicopathological and biochemical phenotype is uncertain. Results: The biochemical characteristics and transmission properties of the newly generated vCJD prions are not affected by the host PRNP genotypes. Conclusion: Secondary vCJD infection can be adequately diagnosed by biochemical analysis and experimental transmission. Significance: Effective means to identify secondary vCJD infection are presented.

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Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study

Cited by 137 publications

References 9 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes

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