Disease-Associated Prion Protein Elicits Immunoglobulin M Responses In Vivo

Tayebi, Mourad; Enever, Perry; Sattar, Zahid; Collinge, John; Hawke, Simon

doi:10.2119/2004-00027.tayebi

Cited by 14 publications

(18 citation statements)

References 50 publications

(50 reference statements)

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“…Interestingly, although 5D6 binds to a conformational epitope, reactivity of this Mab is not lost, but rather enhanced upon PrP denaturation. It has previously been reported (Tayebi et al, 2004) that heat denaturation is not sufficient to disrupt the polymeric structure of PrP Sc . Furthermore, the Mabs were equally immunoreactive by ELISA to both PrP C from uninfected brains and total PrP (normal and abnormal PrP isoforms)in non-denatured brain homogenate.…”

Section: Resultsmentioning

confidence: 93%

PrP antibody binding-induced epitope modulation evokes immunocooperativity

Chang

Miller

Bulgin

et al. 2008

Journal of Neuroimmunology

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We have characterized the antibody-antigen binding events of the prion protein (PrP) utilizing three new PrP-specific monoclonal antibodies (Mabs). The degree of immunoreactivity was dependent on the denaturation treatment with the combination of heat and SDS resulting in the highest levels of epitope accessibility and antibody binding. Interestingly however, this harsh denaturation treatment was not sufficient to completely and irreversibly abolish protein conformation. The Mabs differed in their PrP epitopes with Mab 08-1/11F12 binding in the region of PrP 93-122 , Mab 08-1/8E9 reacting to PrP and Mab 08-1/5D6 directed to an undefined conformational epitope. Using normal and infected brains from hamsters, sheep and deer, we demonstrate that the binding of PrP to one Mab triggers PrP epitope unmasking, which enhances the binding of a second Mab. This phenomenon, termed positive immunocooperativity, is specific regarding epitope and the sequence of binding events. Positive immunocooperativity will likely increase immunoassay sensitivity since assay conditions for PrP Sc detection does not require protease digestion.

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Section: Resultsmentioning

confidence: 93%

PrP antibody binding-induced epitope modulation evokes immunocooperativity

Chang

Miller

Bulgin

et al. 2008

Journal of Neuroimmunology

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“…Previously reported results [55] also indicated that elevated IgM titers were produced in Prnp Ϫ/Ϫ mice immunized with murine Rocky Mountain Laboratory scrapie PrP Sc -coated affinity beads. By contrast, our results showed that levels of specific IgM are low, at least at the point of maximal humoral immune response, regardless of whether ODN 1826 was administered.…”

Section: Discussionmentioning

confidence: 74%

CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrPSc in mice immunized with 139A scrapie-associated fibrils

Spinner

LaFauci

Meeker

et al. 2007

Journal of Leukocyte Biology

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Prion diseases are characterized by conversion of the cellular prion protein (PrP(C)) to a protease-resistant conformer, the srapie form of PrP (PrP(Sc)). Humoral immune responses to nondenatured forms of PrP(Sc) have never been fully characterized. We investigated whether production of antibodies to PrP(Sc) could occur in PrP null (Prnp(-/-)) mice and further, whether innate immune stimulation with the TLR9 agonist CpG oligodeoxynucleotide (ODN) 1826 could enhance this process. Whether such stimulation could raise anti-PrP(Sc) antibody levels in wild-type (Prnp(+/+)) mice was also investigated. Prnp(-/-) and Prnp(+/+) mice were immunized with nondenatured 139A scrapie-associated fibrils (SAF), with or without ODN 1826, and were tested for titers of PrP-specific antibodies. In Prnp(-/-) mice, inclusion of ODN 1826 in the immunization regime increased anti-PrP titers more than 13-fold after two immunizations and induced, among others, antibodies to an N-terminal epitope, which were only present in the immune repertoire of mice receiving ODN 1826. mAb 6D11, derived from such a mouse, reacts with the N-terminal epitope QWNK in native and denatured forms of PrP(Sc) and recombinant PrP and exhibits a K(d) in the 10(-)(11) M range. In Prnp(+/+) mice, ODN 1826 increased anti-PrP levels as much as 84% after a single immunization. Thus, ODN 1826 potentiates adaptive immune responses to PrP(Sc) in 139A SAF-immunized mice. These results represent the first characterization of humoral immune responses to nondenatured, infectious PrP(Sc) and suggest methods for optimizing the generation of mAbs to PrP(Sc), many of which could be used for diagnosis and treatment of prion diseases.

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“…The results here show an exclusive IgG response with expected T lymphocyte involvement. Our studies have, by sharp contrast, led to an exclusive IgM response in both Prnp 0/0 and wild-type mice and complete failure to isotype switch to IgG, suggesting that the antigendelivery method we have used helps to expose the 'conformational' motifs needed in the context of a specific B-lymphocyte response [83]. Active immunization with native prion adsorbed onto immunomagnetic beads has delayed disease onset and led to chronic stimulation of B lymphocytes, as measured by the IgM antibody titer during the incubation period [TAYEBI & HAWKE, UNPUBLISHED DATA].…”

Section: Immune-based Therapy In Prion Diseasesmentioning

confidence: 77%

“…We have demonstrated that B lymphocytes could be stimulated to produce an exclusive antiprion antibody response of the IgM isotype in vivo [83]. Through novel antigen-delivery systems, we could generate antibodies that recognize both isoforms of the PrP.…”

Section: Immunobiology Of the Prion Proteinmentioning

confidence: 99%

A role for B lymphocytes in anti-infective prion therapies?

Tayebi

Bate

Hawke

et al. 2007

Expert Review of Anti-infective Therapy

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The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of a number of neurodegenerative conditions affecting the nervous system. These disorders include prion and Alzheimer's diseases and are of enormous importance for public health. It has become apparent over the last 20 years that specificity and application in prion diseases' diagnostic and therapeutic situations are the most important considerations in designing strategies for the generation of antiprion antibodies. Specific antiprion therapeutics have been suggested and the establishment of the 'proof-of-principle' that the use of epitope-specific antiprion antibodies leads to indefinite delay of disease onset, has increased momentum for its use, although caution should be exerted prior to the application of new therapeutic strategies in a clinical set up. Furthermore, in vivo stimulation of immune-competent cells to specifically recognize and neutralize the abnormally folded isoform should also be pursued.

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Disease-Associated Prion Protein Elicits Immunoglobulin M Responses In Vivo

Cited by 14 publications

References 50 publications

PrP antibody binding-induced epitope modulation evokes immunocooperativity

PrP antibody binding-induced epitope modulation evokes immunocooperativity

CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrPSc in mice immunized with 139A scrapie-associated fibrils

A role for B lymphocytes in anti-infective prion therapies?

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