Variation in concentration of prion protein in the peripheral blood of patients with variant and sporadic Creutzfeldt‐Jakob disease detected by dissociation enhanced lanthanide fluoroimmunoassay and flow cytometry

Fagge, Tim; Barclay, G. Robin; MacGregor, Ian; Head, Mark W.; Ironside, James W.; Turner, Marc

doi:10.1111/j.0041-1132.2005.04342.x

Cited by 13 publications

(13 citation statements)

References 36 publications

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“…In contrast to an earlier report (45), we were able to detect low levels of PrP C expression using the sandwich CDI on purified granulocytes, monocytes, CD4 + T cells, CD8 + T cells, B cells, and platelets (Fig. 4).…”

Section: Discussioncontrasting

confidence: 99%

“…3) (45, 46), we hesitate to assign importance to this finding for several reasons. First, our sample size was small ( n =3-5) and second, the differences were only statistically significant after a small subpopulation of platelets with an uncharacteristically high level of PrP (172,806 ± 25,504) was excluded from the analysis (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt–Jakob disease

Choi

Geschwind

Deering

et al. 2009

Laboratory Investigation

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Recent cases of prion transmission in humans following transfusions using blood donated by asymptomatic variant Creutzfeldt-Jakob disease (CJD) patients implicate the presence of prion infectivity in peripheral blood. In this study, we examined the levels of the normal, cellular prion protein (PrPC) and the disease-causing isoform (PrPSc) in subpopulations of circulating white blood cells (WBC) from sporadic (s) CJD patients, age-matched neurological controls and healthy donors. Though widely distributed, the highest levels of PrPC were found in a subpopulation of T lymphocytes: ~12,000 PrPC molecules were found per CD4+CD45RA-CD62L- effector memory T helper cell. While platelets expressed low levels of PrPC on their surface, their high abundance in circulation resulted in the majority of PrPC being platelet associated. Using quantitative FACS analysis, we found that neither WBC composition nor the amount of cell-surface PrPC molecules was altered in patients dying of sCJD. Eight different WBC fraction types from the peripheral blood of sCJD patients were assessed for PrPSc. We were unable to find any evidence for PrPSc in purified granulocytes, monocytes, B cells, CD4+ T cells, CD8+ T cells, NK cells, non-classical γδT cells, or platelets. If human WBCs harbor prion infectivity in sCJD patients, then the levels are likely to be low.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt–Jakob disease

Choi

Geschwind

Deering

et al. 2009

Laboratory Investigation

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“…The observed change in CD230 fluorescence was, however, not detectable in our macaques when samples were stained with MoAb 3F4. This agrees with findings of 3F4‐stained blood samples from vCJD patients 37 . Thus, it is tempting to speculate that conformational changes were the underlying mechanism in our study, too, as was described in in vitro 5 and in in vivo models 6 .…”

Section: Discussionsupporting

confidence: 92%

Increase in CD230 (cellular prion protein) fluorescence on blood lymphocytes in bovine spongiform encephalopathy–infected nonhuman primates

et al. 2010

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BACKGROUND: The cellular prion protein (PrPc) plays a central role in prion diseases such as variant Creutzfeldt‐Jakob disease. This disease can be transmitted by blood transfusion. However, the exact kinetics of blood infectivity and the blood fraction carrying infectivity have not yet been identified. STUDY DESIGN AND METHODS: Simian PrPc epitopes were mapped by flow cytometry using monoclonal antibodies (MoAbs). A whole blood/no wash protocol was established, validated, and applied to investigate peripheral blood cell–associated PrPc expression profiles in bovine spongiform encephalopathy (BSE)‐infected cynomolgus monkeys and age‐/sex‐matched controls. In addition, physiologic expression patterns on blood cells and in lymphoid tissues were determined. RESULTS: In BSE‐infected macaques, blood lymphocyte–associated PrPc fluorescence gradually increased years before the onset of clinical signs (pF test < 0.0001). The increase in fluorescence intensity was detectable with MoAb 12F10, whereas we failed to detect an increase with 3F4. In parallel, plasma concentrations of soluble CD230 also increased. Centrifugation of lymphocytes almost completely eliminated differences between infected and noninfected animals, most likely caused by a partial loss in cell‐associated CD230 into the plasma supernatant. CONCLUSION: Blood lymphocytes from asymptomatically infected as well as diseased macaques were characterized by increased CD230 fluorescence, and phosphatidylinositol‐phospholipase C–resistant PrP molecules contributed at least partially to this increase. Conformational changes within PrPc molecules may be the underlying mechanism for the increased PrPc fluorescence. This cell‐associated phenomenon contributed at least partially to an increase in soluble plasma‐derived PrPc levels. It is not yet known whether these changes reflect infectivity.

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“…A decrease in PrP might be predicted by neuronal loss, but its alteration in the remaining neuronal population suggests a pathological change in antigen density. It has recently been reported that PrP C , as detected by dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA), is reduced in whole blood samples of variant Creutzfeldt-Jakob disease patients and non-TSE neurological patients; however, this decrease may be off-set by an increase of PrP C in platelet-depleted plasma, suggesting a change in blood 'compartmentalization' of PrP C rather than the reduction observed here at the surface of brain cells [18]. Increased GFAP staining was noted in methanolfixed prion-infected brain cells of TSE-infected mice, consistent with activation and proliferation of astrocytes.…”

Section: Discussionmentioning

confidence: 61%

Decreased cell surface prion protein in mouse models of prion disease

Griffin

Terry²,

Jackman³

et al. 2007

NeuroReport

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Transmissible spongiform encephalopathies are infectious neurodegenerative diseases caused by prions, composed of ordered aggregates of misfolded cellular prion protein. Neural antigen density of prion protein, Thy-1 and glial fibrillary acidic protein was analyzed using flow cytometry of dissociated mouse brain cells after inoculation with mouse-adapted transmissible spongiform encephalopathy agents. Transmissible spongiform encephalopathy gliosis was demonstrated by increased intracellular immunoreactivity for glial fibrillary acidic protein compared with controls. Immunoreactivity for cell surface prion protein was reduced 2.8-3.8-fold compared with control brain cells, whereas surface Thy-1 protein was reduced 1.5-4-fold. Double-staining protocols revealed loss of brain cells highly immunoreactive for prion protein and Thy-1, with a preferential reduction of prion protein, suggesting that prion protein expression, trafficking or consumption may be affected early in disease.

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Variation in concentration of prion protein in the peripheral blood of patients with variant and sporadic Creutzfeldt‐Jakob disease detected by dissociation enhanced lanthanide fluoroimmunoassay and flow cytometry

Abstract: There are differences in free and cell-associated PrP found in blood of CJD patients and control groups, some of which might be useful with other tests in disease profiling as an aid to diagnoses.

Cited by 13 publications

References 36 publications

Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt–Jakob disease

Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt–Jakob disease

Increase in CD230 (cellular prion protein) fluorescence on blood lymphocytes in bovine spongiform encephalopathy–infected nonhuman primates

Decreased cell surface prion protein in mouse models of prion disease

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