Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis

Kane, Sarah J.; Farley, Taylor K.; Gordon, Elizabeth; Estep, Joshua; Bender, Heather; Moreno, Julie A.; Bartz, Jason C.; Telling, Glenn C.; Pickering, Matthew C.; Zabel, Mark D.

doi:10.4049/jimmunol.1701100

Cited by 9 publications

(11 citation statements)

References 30 publications

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“…6,35 Other potential components of B-cell exosome “cargo” with possible toxic effects would be proteins derived from Epstein-Barr virus, human endogenous retrovirus, 36,37 or prion-like proteins that affect protein folding in the target cells, 38 some known to be associated with B cells. 39 It is possible, although we believe unlikely, that the exosomes from B cells of patients with MS lack or have reduced amounts of a growth factor important for OLs and neuronal survival in vitro leading to death by apoptosis. 40…”

Section: Discussionmentioning

confidence: 92%

Exosome-enriched fractions from MS B cells induce oligodendrocyte death

Benjamins

Nedelkoska

Touil

et al. 2019

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo identify whether factors toxic to oligodendrocytes (OLs), released by B cells from patients with MS, are found in extracellular microvesicles enriched in exosomes.MethodsConditioned medium (Sup) was obtained from cultures of blood B cells of patients with MS and normal controls (NCs). Exosome-enriched (Ex-En) fractions were prepared by solvent precipitation from Sup containing bovine serum and from serum-free Sup by ultracentrifugation (UC) or immunoprecipitation (IP) with antibodies to CD9. Ex-En fractions were diluted 1:4 with OL culture medium and screened for toxic effects on cultured rat OLs as measured by trypan blue uptake. Proteomic analysis was performed on Sup fractions.ResultsMS B cell–derived Ex-En fractions prepared from Sup by solvent extraction, UC, or IP induced OL death, whereas corresponding Ex-En fractions from NC showed little toxicity. Proteomic analysis of Sup demonstrated enrichment of proteins characteristic of exosomes from both NC and MS B-cell Sup. Ontology enrichment analysis suggested differences in the types and cargo of exosomes from MS Sup compared with NC, with proteins related to cell surface, extracellular plasma membrane, and gliogenesis enriched in MS.ConclusionsMuch of the in vitro toxicity of Sup from B cells of patients with relapsing-remitting MS is found in Ex-En fractions, as confirmed by 3 methods. Proteomic analysis of B-cell Sup indicates multiple differences between MS and NC.

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Section: Discussionmentioning

confidence: 92%

Exosome-enriched fractions from MS B cells induce oligodendrocyte death

Benjamins

Nedelkoska

Touil

et al. 2019

Neurol Neuroimmunol Neuroinflamm

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“…From the host viewpoint, mature FDC are necessary for prion replication [ 9 , 14 – 20 , 58 , 59 ], being ontogenetically present or induced by chronic inflammation [ 60 ]. Co-factors, including notably complement or complement receptors [ 61 – 63 ], have been proposed to be involved. However, to the best of our knowledge, there is no evidence that such co-factors are involved in strain selection in the lymphoid tissue.…”

Section: Discussionmentioning

confidence: 99%

“…From the host viewpoint, mature FDC are necessary for prion replication [9, 14-20, 58, 59], being ontogenetically present or induced by chronic inflammation [60]. Co-factors, including notably complement or complement receptors [61][62][63], have been proposed to be involved. T2 Ov prions in tg338 mice are shown for comparison.…”

Section: Fig 6 Prp C -Level Dependent Selection Of Prions With Diffementioning

confidence: 99%

Host prion protein expression levels impact prion tropism for the spleen

et al. 2020

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Prions are pathogens formed from abnormal conformers (PrP Sc) of the host-encoded cellular prion protein (PrP C). PrP Sc conformation to disease phenotype relationships extensively vary among prion strains. In particular, prions exhibit a strain-dependent tropism for lymphoid tissues. Prions can be composed of several substrain components. There is evidence that these substrains can propagate in distinct tissues (e.g. brain and spleen) of a single individual, providing an experimental paradigm to study the cause of prion tissue selectivity. Previously, we showed that PrP C expression levels feature in prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrP C in their brains resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrP C levels, whereas a minor substrain replicated preferentially on high expresser mice. Considering that PrP C expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrP C dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN isolates in the spleen from high expresser mice correlated with the replication rate dependency on PrP C amount. There was a prominent spleen colonization by the substrain preferentially replicating on low expresser mice and a relative incapacity of the substrain with higher-PrP C level need to propagate in the spleen. Early colonization of the spleen after intraperitoneal inoculation allowed neuropathological expression of the lymphoid substrain. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high expresser mice, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low expresser mice, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrP C expression levels are instrumental in prion lymphotropism.

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“…The long-term retention of antigens on FDC enables B cells to generate effective antigen-specific antibody responses [ 62 , 63 , 64 ]. FDC similarly trap and retain prions on their surfaces as complement-bound complexes [ 65 , 66 , 67 , 68 , 69 , 70 , 71 ].…”

Section: Prions First Replicate Upon Follicular Dendritic Cells Inmentioning

confidence: 99%

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Mabbott

Bradford

Pal

et al. 2020

IJMS

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Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

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Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis

Cited by 9 publications

References 30 publications

Exosome-enriched fractions from MS B cells induce oligodendrocyte death

Exosome-enriched fractions from MS B cells induce oligodendrocyte death

Host prion protein expression levels impact prion tropism for the spleen

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

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