title: Genetic prion disease: no role for the immune system in disease pathogenesis?
abstract: Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK)-resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion-infected immune cells infiltrate into the CNS, as is the case for scrapie-infected mice induced for experimental autoimmune encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK-resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity.
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Friedman-Levi
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Orli
authors.initials: O
authors.lastname: Binyamin
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Kati
authors.initials: K
authors.lastname: Frid
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Ovadia
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel gabizonr@hadassah.org.il.
authors.forename: Ruth
authors.initials: R
authors.lastname: Gabizon
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015870:Gene Expression; D006801:Humans; D007107:Immune System; D051379:Mice; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D018620:PrPSc Proteins