Paraffin-embedded-tissue-blot-Analyse des PrPsc-Vorkommens im lymphatischen Gewebe bei sporadischer Creutzfeldt-Jakob-Erkrankung
Paraffin-embedded-tissue-blot-analysis of PrPsc-deposition in lymphoreticular tissue in sporadic Creutzfeldt-Jakob disease
by Lena Jytte Cordes
Date of Examination:2021-08-18
Date of issue:2021-08-18
Advisor:Prof. Dr. Walter Schulz-Schaeffer
Referee:Prof. Dr. Walter Schulz-Schaeffer
Referee:PD Dr. Felix Bremmer
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Abstract
English
Prion diseases comprise a neurodegenerative group of diseases in humans and animals whose common feature is that they are triggered by an incorrectly folded endogenous (PrPc) protein (PrPsc), are always fatal and are potentially transmissible within a species and across species. With regard to human prion diseases, a distinction is made between sporadic (idiopathic), hereditary (genetic) and acquired (transmissible) prion diseases. In addition to differences in etiopathogenesis, incubation time, clinical characteristics, diagnostics and neuropathology, there is an important difference between sCJD and vCJD in terms of their potential transferability. Where in sCJD a possible transferability of this disease is only known through central inoculation via contaminated medical devices, peripheral transfer via blood products is also possible with vCJD. With regard to the latter disease, the population of Great Britain in particular is concerned about the detection of PrPsc in peripheral tissue after oral entry of the BSE pathogen into the human body, as this occurs in the lymphoretricular system (LRS) or in the blood even before the onset of clinical symptoms. It has also already been possible to detect transmission through blood donations. To make matters worse, the prion diseases have so far only been reliably diagnosed by a histological examination of brain tissue (pre- or post-mortem). Since the discovery by Hill et al in 1999 and Hilton et al in 2002 and 2004 of PrPsc in the lymphatic tissue (tonsils and appendix) in vCJD patients before the onset of clinical symptoms, hope has been spreading that this disease can be diagnosed preclinically through targeted biopsies. There are also reports of positive PrPsc evidence in blood samples and being able to use them as a diagnostic tool. However, these results only provide a diagnostic benefit and knowledge about possible differing pathomechanisms if they can be distinguished from other human prion diseases, in particular from sCJD. To date there was still no negative proof of the examined and relevant tissue samples of the sCJD patients with the most sensitive examination method to date, the PET blot method, so that these negative proofs of the sCJD tissue have to be considered in a differentiated manner. I have now been able to close this diagnostic gap with this investigation. With the help of various tissue types of the LRS of human sCJD patients discussed in the literature, I was able to demonstrate in comparison with corresponding tissue from classic scrapie cases that even with the help of the PET blot method, no PrPsc detection in the lymphatic tissue of sCJD patients , iCJD patients and in the tissue of other neurodegenerative diseases is possible, so that it can be confirmed that so far only vCJD in the area of human prion diseases has positive evidence (with the help of Western blot, immunohistochemistry, bioassay and PET blot) for PrPsc in lymphoreticular tissue. The lymphoreticular tissue of classic scrapie could be used as a positive control, since this, like bovine spongiform encephalopathy (BSE) or chronic wasting disease (CWD), represent further animal prion diseases that are the only ones tested positive for PrPsc in lymphoreticular tissue. But why the PrPsc can only be detected in lymphatic tissue with regard to vCJD in humans, whether this is due to the different transmission routes, prion pathogen strains, incubation times, the genetic requirements or the age of the host, remains the subject of research, as this has effects not only on the diagnosis and therapy of prion diseases themselves, but also on other so-called protein aggregation diseases, such as M. Alzheimer or M. Parkinson.
Keywords: prion; vCJD; sCJD; BSE; lymphoreticular tissue; PET-blot; CNS; PNS; TSE; immunhistochemistry