NR AFKB
AU Hilton,D.A.; Fathers,E.; Edwards,P.; Ironside,J.W.; Zajicek,J.
TI Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease
QU Lancet 1998 Aug 29; 352(9129): 703-4
KI Lancet. 1999 Apr 10; 353(9160): 1271. PMID: 10217106
PT letter
VT
David A Hilton, Edward Fathers, Philip Edwards, James W Ironside, John Zajicek
A variant of Creutzfeldt-Jakob disease (CJD) was identified in 1996;1 there is evidence for a link between variant CJD and bovine spongiform encephalopathy (BSE).2,3 The proportion of the population exposed to infectious amounts of the BSE agent through consumption of infected meat is unknown, therefore it is difficult to predict the number of future cases of variant CJD. Prion protein (PrP) has been found in the tonsillar tissues from sheep infected with scrapie,4 and at necropsy from a patient with variant CJD.5 We describe our findings in an appendix, removed 8 months before the onset of disease, from a patient with variant CJD.
A 45-year-old man developed numbness of his face and right hand in May, 1996. Investigations included T2-weighted cranial magnetic-resonance imaging (MRI) which showed three small high-signal white-matter lesions. Multiple sclerosis was suspected. His sensory disturbances spread to his trunk and legs. He was treated for depression in April, 1997. Later that year he became hyperactive, disinhibited, and had aggressive outbursts. He also had intermittent deafness. In November, 1997, he had difficulty writing, slurred speech, and ataxia. A repeat MRI was unchanged. Visual evoked responses and examination of cerebrospinal fluid were normal. By early in 1998, his ataxia had deteriorated and his symptoms led to assessment in a psychiatric unit. Although systemic markers for vasculitis were negative, a brain biopsy was done in April, 1998, to exclude this treatable condition. Brain biopsy showed changes of variant CJD with scattered small cortical plaques surrounded by vacuoles and immunocytochemistry (with monoclonal anti-PrP antibodies 3F4 and KG9) showed extensive PrP deposition within plaques, and around neurons and blood vessels.
In September, 1995, he had had an appendectomy after 2 days of right iliac-fossa pain and fever. Histology of the appendix did not show acute appendicitis. Immunocytochemistry in May, 1998, with monoclonal antibodies 3F4 and KG9, showed immunoreactivity for PrP in the cytoplasm of scattered cells, predominantly in germinal centres (figure A). No staining was seen after omission of antibodies. The morphology of these immunoreactive cells suggested that they were follicular dendritic cells, which was confirmed by double labelling with antibodies to CD21, which co-localised to PrP immunoreactive cells (figure B). Immunoreactivity for PrP was not seen in any of 10 control appendices investigated.
Bild
Low-power view of appendix after immunocytochemistry for PrP (A) and high-power view of germinal centre after double labelling for PrP and CD21 (B)
Scattered cytoplasmic PrP immunoreactivity (brown reaction product) is seen within germinal centre cells which have morphology of follicular dendritic cells. Coarse deposits of PrP (black reaction product) are seen within the cytoplasm of CD21 immunoreactive cells (brown reaction product).
Demonstration of PrP within the cytoplasm of follicular dendritic cells of the appendix mirrors the findings in tonsillar lymphoid tissue.4,5 Involvement of the tonsillar tissue before onset of disease has been shown from the age of 10 months in sheep infected with scrapie; however, our findings are the first demonstration of PrP in tissue in human beings during the incubation period of CJD. Involvement of gut-associated lymphoid tissue before the clinical onset of disease is in keeping with an enteric route of entry for the variant CJD agent.
An implication of the presence of PrP in the appendix during the incubation period of variant CJD is that it offers the opportunity for large scale screening of appendectomy and, presumably, tonsillectomy, specimens removed since the onset of the BSE epidemic. Appendectomy specimens are routinely sent for histological examination and are usually available for further study. Although the incidence of human exposure to the BSE agent may be small, approximately 44 000 appendectomies are done in the UK each year (data from Royal College of Surgeons). Such a study would provide new data on the proportion of the population at risk of developing variant CJD, although it is not known at what stage during the incubation period of variant CJD that lymphoid tissue becomes involved or whether this involvement will inevitably lead to the development of neurological disease.
1 Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 921-25 [PubMed].
2 Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 1997; 389: 498-501 [PubMed].
3 Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion stain variation and the aetiology of 'new variant' CJD. Nature 1996; 383: 685-90 [PubMed].
4 Schreuder BEC, van Keulen LJM, Vromans MEW, Langeveld JPM, Smits MA. Preclinical test for prion diseases. Nature 1996; 381: 563 [PubMed].
5 Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 1997; 349: 99-100.
Departments of Histopathology and Neurology, Derriford Hospital, Plymouth PL6 8DH, UK (D Hilton); and National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK
ZR 5
MH Appendix/metabolism/*pathology; Case Report; Creutzfeldt-Jakob Syndrome/metabolism/*pathology; Human; Immunohistochemistry; Male; Middle Age; Prions/metabolism; Time Factors
SP englisch
PO England
EA pdf-Datei und HTML-Version
OR Prion-Krankheiten H