朊病毒致病机理的研究进展

就细胞型朊蛋白PrP^c的分子生物学特性、朊蛋白的生理功能、致病性朊蛋白PrP^sc对免疫系统的影响、朊病毒的外周致病机理以及相关细胞因子、化学因子与朊病毒神经侵袭之间的关系、朊病毒从外周到中枢的转运机制、入侵门户、血液传播及朊病的其他病理标志和检测方法的研究做一综述。     

The prion hypothesis and the human prion diseases

Our understanding of the pathogenesis of the transmissible spongiform encephalopathies (TSE) has made terrific headway over the past 40 years and some scientists are even of the opinion that this group of diseases belongs to the neurodegenerative syndromes best understood. On the other hand, the investigation of TSE has led to a multitude of unexpected and surprising results and consequently has initiated impassioned discussions among scientists. Although the human forms of TSE are very rare, the wildfire-like spread of the bovine spongiform encephalopathy (BSE) raises the pressing question as to whether BSE is communicable to humans. This overview summarizes some current hypotheses about the nature of the infectious agent and about the pathogenesis of the damage of the central nervous system.     

Transgenic animals and prion diseases

Extract

Thank you for the opportunity to respond to Peter Wills's letter on transgenic animals and prion diseases. Dr Wills has written an interesting letter, but the reader must note that only extreme cases are being argued. No biotech process has yet sought to produce a biological molecule which is non-native to the transgene, and to suggest, for example, that transgenic sheep producing human growth hormone will produce an aberrant protein of pathological potential is stretching a point.     

Rodent models for prion diseases

Until today most prion strains can only be propagated and the infectivity content assayed by experimentally challenging conventional or transgenic animals. Robust cell culture systems are not available for any of the natural and only for a few of the experimental prion strains. Moreover, the pathogenesis of different transmissible spongiform encephalopathies (TSE) can be analysed systematically by using experimentally infected animals. While, in the beginning, animals belonging to the natural host species were used, more and more rodent model species have been established, mostly due to practical reasons. Nowadays, most of these experiments are performed using highly susceptible transgenic mouse lines expressing cellular prion proteins, PrP, from a variety of species like cattle, sheep, goat, cervidae, elk, hamster, mouse, mink, pig, and man. In addition, transgenic mice carrying specific mutations or polymorphisms have helped to understand the molecular pathomechanisms of prion diseases. Transgenic mouse models have been utilised to investigate the physiological role of PrP(C), molecular aspects of species barrier effects, the cell specificity of the prion propagation, the role of the PrP glycosylation, the mechanisms of the prion spread, the neuropathological roles of PrP(C) and of its abnormal isoform PrP(D) (D for disease) as well as the function of PrP Doppel. Transgenic mouse models have also been used for mapping of PrP regions involved in or required for the PrP conversion and prion replication as well as for modelling of familial forms of human prion diseases.     

Molecular subtype-specific clinical diagnosis of prion diseases

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare transmissible disease caused by accumulation of pathological prion protein (PrP(sc)) in the CNS. According to the codon 129 polymorphism (methionine or valine) and the prion protein type 1 or 2, a classification into distinct subtypes was established. Further analysis of these subtypes detected atypical clinical forms with longer disease duration or younger age at onset. The CJD subtype influences sensitivity of the technical investigations such as 14-3-3 in CSF, periodic sharp wave complexes in the EEG or hyperintense basal ganglia in MRI. A further characterization of these subtypes is important for reliable diagnosis and identification of rare disease variants. The aim is to establish specific patterns of test results and clinical findings. These improvements in diagnostics may be the reason for the apparent increase in sCJD incidence in Germany from 0.9 in 1994 to 1.6 in a million in 2005. Despite careful surveillance, no patient with variant CJD has been detected to date in Germany. Here we present the data of the CJD surveillance of the last 13 years. Additionally, the improvements in diagnostics and differential diagnosis are discussed.     

Cellular prion proteins in humans and cattle but not sheep are characterized by a low-solubility phenotype

A feature of transmissible spongiform encephalopathies is the accumulation of infectious prion proteins (PrP^Sc), which are formed by the conversion of physiological prion proteins (PrP^C). As PrP^C, which is modified posttranslationally with various types of glycoproteins, serves as the substrates for PrP^Sc conversion, various PrP^C subtypes may play a role in the formation of PrP^Sc and species-specific transmission; the cattle disease BSE is transmissible naturally to humans, but the sheep disease scrapie is not. To reveal new mechanisms modulating prion conversion, we analyzed the PrP^C profiles by determining the differential PrP^C protein solubilities in the anionic and nonionic detergents N-lauroylsarcosine, N-octyl-β-d-glucopyranoside, CHAPS and deoxycholic acid. We compared the resulting solubility profiles of human PrP^C with the solubility profiles of PrP^C from sheep and cattle. The PrP^C subtypes were differentially soluble. However, non-glycosylated PrP^C from cattle and human was found explicitly in the insoluble fraction, while non-glycosylated ovine PrP^C was detected in the soluble fraction. These findings indicate the existence of low-solubility PrP^C phenotypes in cattle and humans.     

Trace elements and prion diseases: a review of the interactions of copper, manganese and zinc with the prion protein

Transmissible spongiform encephalopathies (TSEs) are a family of neurodegenerative diseases characterized by their long incubation periods, progressive neurological changes, and spongiform appearance in the brain. There is much evidence to show that TSEs are caused by an isoform of the normal cellular surface prion protein PrPC. The normal function of PrPC is still unknown, but it exhibits properties of a cupro-protein, capable of binding up to six copper ions. There are two differing views on copper's role in prion diseases. While one view looks at the PrPC copper-binding as the trigger for conversion to PrPSc, the opposing viewpoint sees a lack of PrPC copper-binding resulting in the conformational change into the disease causing isoform. Manganese and zinc have been shown to interact with PrPC as well and have been found in abnormal levels in prion diseases. This review addresses the interaction between select trace elements and the PrPC.     

Immune mechanisms in the pathogenesis of viral diseases: a review.

Three immunopathological mechanisms may determine the pathogenesis of viral diseases in animals. (1) A variety of viruses causes transient or prolonged immunosuppression by infecting lymphoreticular tissues and interacting with components of the immune system. (2) In persistent viral infections effective immune responses may result in tissue damage. The mechanisms involved are T-cell-mediated destruction of infected cells and delayed-type hypersensitivity. (3) In a number of viral diseases pathogenic immune complexes are formed when antibodies are produced and react with viral antigen molecules persisting in the host. The selected examples of immune dysfunction are the focus of this review.     

Molecular pathogenesis of bovine paratuberculosis and human inflammatory bowel diseases

Paratuberculosis (Ptb), caused by Mycobacterium avium subsp. paratuberculosis (Map), is a chronic enteritis that affects many ruminants and other wild animals worldwide. Ptb is a great concern in animal health and in etiology of human Crohn's disease (CD). In the present study, we detected Map-specific insertion sequence IS900 of DNA in tissue sections surgically removed from lesions of patients with CD (29 samples), ulcerative colitis (UC) (17 samples), and non-inflammatory bowel disease (IBD) (20 samples). We then compared the histopathological findings of 29 CD and 17 UC cases with those of 35 cases of bovine Ptb, since few comparative pathological studies of human IBD and Ptb have been conducted. The QPCR examination indicated positive results in 13.37% of CD cases, 3.57% of UC cases, and 10% of non-IBD cases. Human CD tissues typically exhibited destructive full thickness enteritis with severe lympho-plasma infiltration and scattered additional granulomas; UC lesions exhibited much less inflammation than CD lesions. Non-IBD control samples did not exhibit pathological changes. Human CD and UC lesions were very different from Ptb lesions that are characterized by predominant granuloma formation. Immunohistochemistry for Map antigen and acid-fast staining were negative in all human IBD cases but were always positive in Ptb cases. Our present comparative study strongly suggests that we reconsider the previous hypothesis that "Map infection" causes CD, even though human intestines were considered to have been exposed to the Map antigen containing the DNA.     

猪圆环病毒病及其相关疾病

猪Ⅱ型圆环病毒(PCV-2)仅靠其自身的力量极少可引起健康猪出现临床疾病。本文主要介绍PCV-2的协同感染因子,因为这些或/和其它环境因子对诱发与PCV-2有关的完整临床症状是非常重要的。     

The prion hypotheses

Abstract

Extract

I read with interest the letter by P.R. Wills (New Zealand Veterinary Journal 44, 33-36, 1996). I hope someone more learned than I will reply, because I think a reply is necessary. Some post-modem science seems to be bypassing basic scientific principles. Isn't science all about analysis of observations, the measurement of entities that can be quantitated — data, finding, etc. — not just intuition?