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From: TSS ()
Comparative evidence for a link between Peyer's patch development and susceptibility to transmissible spongiform encephalopathies BMC Infectious Diseases 2006, 6:5 doi:10.1186/1471-2334-6-5 Published 11 January 2006 Abstract (provisional) Background Epidemiological analyses indicate that the age distribution of natural cases of transmissible spongiform encephalopthies (TSEs) reflect age-related risk of infection, however, the underlying mechanisms remain poorly understood. Using a comparative approach, we tested the hypothesis that, there is a significant correlation between risk of infection for scrapie, bovine spongiform encephalopathy (BSE) and variant CJD (vCJD), and the development of lymphoid tissue in the gut. Methods Using anatomical data and estimates of risk of infection in mathematical models (which included results from previously published studies) for sheep, cattle and humans, we calculated the Spearman's rank correlation coefficient, rs, between available measures of Peyer's patch (PP) development and the estimated risk of infection for an individual of the corresponding age. Results There was a significant correlation between the measures of PP development and the estimated risk of TSE infection; the two age-related distributions peaked in the same age groups. This result was obtained for each of the three host species: for sheep, surface area of ileal PP tissue vs risk of infection, rs = 0.913 (n = 19, P < 0.001), and lymphoid follicle density vs risk of infection, rs = 0.933 (n = 19, P < 0.001); for cattle, weight of PP tissue vs risk of infection, rs = 0.693 (n = 94, P < 0.001); and for humans, number of PPs vs risk of infection, rs = 0.384 (n = 46, P = 0.008). In addition, when changes in exposure associated with BSE-contaminated meat were accounted for, the two age-related patterns for humans remained concordant: rs = 0.360 (n = 46, P = 0 .014). Conclusions Our findings suggest that, for sheep, cattle and humans alike there is an association between PP development (or a correlate of PP development) and susceptibility to natural TSE infection. This association may explain changes in susceptibility with host age, and differences in the age-susceptibility relationship between host species. snip... and estimated risks of TSE infection differ between sheep, cattle and humans, in each case the two are associated. However, these results do not distinguish effects of agerelated changes in exposure to TSE infection from age-related changes in susceptibility. To make this distinction we need to consider how oral exposure to TSE infection might change with age for each species. containing recycled infected cattle tissues [26]. MBM used to be incorporated as a protein source in concentrated feedstuffs and fed to both calves and adult cattle. However, there is no clear correlation with the estimated age-infection function (Figure 2(B)): almost all calves were exposed to MBM by 6 weeks of age; exposure then fluctuated up to 24 months old but, especially for dairy cows, rose again in adulthood [27, 28]. This route of BSE transmission is thought now to have been eliminated by feed production regulations introduced in 1988 and 1996. BSE-contaminated cattle tissues [29]. Humans consume solid foods from 4-6 months of age with average consumption of bovine carcass meat peaking during childhood and tending to fall thereafter (see Figure 3 in [6]). This route of transmission is thought now to have been eliminated by food production regulations introduced in the UK in 1996. Here, putative exposure is more closely aligned with PP development [6] but, as reported above, when age-related exposure is taken into account, there remains an association between PP development and estimated susceptibility. likely to include grazing on pasture contaminated with scrapie, possibly by infected foetal membranes [30]. Lambs typically begin to graze at 6-14 weeks and continue to do so throughout their lives. Exposure by this route would not be correlated with the estimated age-infection function (Figure 2(A)). offspring in utero or via breast milk (self-evidently age-dependent) is thought to play a minor role, if any: currently available estimates of the fraction of cases due to maternal transmission are 0-8% for scrapie in sheep [23], 0-14% for BSE in cattle [31], and 0% for vCJD in humans (Will et al., unpublished data). Other suggested routes include skin scarification (as demonstrated experimentally in mice [32]), food-borne infection via oral lesions [33], for scrapie possibly even mechanical transmission involving arthropods [34], and for vCJD, iatrogenic transmission [3]. However, there is no evidence that exposure via any of these routes varies with age in a manner corresponding to the estimated risk of infection functions (Figure 2) indicators of lymphoid tissue development; alternative measures in PP development may be at least as appropriate (for example, in sheep, counts of functionally mature FDCs). Moreover, this analysis assumes that both the anatomical data and the age-susceptibility estimates available are representative of each host species in general and not just the specific populations examined. Similarly, it is assumed that the associations studied have not been distorted by other factors (e.g. history of exposure to gut pathogens) which might influence PP development and/or susceptibility to TSEs. development and susceptibility to TSEs is seen not just in one host species but in three host species with different relationships between these variables and age. This kind of comparative study is especially useful in cases such as this where experimental manipulations (e.g. of PP development) are not feasible. Taken together, the epidemiological, anatomical and pathological evidence are consistent with the hypothesis that PP development or a close correlate of PP development is a major determinant of the observed age distribution of natural cases of TSEs in sheep, cattle and humans. This implies that the age groups most at risk of TSE infection (given that the individuals are exposed and have a susceptible PrP genotype) are indicated by the development of Peyer’s patches in the gut. http://www.biomedcentral.com/content/pdf/1471-2334-6-5.pdf TSS
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