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From: TSS ()
Subject: Comparative evidence for a link between Peyer's patch development and susceptibility to transmissible spongiform encephalopathies
Date: January 15, 2006 at 5:57 pm PST

Comparative evidence for a link between Peyer's patch development and susceptibility to transmissible spongiform encephalopathies
Suzanne G St.Rose , Nora Hunter , Louise Matthews , James D Foster , Margo E Chase-Topping , Loeske EB Kruuk , Darren J Shaw , Susan M Rhind , Robert G Will and Mark EJ Woolhouse

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.



Our results show that, whilst both age-related changes in the development of PP tissue

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.

For BSE in cattle, epidemiological studies have implicated meat and bone meal (MBM)

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.

For vCJD in humans, the most likely vehicle for exposure is food products containing

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.

For scrapie in sheep, the vehicle(s) of oral exposure are less well understood, but are

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)).

The importance of other transmission routes is less clear. Transmission from mother to

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)

The measures of PP development (area, weight or number) used in this study are crude

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.

Given these caveats, it is nonetheless striking that an association between PP

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.


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