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Letter
Age and Transmissible Spongiform
Encephalopathies
Dennis M. Heisey*
and Damien O. Joly†
*United States Geological Survey, Madison, Wisconsin, USA; and †University
of Wisconsin, Madison, Wisconsin, USA
Suggested citation
for this article:
Heisey DM, Joly DO. Age and transmissible spongiform encephalopathies.
Emerg Infect Dis [serial on the Internet]. 2004 June [date cited].
Available from: http://www.cdc.gov/ncidod/EID/vol10no6/03-1130.htm
To the Editor: Bacchetti (1) notes "Our
findings suggest that the possibility should not be discounted that biological
factors peaking in the third decade of life may promote variant Creutzfeldt-Jakob
disease (vCJD) prion replication and consequent development of disease."
Such age specificity of disease risk may be a general feature of transmissible
spongiform encephalopathies, which suggests that a general mechanism should
be sought. A likely candidate for this mechanism is senescence-related
immune system defects.
In a study of scrapie outbreaks in four sheep flocks, the incidence of
clinical cases peaked in sheep 2–3 years of age, despite very different
forces of infection at work and very large differences in disease incidence
(2). Similar age specificity has been observed in cattle
infected with bovine spongiform encephalopathy (3), which
is believed to be the causal agent of variant Creutzfeldt-Jakob disease.
There is evidence that an age-specific peak in prevalence also occurs
in chronic wasting disease, a laterally transmitted spongiform encephalopathy
of North American cervids, specifically elk, mule deer, and white-tailed
deer. For example, data on prevalence of chronic wasting disease in mule
deer (Figures 4B and 4A of [4]) suggest the existence
of age-specific peaks. In aggregate, these observations suggest that a
general mechanism might produce the marked decline in disease risk as
age increases.
In 1979, Dickinson and Outram (5) conjectured that,
in some experiments, scrapie responsiveness is the opposite of what one
normally expects with an infection, "raising the possibility that,
far from being inimical, some part of the host's immune system is essential
and may even play the role of a Trojan Horse for these agents when infection
occurs by a peripheral route." This theory appears well founded for
transmissible spongiform encephalopathies in general. Disease-associated
forms of resistant prion protein (PrPRes) are likely transported
from the gut to lymphoid tissue by cells such as migrating intestinal
dendritic cells (6). Once in the lymphoid tissue PrPRes
appears to be amplified by follicular dendritic cells (6)
and then enters the nervous system. Defects in either the complement pathway
or follicular dendritic cells result in resistance to peripheral scrapie
infection (7,8), and this resistance likely occurs for
peripheral transmissible spongiform encephalopathy infections in general.
Both in vitro and in vivo animal and human studies demonstrate age-related
declines in both humeral and cellular components of the immune system
(9). In old (23 months) mice, the normal functioning
of follicular dendritic cells appears to be strongly impaired when compared
with young mice (10); according to researchers, "Antigen
transport was defective and only a small fraction of antigen transport
sites developed." (10). Furthermore, follicular
dendritic cells were ultrastructurally atrophic, retained little antigen,
and produced no iccosomes. By interfering with normal follicular dendritic
cell function, age likely has the same effect on transmissible spongiform
encephalopathies as has been observed due to dedifferentiation of follicular
dendritic cells (8). Senescence of the immune system
function could interfere with transmissible spongiform encephalopathy
pathogenesis in other ways as well, such as impairing migrating intestinal
dendritic cells or complement pathways involved in complexing PrPRes
to follicular dendritic cells.
This hypothesis could be readily tested by intracerebral versus peripheral
PrPRes challenge of young versus old animals. Because the intracerebral
challenge bypasses the immune system portal, old, peripherally challenged
animals should show a disproportionate reduction in disease risk if immune
system senescence is important in regulating pathogenesis.
References
- Bacchetti P. Age
and variant Cretzfeldt-Jakob disease. Emerg Infect Dis 2003;9:1611–2.
- Redman CA, Coen PG, Matthews L, Lewis RM, Dingwall WS, Foster JD,
et al. Comparative
epidemiology of scrapie outbreaks in individual sheep flocks. Epidemiol
Infect 2002;128:513–21.
- Anderson RM, Donnelly CA, Ferguson NM, Woolhouse ME, Watt CJ, Udy
HJ, et al. Transmission
dynamics and epidemiology of BSE in British cattle. Nature 1996;382:779–88.
- Miller MW, Williams ES, McCarty CW, Spraker TR, Kreeger TJ, Larsen
CT, et al. Epizootiology
of chronic wasting disease in free-ranging cervids in Colorado and Wyoming.
J Wildl Dis 2000;36:676–90.
- Dickinson AG, Outram GW. The scrapie replication-site hypothesis and
its implications for pathogenesis. In: Slow Transmissible Diseases of
the Nervous System. Volume 2; New York: Academic Press; 1979. p.13–31.
- Huang FP, Farquhar CF, Mabbott NA, Bruce ME, MacPherson GG. Migrating
intestinal dendritic cells transport PrPSc from the gut.
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- Mabbott NA, Bruce ME, Botto M, Walport MJ, Pepys MB. Temporary
depletion of complement component C3 or genetic deficiency of C1q significantly
delays onset of scrapie. Nat Med 2001;4:485–7.
- Mabbott NA, Young J, McConnell I, Bruce ME. Follicular
dendritic cell dedifferentiation by treatment with an inhibitor of the
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- Szakal AK, Kapasi ZF, Masuda A, Tew JG. Follicular
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