Age and transmissible spongiform encephalopathies.

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 (Pr[P.sup.Res]) are likely traosported from the gut to lymphoid tissue by cells such as migrating intestinal dendritic cells (6). Once in the lymphoid tissue Pr[P.sub.Res] 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 Pr[P.sup.res] to follicular dendritic cells.

This hypothesis could be readily tested by intracerebral versus peripheral Pr[P.sup.Res] 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.

Dennis M. Heisey * and Damien O. Joly ([dagger])

* United States Geological Survey, Madison, Wisconsin, USA; and ([dagger]) University of Wisconsin, Madison, Wisconsin, USA

References

(1.) Bacchetti P. Age and variant Cretzfeldt-Jakob disease. Emerg Infect Dis. 2003;9:1611-2.

(2.) Redman CA, Coen PG, Matthews L, Lewis RM, Dingwall WS, Foster JD, et al. Comparative epidemiology of scrapie out-breaks in individual sheep flocks. Epidemiol Infect. 2002;128:513-21.

(3.) 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.

(4.) 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.

(5.) 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.

(6.) Huang FP, Farquhar CF, Mabbott NA, Bruce ME, MacPherson GG. Migrating intestinal dendritic cells transport Pr[P.sup.Sc]. from the gut. J Gen Virol. 2002;83:267-71.

(7.) Mabbott NA, Bruce ME, Bono 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.

(8.) Mabbon NA, Young J, McConnell I, Bruce ME. Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol. 2003;77: 6845-54.

(9.) Burns EA, Leventhal EA. Aging, immunity, and cancer. Cancer Control. 2000;7: 513-22.

(10.) Szakal AK, Kapasi ZF, Masuda A, Tew JG. Follicular dendritic cells in the alternative antigen transport pathway: microenvironment, cellular events, age and retrovirus related alterations. Semin Imnunol. 1992;4:257-65.

Address for correspondence: Dennis M. Heisey, USGS-National Wildlife Health Center, 6006 Schroeder Road, Madison, WI 53711, USA; fax: [phone]; email: [e-mail]