NR AADT
AU Aguzzi,A.
TI Neuro-immune connection in spread of prions in the body?
QU Lancet 1997 Mar 15; 349(9054): 742-3
PT journal article, Editorial
VT
The enigma surrounding the nature of the infectious agent causing transmissible spongiform encephalopathies (the "prion") captivates the attention of scientists and media alike. Do prions really consist only of PrPsc (an abnormally folded cellular protein [1]), or do they contain additional, undiscovered components?[2] For all its fascination, this controversy threatens to obscure the many other questions about prion diseases that demand urgent answers, especially since the occurrence of "new variant" Creutzfeldt-Jakob disease (nvCJD), which is thought to result from the ingestion of bovine spongiform encephalopathy prions.
Fortunately, some of these questions can be addressed before certainty has been attained about the physical make-up of prions. For example, the remarkable ability of this agent to invade the nervous system deserves some close attention. What happens, precisely, when prions gain access to the gastrointestinal tract? Which pathways are exploited by prions to spread across the body and reach the central nervous system (CNS)? Are there "reservoirs" in the body where prions multiply silently during the incubation phase of the disease? Answering these questions may help in devising ways to interfere with the march of prions from peripheral sites to CNS.
Hill and colleagues[3] have provided striking evidence for invasion of the human immune system by nvCJD prions. "Type 4"-PrPsc, which is the hallmark of the new disease,[4] accumulates in the lymphoid tissue of tonsil in such large amounts that it can easily be detected with antibodies on histological sections. Besides providing a useful diagnostic tool, this discovery highlights the fact that nvCJD affects more systems of the body than only the CNS.
That prions can "go immune" is not new. A wealth of early studies points to the importance of prion replication in lymphoid organs.[5] In mice, infectivity can be demonstrated in the spleen as early as 4 days after both intraperitoneal and, surprisingly, intracerebral infection. Replication of the infectious agent in the spleen precedes intracerebral replication, even if the infection is introduced intracerebrally. Infectivity can accumulate in all components of the lymphorecticular system, including lymph nodes and intestinal Peyer's patches, where it replicates almost immediately following oral administration of prions.
The nature of the cells supporting prion replication within the lymphoreticular system is uncertain. Splenectomy experiments after intraperitoneal infection have suggested that the critical cells are long lived. Follicular dendritic cells would be a prime candidate, and indeed PrPsc accumulates in such cells of wild-type and nude mice (which have a selective T-cell defect), but intraperitoneal infection does not lead to replication of prions in the spleen or to cerebral scrapie in mice with severe combined immunodeficiency (SCID) (whose follicular dendritic cells are thought to be functionally impaired).6 Transfer of spleen cells to SCID mice restores ability to infect organs within the peritoneal cavity.7 This finding suggests that cellular requirements for prion replication may be different from those for prion transport: the former may need follicular dendritic cells, whereas the latter may be dependent on lymphocytes.
[Image]
The findings referred to above suggest that prions "misuse" immune cells to travel from the site of infection to the lymphoreticular system. Do immune cells suffice to transport the agent all the way from lymphoreticular system to the CNS (figure, A)? This is unlikely, since lymphocytes do not normally cross the blood-brain barrier (unless they have a specific reason to do so). Moreover, disease and prion replication occur first in the CNS segments to which the sites of peripheral inoculation relate,8 implying that the agent spreads through the peripheral nervous system, the way the rabies virus and herpesviruses do.
How then might prions spread in the body? Perhaps prions injected intraperitoneally are first brought to follicular dendritic cells by mobile immune cells. Then peripheral nerve endings are invaded in a lymphocyte-dependent fashion. Eventually, the CNS is reached, and further spread occurs transsynaptically and along fibre tracts (figure, B).
Is it possible to interfere with this chain of events without resorting to physical ablation of prion-carrying cells (as in the case of SCID mice)? The normal prion protein, PrPc, may offer an intriguing handle. PrPc is crucial for prion spread within the CNS,[9] and it is not unlikely to be required also for spread of prions from peripheral sites to CNS. If the latter suspicion is confirmed, a true opportunity may arise for interference with prion spread and, therefore, for secondary prevention of encephalopathy after exposure to prions. Given the availability of transgenic and knockout mice[10,11] for PrPc, answers to these questions should not be far away.
Adriano Aguzzi
Department of Pathology, University Hospital, Zürich CH-8091, Switzerland
1 Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982; 216: 136-44.
2 Lasmézas CI, Deslys JP, Robain O, et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 1997; 275: 402-05.
3 Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 1997; 349: 99.
4 Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of "new variant" CJD. Nature 1996; 383: 685-88.
5 Eklund CM, Kennedy RC, Hadlow WJ. Pathogenesis of scrapie virus infection in the mouse. J Infect Dis 1967; 117: 15-22.
6 Muramoto T, Kitamoto T, Hoque MZ, Tateishi J, Goto I. Species barrier prevents an abnormal isoform of prion protein from accumulating in follicular dendritic cells of mice with Creutzfeldt-Jakob disease. J Virol 1993; 67: 6808-10.
7 Lasmézas CI, Cesbron JY, Deslys JP, et al. Immune system-dependent and independent replication of the scrapie agent. J Virol 1996; 70: 1292-95.
8 Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: evidence for neural spread of infection to the CNS. J Gen Virol 1980; 51: 183-87.
9 Brandner S, Raeber A, Sailer A, et al. Normal host prion protein (PrPc) required for scrapie spread within the central nervous systme. Proc Natl Acad Sci USA 1996; 93: 13148-51.
10 Büeler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell 1003; 73: 1339-47.
11 Fischer M, Rulicke T, Raever A, et al. Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. Embo J 1996: 15: 1255-64.
ZR 11
MH Animal; Human; Nervous System/physiopathology; Prion Diseases/immunology/physiopathology/*transmission; Prions/metabolism
AD Department of Pathology, University Hospital, Zürich, Switzerland.
SP englisch
PO England