What is the immune response to prion diseases?

Definition

Prion diseases are rare and fatal degenerative brain disorders caused by mutated proteins in the brain that
aggregate and form visible “holes” that show a spongy appearance seen through a
microscope, hence the name “spongiform encephalopathies.” Certain prion diseases,
such as scrapie (a disease of sheep and goats), and two human
diseases, Creutzfeldt-Jacob disease (CJD) and kuru, are transmitted by an infectious agent, namely a
prion. Variant CJD and Gerstmann-Sträussler-Scheinker syndrome are two familial
forms of prion diseases and are considered genetically inherited neurodegenerative disorders.

The causative agent of prion diseases is the cell surface prion protein (PrPc). PrPc is expressed on the surface of almost all cells in the body but are in extremely high concentrations on neurons in the peripheral and central nervous systems. However, no evidence has been found of an immune response or antibody detection against prions.

Immune System

Controversy surrounds the role of the immune system in prion disease. On one hand, a potential
exists for immunization as a form of treatment; on the other hand, the involvement
of the immune system may actually play a role in promoting disease in lymphoid
organs and may be a detrimental factor in establishing a disease state. Prion
diseases are unusual because they lack any nucleic acid, which is the chemical
building block of deoxyribonucleic acid (DNA), which makes up the genes that
generally code for proteins. Therefore, the pathogenic potential of prions lies in
their protein conformation, which can induce the transformation of the host
cellular protein (PrPc) to the disease state (PrPsc).

Prions use the immune system and lymphoreticular cells to gain access to the
brain. It has been shown that a humoral immune response to the prion protein
(PrPc) may inhibit prion infection. Reports in the literature using the mouse as a
model have shown that anti-PrPc antibodies can possibly prevent prion disease.
This suggests that immunization can possibly help to prevent prion infection and
manifestation of disease. However, data demonstrates that there is a lack of
immune response against prions, and that the immune system may actually help,
rather than hinder, the propagation of prions.

PrPc and the Lack of Immune Response in Scrapie Disease

Scrapie is a prion disease of rodents, sheep, and goats, and it expresses a
modified cellular form of the prion protein (PrPsc). Scientists have shown that
scrapie infection fails to elicit an immune response. There are no
antibodies detected against prions because the PrPsc is a
modified version of a host cellular prion protein (PrPc). Therefore, organisms
will not see the modified scrapie version as foreign. Thus, host organisms of
prion infection are tolerant of both PrPc and PrPsc and cannot consequently induce
an immune response by either scrapie infections or immunization with scrapie
prions injected to elicit a response. Because the cell surface prion protein is
found in most cells, including lymphocytes of the immune system, a prion
infection—which is not seen as foreign by T-lymphocytes—will not generate an immune response.

Lymphoid Tissues

There is evidence suggesting that the lymphoid system, including the spleen,
lymph nodes, bone marrow, and peripheral blood, may influence the course of
prion
diseases. Data suggest a number of possibilities for prion
disease: The susceptibility of prion infection correlates with the maturation of
the immune system during the growth and development of an organism;
corticosteroids, made by the lymphoid system, reduce the
susceptibility to scrapie in experimental animal studies; stimulated white blood
cells increase the susceptibility of scrapie; removal of the spleen delays the
onset of clinical symptoms of mice that were infected with prions; and studies
with immunodeficient mice have shown more precision in the role of the immune
system in prion disease.

The lymphoid organs have also been shown to replicate prions. The immune system is able to propagate PrPsc proteins even while the brain remains unaffected. The involvement of the lymphoid system in prion infection may involve a specific factor in lymphoid cells that aid in prion replication. These may involve chaperone proteins, which help to enhance production of other proteins.

Impact

One interesting fact regarding the involvement of the immune system in prion disease is that no significant pathologic lesion occurs, whereas infection of the brain is always accompanied by vascular degeneration, astrocytosis, neuronal loss, and possibly amyloid deposition. Future studies on the mechanism by which prion diseases interact with the immune system, and particularly the lymphoid cells, may lead to a better design of drugs that could impair the peripheral steps in prion disease.

The involvement of the immune system in prion diseases remains debatable. More scientific information is needed to determine if the immune system plays a large role and, if it does, whether that role has a generally positive or negative affect on prion disease states.

Bibliography

Aucouturier, P., et al. “Short Analytic Review: Prion Diseases and the Immune System.” Clinical Immunology 96, no. 2 (2000): 79-85.

Berg, L. J. “Insights into the Role of the Immune System in Prion Diseases.” Proceedings of the National Academy of Science 91 (1994): 429-432.

Murphy, Kenneth, Paul Travers, and Mark Walport. Janeway’s Immunobiology. 7th ed. New York: Garland Science, 2008.

Polymenidou, M., et al. “Humoral Immune Response to Native Eukaryotic Prion Protein Correlates with Anti-Prion Protection.” Proceedings of the National Academy of Science 101 (2004): 14670-14676.

Prusiner, Stanley B. “The Prion Diseases.” Scientific American 272, no. 1 (January, 1995): 48-57.

_______, ed. Prion Biology and Diseases. 2d ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2004.