Monday Article #57: An insight into Prion Immune Response
Human prion diseases are rapidly progressive and fatal neurovegetative conditions caused by a disease-causing isoform of the native prion protein. The prion gene (PRNP) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic and acquired. 
Scrapie, a disease of sheep and goats, as well as two human diseases, Creutzfeldt-Jakob disease and kuru is transmitted by an infectious agents called a prion. In addition, there are two familial form of prion diseases, which is an alternative form of Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker (GSS) syndrome, which is genetically inherited neurodegenerative disorders. 
The molecular nature of the prion particles, and the mode of transmission of infectious disease, remained an enigma. Early 1980s, it was first suggested that infectious prion particles may completely lack of nucleic acid genome.  It has also been noted for years that no immune response seems to accompany scrapie inoculation and the onset prion disease.
Immune Response to Prion Disease
Scrapie infection fails to induce an immune response. The potential for this lack of immune response to the infectious scrapie particle came with the discovery of PrPSc, that is a modified form of a host cellular protein PrPC. The modification is done so that organisms may not view the scrapie particle as foreign particle. The outcome of investigation into immune response to PrP has verified that host organism is tolerate to both PrPSc and PrPC, furthermore that this state of tolerant is not broken wither by scrapie infection or by immunization with scrapie prions injected in adjuvant. For instance, immunization of mice with hamster PrPC generates a range of antibodies, all of which react with hamster PrPC but not with mice PrPC. 
This tolerance observed with the PrPis different from. The situation seen with other brain antigens – for example, the myelin basic protein (MBP) component of nerve myelin sheaths. Immune responses to MBP have been extensively studied by immunologists, as this protein is the target of autoimmune diseases. Immunisation of mice with MBP in adjuvant elicits a strong response of MBP-reactive T-cells to the central nervous system and to the onset of autoimmune. . Studies such as these have been extended by a variety of transgenic mouse experiments demonstrating that self-antigens that are present in normal animals. This situation arises, in particular, with regard to antigens that peripherally expressed and thus not present in the thymus to include clonal deletion of reactive T cells during development. These transgenic mouse experiments have indicated that a state of tolerance persists unless self-reactive T cells are activated to respond by extreme or unusual circumstances. 
One interpretation of the absence of immune response to scrapie is that scrapie infection fails to activate the non- specific immune mediators that normally signal invasion by a pathogenic microorganism. For instance, viral and bacterial infection of interferons, tumour necrosis factor, interleukin I and interleukin II. These factors have a variety of effects, such as activation and recruitment of phagocytic cells, including macrophages, to the site of infection. One outcome of these non-specific immune functions is to that, at a normal state site of infection, macrophages are present to phagocytose process, and present antigen to T-cells, thereby initiating an antigen-specific immune response. In addition, the presence of IL-1 and IL-6 greatly enhances the activation and differentiation of T cells and B cells, respectively. 
A simplified model of T cell-dependent and independent B cell activation. Binding of antigen to IgM on the surface of B cells provides the first activation signal. (A) T cells that recognize antigen processed by the B cell and presented in MHC II molecules provide the second signal, typically through its CD40 ligand binding CD40 on the B cell during infections with classic pathogens. (B) Prion-specific T cells are absent during prion infection. Other innate immune receptors, like CD21 or TLRs, can provide secondary signals without T cells in response to (C) bacteria, but not to (D) prions. 
Figure 1: Prions fail to activate B cells with or without T cell help
In the absence of these non-specific mediators, as in the absence of adjuvant, even foreign proteins do not elicit an immune response. The absence of immune response to scrapie, even in PrP-deficient mice, indicate that the immune system is blind to scrapie infection and replication. For some reason – perhaps the lack of bacterial cell wall components, the lack of endotoxins released during many bacterial infection, or the lack of cell damage induced goes unnoticed by the immune system. This situation us presumably exacerbated in normal (PrP+) mice, in which the infectious particle is composed of self-components and a state of immune tolerance to PrP exists. 
In conclusion, a successful approaches to treating prion diseases cannot depend on activating the immune system to provide an important ally in the fight to curb the progress of disease. Instead direct intervention in the process of PrP provides a more realistic target for a pharmacological attack on prion disease. The recent advances in prion research have gone a long way to confirming many of the original predictions, particularly the absences of nucleic acid genome in the infectious particle. Unfortunately, in the battle against prion disease, little help is forthcoming from the immune response. 
 Brian S. Appleby, Shashirekha Shetty, Mohamed Elkasaby . (2022, October 05). Genetics asepcts of human prion diseases. Retrieved from frontiers: https://www.frontiersin.org/articles/10.3389/fneur.2022.1003056/full
 S B Prusiner, D Groth, A Serban, R Koehler, D Foster, M Torchia, D Burton, S L Yang, and S J DeArmond. (1993 , November 15 ). Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Retrieved from NIH : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC47826/
 Mark Rogers, Fruma Yehiely, Michael Scott, and Stanle B. Prusiner . (1993 , April ). Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells . Retrieved from NLM: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46263/pdf/pnas01467-0074.pdf
 Oldstone, M. B. A., Nerenberg, M., Southern,. P., Price, J and Lewicki, J. . (1991 ). Cells . 319-331 .
 Paul, W. (1989). Fundamental Immunology . New York : Raven .
 Mrk D. Zabel and Anne C. Avery . (2015, February ). Prions- Not your Immunologist's Pathogen . Retrieved from NIH : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335031/
 L J Berg. (1994 , January ). Insights into the role of the immune system in prion disease. Retrieved from NIH : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC42961/
This article was prepared by Emeralda Erna Nordin