This week has been a difficult, but has produced a new positive direction for the proliferation components of my model. Early in my research I came across antigen presentation to immune cells as a quintessential component of inflammation. DCs and macrophages can act as APCs (antigen presenting cells) and as well as being able to carry PrPSc in their regular circulation. I dismissed the subject because I found no evidence of PrPC or PrPSc acting as anitgens or that antibodies were formed for their ligation. I saw no dire reason to include dynamic interactions with T cell (and several subtypes) if there was nothing to engage their specific immune response. I was wrong. Though DCs through induced maturation process do migrated between the blood, brain, and lymphodial system, they do not directly interact with the non-migratory FDCs in the spleen and lymph node B cell follicles/germinal systems. I have pinpointed FDCs as key spots for PrPSc accumulation and conversion after peripheral infection, but it remained unclear how they left these areas except that neuroinvasion was seem after a certain critical titer load of the scrapie protein. So I looked at what comes in contact with FDCs, turns out B cells and naïve T cells circulate into these areas, and likes a game of tragic telephone can transfer the scrapie protein between them. T cell response can be induced by a prion infection, become primed in the LN or spleen and then reactivated in the perivascular space following cytokine and growth factor mediated TEM of the CSF and BBB. Macrophages and phagocytic DC act as APCs for the reactivation of migrated T cells and then relocalized to neurons damaged by a previous viral infection. A previous infection may not be necessary for prion proliferation because inflammation could be an indirect result of PrP loss-of-function, but an induced specific immune response in concatenation with peripheral prion infection could significantly increase the severity to the disease.

This previous week has been used to learn details of T cell subtype specification  and details of response (cytokine production, exchange, membrane proteins, Th1, Th2, Th17, etc.) Another topic explored included a look back at demyelination in prion disease. Demyelination and myelin-specific T cell response is an important part of multiple sclerosis. MS and prion disease can similarly be perceived as autoimmune diseases. Astrocyte malfunction and sequential phagocytic phenotype takes up apoptotic oligodendrocytes. Improper recycling of myelin can lead to further axonal damage and myelin-specific T cell response. There has been evidence of chronic demyelination pathogenesis in prion disease MOG-specific T cell response could fulfill the need of specific immune response for prion proliferation, but this under the assumption that prions are already present in the brain. Demyelination could still trigger further proliferation to other parts of the brain and body.

Here is a diagram from one article detailing T cell migration. I found it helpful.

T cell prolif

Photo credit:

Goverman, J. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol. 9(6): 393- 221; 2009.