Week IX

This week has focused on cytokine production and specialized activation of T cell subtypes included in my model (Th17, Th1, Th2) as well as microglia and CNS invasive CD11+ expressing cells like macrophages and dendritic cells. There are many involved and I won’t go into the specifics of what produces what and where they go, only that several pool into the same compartment and add to one amount. Main cytokine circulation occurs in the CNS and lymph node (LN). PGE2 serves a prominent loe in the activation and feedback regulation of IL-23 and IL-17 for TH1 and Th2 activity. I have T cells being activated and interacting with B cells and naturally in-circulating DCs and macrophages. PrPSc enters the LN after being taken up in an unclear method by M cells from the intestinal lumen like other pathogen, and then cross infect cells in Peyer’e Patches that regular populate them and then go into draining LNs. Either by uptake of infection, DCs and macrophages become prion carriers, once in the lymph node they can interact with B cells or directly within germinal centers (which may be preformed by a pre-existing infection). Follicular dendritic cells which highly express PrPC become proliferation sites for the scrapie protein, cross infecting T cells, which then recirculate into the blood and to new sites of injury with a pro-inflammatory goal. If T cells are recruited into the CNS in response to damaged neurons they will cross the BBB barrier, otherwise it seems unlikely that the T cells will enter the CNS enough if at all to infect cells there. Therefore, in pre-existing CNS damage is not occurring, how does the prion enter the brain to trigger more damage and more frequent neuroinvasion of cytotoxic and regulatory cells all potentially cross-infected with prions. This has yet to be elucidated.

Another problem occurs when trying to figure out if the body in naturally capable of developing a specific immune response for the scrapie protein. Past attempts to produce a prion antibody/serum has shown limited success due to variations between prion strains. Antibodies produced and utilized by reactivated T cells in the CNS could also target positively acting PrPC unintentionally as it and the scrapie isoform have the same amino acid sequence, just different conformation.