The Autoimmune Cross-targeting hypothesis is that autoimmunity is triggered when two infections exist on a cell simultaneously: one on the inside like a virus and one on the outside like a bacteria. The immune system gets confused when attacking both the inside and the outside and thus the entire tissue is attacked.
How does this hypothesis fit with the known models like NOD mice?
NOD mice are deficient in TCR on T cell regulator cells
https://www.ncbi.nlm.nih.gov/pubmed/9075796
(here is a simplified summary)
TCR is the T cell receptor which looks into the MHC mailbox of infected cells.
T regulator cells wear TCR and Foxp3. Stimulation of TCR triggers Il-10 secretion and Foxp3 to stop being worn.
Foxp3 suppresses the pathway to viral infection attack through T effector cells.
Il-10 suppresses the pathways to large infection attack through T helper cells. (Th1 and Th2)
Thus when there is something in a MHC mailbox the TCR is triggered and the cells progress down the viral infection pathway.
T regulator cells watch over 4 types of Tcells: Th1 Th2 Th17 Teff
Th1 are the helper T cells involved with large infections thus stimulation of B cells.
Th2 are the helper T cells involved with hidden infections/ allergy reactions.
Th17 are the helper T cells involved with inflammation following tissue damage.
T effector cells are the T cells that go to a site of viral infections in search of antigen.
TCR ( the T cell receptor) has a key involvement with each of these T cell types.
TCR is the receptor that T cells use to look at the MHC (HLA) mailbox which reflects the internal infections.
Again, when the TCR of the T regulator cell see an antigen in this mailbox it down regulates FOXp3 which favors T effector cells to go look for viruses and secretes il-10 which inhibits the pathways to Th1 and Th2, the larger infections pathway. So what happens when TCR is removed?
Jak3 cytokine is released by damaged tissue and binds to without triggering the TCR. Jak3 is "removing" the TCRs. When Jak3 binds to TCR it favors Th17 development. Hence the reason that TCR deficient NOD mice have increased Th17 cells. NOD mice simply don't have some TCRs.
NOD mice and Th17 increased
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755057/
NOD mice are deficient in TCR on T cell regulators
https://www.ncbi.nlm.nih.gov/pubmed/9075796
The key here is that NOD mice develop autoimmune diabetes because of the missing TCRs. The large infection pathway is never completely off, not enough il-10 is made.
Coxsackievirus infection of NOD mice triggers diabetes (Foxp3 removed and viral pathway used)
https://www.ncbi.nlm.nih.gov/pubmed/17376828
When the Foxp3 was ablated in NOD mice diabetes occurred within 3 days. (no virus needed just the viral pathway opened)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998796/
NOD mice with just a bacterial infection have been shown not to develop diabetes (salmonella shown here but any large infection would probably show the same thing)
https://www.ncbi.nlm.nih.gov/pubmed/15376194
The reason is that the viral infection pathway is fully inhibited. NOD mice are the missing TCRs not Foxp3. The Foxp3 will stay on the T regulators keeping the inhibition strong. If anything NOD mice have weaker responses to viral infections because less TCRs are there to turn the viral pathway response on.
What triggers autoimmune disease is the simultaneous activation of the immune system pathways, both pathways activated at the same time: the large and the viral.
To test this: mice models with plenty of TCRs but weak binding Foxp3s then exposure to bacterias like e.coli which should trigger celiac and/or type one diabetes because the viral pathway won't be completely off.
How does this hypothesis fit with the known models like NOD mice?
NOD mice are deficient in TCR on T cell regulator cells
https://www.ncbi.nlm.nih.gov/pubmed/9075796
(here is a simplified summary)
TCR is the T cell receptor which looks into the MHC mailbox of infected cells.
Foxp3 suppresses the pathway to viral infection attack through T effector cells.
Il-10 suppresses the pathways to large infection attack through T helper cells. (Th1 and Th2)
Thus when there is something in a MHC mailbox the TCR is triggered and the cells progress down the viral infection pathway.
Th1 are the helper T cells involved with large infections thus stimulation of B cells.
Th2 are the helper T cells involved with hidden infections/ allergy reactions.
Th17 are the helper T cells involved with inflammation following tissue damage.
T effector cells are the T cells that go to a site of viral infections in search of antigen.
TCR ( the T cell receptor) has a key involvement with each of these T cell types.
TCR is the receptor that T cells use to look at the MHC (HLA) mailbox which reflects the internal infections.
Again, when the TCR of the T regulator cell see an antigen in this mailbox it down regulates FOXp3 which favors T effector cells to go look for viruses and secretes il-10 which inhibits the pathways to Th1 and Th2, the larger infections pathway. So what happens when TCR is removed?
Jak3 cytokine is released by damaged tissue and binds to without triggering the TCR. Jak3 is "removing" the TCRs. When Jak3 binds to TCR it favors Th17 development. Hence the reason that TCR deficient NOD mice have increased Th17 cells. NOD mice simply don't have some TCRs.
NOD mice and Th17 increased
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755057/
NOD mice are deficient in TCR on T cell regulators
https://www.ncbi.nlm.nih.gov/pubmed/9075796
The key here is that NOD mice develop autoimmune diabetes because of the missing TCRs. The large infection pathway is never completely off, not enough il-10 is made.
Coxsackievirus infection of NOD mice triggers diabetes (Foxp3 removed and viral pathway used)
https://www.ncbi.nlm.nih.gov/pubmed/17376828
When the Foxp3 was ablated in NOD mice diabetes occurred within 3 days. (no virus needed just the viral pathway opened)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998796/
NOD mice with just a bacterial infection have been shown not to develop diabetes (salmonella shown here but any large infection would probably show the same thing)
https://www.ncbi.nlm.nih.gov/pubmed/15376194
The reason is that the viral infection pathway is fully inhibited. NOD mice are the missing TCRs not Foxp3. The Foxp3 will stay on the T regulators keeping the inhibition strong. If anything NOD mice have weaker responses to viral infections because less TCRs are there to turn the viral pathway response on.
What triggers autoimmune disease is the simultaneous activation of the immune system pathways, both pathways activated at the same time: the large and the viral.
To test this: mice models with plenty of TCRs but weak binding Foxp3s then exposure to bacterias like e.coli which should trigger celiac and/or type one diabetes because the viral pathway won't be completely off.
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