Tuesday, December 13, 2011
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ATP is ??? & its relations to NO levels autoimmune systems/immunizations
http://ajpregu.physiology.org/cgi/content/full/289/3/R738
I suspect that stress acts as an adjuvant by decreasing NO levels. When the immune system is turned on there is what is called the “respiratory burst”, which is the production of superoxide by immune cells. This superoxide pulls down the local NO level and that lower NO level modulates the activity of the lysosome by inhibiting the V-ATPase which acidifies the lysosome and regulates the digestion of cellular contents via autophagy. Under conditions of oxidative stress, autophagy proceeds more slowly and incompletely resulting in more incompletely digested components which are expelled from the cell.
The silver deposits of argyria occur because the silver is reduced to metallic silver in the reducing conditions of the lysosome and is then expelled into the extravascular space where it is permanent. Stuff that is incompletely digested gets expelled too, but then the dendritic cells finish the job (they can’t with silver).
I think this is the generic mechanism for autoimmune sensitization. Low NO, or oxidative stress (they are the same thing) interferes with autophagy via inhibition of the V-ATPase and undigested cellular bits are expelled into the extravascular space. Dendritic cells pick up those bits of incompletely digested cellular contents and (if the local NO level is low), process them with MHC I resulting in autoimmune sensitization. I think this is how the immune sensitization associated with things like primary biliary cirrhosis, stiff person syndrome, and probably MS too.
I say that low NO “interferes”, but actually it is a regulated response. Low NO is one of the signals that indicate a metabolic crisis, where ATP needs to be conserved. Turning off autophagy during an ATP crisis is good ATP crisis management. If you are “running from a bear”, you don’t need to worry about antigens.
Some amount of this autoimmune sensitization might be a feature. When a tumor is growing out of control, it will be metabolically stressed and may expel debris that the immune system picks up on and ultimately attacks. If that site is small and local it may be cleared and resolved. Similarly if you have a parasite or an infection there will be lots of local inflammation which causes metabolic stress and shifts the local dendritic cells more to a non-self bias. I think the problem with autoimmune sensitization is due to low NO causing local metabolic stress which eventually causes autoimmune sensitization.
That might be a generic way to removed damaged cells. If a cell can’t generate enough ATP to sustain itself it will eventually exhibit defective autophagy and oxidative stress due to not enough mitochondria (a consequence of low NO and defective autophagy). If a cell can’t sustain itself it needs to be gotten rid of.
# Sastraon 18 Feb 2008 at 7:46 pm
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