Do reactive oxygen species play a role in autoimmunity? Can we ameliorate autoimmune conditions by reducing high oxidative stress?

Hip

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Some interesting new murine research shows that during a heart attack, the heart muscle creates reactive oxygen species (ROS), and these ROS will modify human proteins in the heart so that the immune system then views the proteins as a foreign (non-human), and thus a potential threat.

These modified proteins are attacked by T-cells in an autoimmune inflammatory fashion. So in this way, ROS appear to trigger an autoimmune attack. The study itself is here.


Now ME/CFS involves increased oxidative stress, so this heart research makes me wonder whether the ROS in ME/CFS patients could be triggering autoimmune conditions or autoimmune attack.

This paper looks at the role of ROS in autoimmunity.

The paper identifies the main intracellular sources of ROS in the body:
There are three major intracellular sources of ROS:
  • (1) Electron leak from the mitochondrial respiratory chain
  • (2) NADPH oxidases
  • (3) Uncoupled nitric oxide synthase reactions
ROS can also be generated by monoamine oxidase, and other oxidases such as xanthine oxidase, lipoxygenases, cyclooxygenases, and monooxygenases.
If we wanted to try to counter these main three ROS sources in ME/CFS, then the following treatments might help:

(1) Mitochondrial ROS can be quenched with the special antioxidant tempol, which is a potent SOD2 / MnSOD memetic (SOD2 is the SOD that works exclusively in the mitochondria). I once took tempol 30 mg for 10 days, and I found it permanently cured my autoimmune psoriasis. Another mitochondrially-targeted antioxidant is MitoQ.​
(2) NADPH oxidase is an enzyme used by the immune system to manufacture the potent ROS called superoxide, in order to kill pathogens via oxidative stress. White blood cells can make superoxide using NADPH oxidase, as can microglia in the brain.​
Since research suggests ME/CFS patients have chronic low-level viral brain infections, possibly microglia in the brain may be constantly pumping out superoxide via NADPH oxidase, in order to try to kill the infection.​
The best known NADPH oxidase inhibitor is apocynin, found in the herb Picrorhiza kurroa. Some years ago I tried a short term test of Picrorhiza kurroa 2000 mg daily for this purpose. I think it may have reduced brain fog.​
(3) Nitric oxide synthase (NOS) is used by the immune system to make nitric oxide, which kills pathogens by nitrosative stress. The paper says that NOS acts on the substrate arginine to release nitric oxide, with the help of the cofactor BH4. But if there is a shortage arginine or BH4, then the reaction uncouples, generating large amounts of superoxide instead, which then reacts with nitric oxide to generate peroxynitrite.​
Since ME/CFS patients may have chronic infections, this may mean NOS is constantly active. So NOS may well run out of substrates, resulting in large amounts of superoxide and peroxynitrite. Thus possibly supplementing with BH4 and arginine to supply the required substrates may help prevent the generation of ROS from nitric oxide synthase. Arginine has also been shown to be antiviral for coxsackievirus B.​
Prof Martin Pall also focuses on the central role of NOS uncoupling in his NO/ONOO- theory of ME/CFS.​

If one were to address all three of the above sources of ROS, this might reduce ROS levels in ME/CFS. This may be generally beneficial, and if the ROS autoimmune theory holds water, might also help ameliorate autoimmune inflammation and assumed autoimmune conditions like POTS which are found in ME/CFS.

Other sources of ROS mentioned in the paper include monoamine oxidase (MAO), the enzyme which breaks down dopamine. The paper suggests MAO inhibitors can be used to reduce the ROS generated by MAO, and says that the MAO inhibitor phenelzine ameliorates MS in a mouse model (you have to avoid tyramine-containing foods with this drug). Other sources of ROS are detailed here.



However, another paper says that too little ROS as well as too much ROS may contribute to the triggering of autoimmunity:
We conclude that ROS have a beneficial impact on the prevention of autoimmune diseases, because ROS deficiency contributes to their initiation and facilitates a disease progression.
increased ROS production can influence several signaling pathways, and therefore could drive a regular immune response toward autoimmunity.
The paper suggests that a balanced degree of ROS is desirable to help prevent autoimmunity:
We conclude that balanced levels of ROS are essential to sustain health and avoid the development of autoimmune diseases.


The first paper I mentioned concludes:
The role of ROS in autoimmunity remains complex. ROS accumulation has been implicated both in the initiation and progression of autoimmunity, but is still unclear whether it represents a bona fide trigger or a harmless accompaniment.

It is, however, intriguing to consider the development of selective ROS inhibitors as a tool that could be used to treat a broad spectrum of autoimmune diseases.
 
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Hoosierfans

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@Hip you mention these products:

(1) Mitochondrial ROS can be quenched with the special antioxidant tempol, which is a potent SOD2 / MnSOD memetic (SOD2 is the SOD that works exclusively in the mitochondria). I once took tempol 30 mg for 10 days, and I found it permanently cured my autoimmune psoriasis. Another mitochondrially-targeted antioxidant is MitoQ.
(2) NADPH oxidase is an enzyme used by the immune system to manufacture the potent ROS called superoxide, in order to kill pathogens via oxidative stress. White blood cells can make superoxide using NADPH oxidase, as can microglia in the brain.​
Since research suggests ME/CFS patients have chronic low-level viral brain infections, possibly microglia in the brain may be constantly pumping out superoxide via NADPH oxidase, in order to try to kill the infection.​
The best known NADPH oxidase inhibitor is apocynin, found in the herb Picrorhiza kurroa. Some years ago I tried a short term test of Picrorhiza kurroa 2000 mg daily for this purpose. I think it may have reduced brain fog.​
(3) Nitric oxide synthase (NOS) is used by the immune system to make nitric oxide, which kills pathogens by nitrosative stress. The paper says that NOS acts on the substrate arginine to release nitric oxide, with the help of the cofactor BH4. .​


Do you have a source for them? I’m already trialing Kuvan (BH4), so interested in the Tempol and the apocynin.
 

Hip

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Do you have a source for them? I’m already trialing Kuvan (BH4), so interested in the Tempol and the apocynin.
The only source of tempol I know is science.bio. Picrorhiza kurroa you can find just from a Google search. This herb is also called Kutki. I bought the Dr Wakde's brand of Picrorhiza kurroa.