Neurodegeneration Vs Autoimmunity in MS – Which One Comes First, and Which One is More Important?
Why is important to know ? Because understanding which one comes first and which one is more important would allow scientists to find better treatments and to create drugs that target the root (or as close as possible to the root ) cause of the problem .
There is some evidence that neurodegeneration may precede inflammation and autoimmunity in MS. Let’s explore the research:
1. Neurodegeneration may come first and may be more important than inflammation in MS.
MS was traditionally described as an inflammatory, autoimmune condition. Basically, the cells of the immune system would move across the blood brain barrier (which is not working properly in MS), attack the cells of the nervous system and trigger inflammation. The inflammation would often correspond with an acute relapse.
Note: Almost all drugs currently treating MS are based on this theory, targeting the immune system known as either immunomodulatory or immunosuppressant drugs [1].
2.Mitochondrial dysfunction leads to neurodegeneration.
An increasing amount of evidence is showing that the key problem may be the degeneration (which develops because of mitochondrial dysfunction), while inflammation/autoimmunity would come second. In this case, we will need to see drugs that target the neurodegeneration for MS (by the way, there are some drugs approved for other medical conditions, not for MS- that can help treat neurodegeneration).
3. The fact that degeneration may be the first step, and possibly more important than the inflammation/ autoimmune component is supported by the following facts:
In some cases of progressive MS (rare, but they do exist), there are no signs of inflammation (focal inflammation).
Cutting down the inflammation does not stop disease progression. Current drugs (which target the inflammation/autoimmunity) target the immune system and the relapse rate with almost no effect on the disease progression (Tecfidera is an exception).
Stem cell therapy is very effective in decreasing inflammation, but unfortunately does not stop the degeneration of the axons or brain shrinkage (both axonal degeneration and brain atrophy are seen in MS even in the absence of inflammation).
The dysfunction of the mitochondria plays a key role in the degeneration and is also essential in the development of MS. Once they lose myelin, some axons will degenerate while others will survive, and it looks like the mitochondria dictates the fate of these axons. Why is this happening? Because the degenerated axons contain dysfunctional mitochondria, while the survivors contain healthy mitochondria that actually fight degeneration.
Furthermore, the worsening of mitochondrial dysfunction correlates with disease progression and reduces ability to recover from relapses [2, 3].
4. Drugs and supplements that target neurodegeneration and have no effect on inflammation help treat MS. For example, the antioxidants CoQ10 (in human studies) and Mito-Q (in animal models) show benefits in treating the MS and they work predominantly on neurodegeneration, with almost no effect on inflammation [4].
Dimethyl Fumarate (Tecfidera) is the only FDA approved drug for MS that modulates the immune system, but also works against neurodegeneration. Its antioxidant effect derives from its ability to reduce oxidative stress through activating NRF-2 pathway (Note: there is a pretty powerful supplement that also activates NRF-2 pathway, I will talk about this).
5. It is interesting to look at the research done in Parkinson’s diseases (a condition that shares similarities with MS). Maybe scientists did a better job researching Parkinson’s disease? This condition was considered for a long time a neurodegenerative condition and treated accordingly, yet there is increased evidence of autoimmunity [6] .You may have read the news a couple of weeks ago about the discovery of direct evidence that autoimmunity plays a role in Parkinson’s disease. [5]. Maybe the same thing happens in MS , too- and the autoimmune component comes second after neurodegeneration?
Which comes first-neurodegeneration or autoimmunity ? is pretty much like asking : Which came first: the chicken or the egg? The most popular theory is that autoimmunity comes first. However, as noted above, there is evidence that neurodegeneration may come first, and be more important than the autoimmune component, perhaps in a similar fashion with what we see in Parkinson’s. This means that the current drugs (except Tecfidera) are touching just the tip of the iceberg (the autoimmunity). A third option would be that neurodegeneration may develop in the same time with autoimmunity (this theory could be explained by increased levels of TNF-apha which causes both neuroinflammation/autoimmune reaction and degeneration) [7,8]
