Updated Skeleton MS
This recent article from December 2017 fully aligns with and would seem to confirm the thinking on this thread.
https://www.sciencedirect.com/science/a ... 4917300570
on Metabolic defects in multiple sclerosis
[post-script: Earlier publications in this field point to a role of severe oxidative stress in MS
https://www.researchgate.net/publicatio ... Activation
https://www.researchgate.net/publicatio ... _Neurology
https://www.researchgate.net/publicatio ... _pathology
https://www.researchgate.net/publicatio ... expression
https://www.researchgate.net/publicatio ... thogenesis
In these publications from 2008 - 2011, the viral dimension was however still absent. We know better now.... ]
As we already saw, (the number of) mitochondria and ATP availability play a key role in the pathogenesis of MS. Mitochondrial energy disturbances aggravated by a higher energy demand because of demyelinated axons cause a neuro deficiency. In the CIS/RR stage, there is an acute mitochondrial failure due to (herpes Zoster - known to be an inflammatory virus) viral activity. Triggered by Mitochondrial AntiViral Signalling (MAVS) proteins, intracellular antiviral interferon and cytokines mechanisms are induced while NF-KB mobilizes specialized T-cells for clean up.
https://www.researchgate.net/publicatio ... otein_MAVS
Over time, a high oxidative stress develops due to iNOS (re: generally lower blood pressure in MS patients) and EBV B cells (re: generally lower cancer risk in MS patients, EBV which is know to be an onco virus is the major cause for lymphomas in primates). This oxidative stress and high-fat intake (in particular Saturated FA and Trans FA with lipid peroxidation) that inhibits the activity of antioxidant enzymes (e.g. PDI with critical role in neuro degenerative diseases) cause structural damage to the membranes and the endoplasmic reticulum (ER). Saturated fats also seem to help with the spreading of EBV in the genome (Swank?). In turn, with the loss of “healthy intracellular transport pipes”, mitochondria slow down with a lack of ATP as a result causing neuro problems (ion pumps lacks ATP) and neuromuscular problems (low ATP causes soreness and muscular rigidity due to failure to break muscular bonds) and MS progression.
A new skeleton of MS then looks as follows:
1. in summary
: in early CIS/RR phase, acutely impaired mitochondrial working causes acute axon energy deficiency (ATP) and ion pump failure; neurological trauma causes stimulation of synaptic neurons with increased iNOS; in progressive phase: increased level of iNOS at synapsys causes elevated oxidative stress conditions leading to incremental mitochondrial failure causing low ATP and ever faster neuro pathway exhaustion; many years of neuro deficiency causes rigidity and structural changes to muscles
2. viral culprit
, herpes virinae, hundreds of Millions of years with us, immune system suppresses but never got rid of, herpes even in fish, EBV between 40 and 100 Myears where some pathogenicity is left over, VZV (Zoster)/microbleeds, BBB breach, CCSVI and heavy metal industry, hypoperfusion weakens immunity nasopharynx, viral spread/meninges, brain is not immune privileged, viral tolerance of immune system
3. where BBB breach endothelial cells get virally infected in particular MBP/OPC (fast dividing cells, virus learned to go there because it helps virus replication), innate immunity and SNPs and MAVS, intracellular interferon and cytokines antiviral mechanisms, MAVS triggers NF-KB, NF-KB controls T cell differentiation and mobilizes specialized T cells, first peak in graph age of onset CIS/RR, demyelination MBP/OPCs, mechanism repeats itself [in my case every 8-9 years] after period of low immunity, SNPs in X-chromosome and gender bias, SNPs in Japanese population [post script: early role of ROS in active MS lesions]
4. around mid age: genome and microbiome
co-evolved for >2Byears, EBV B cells and Peyer’s Patches, IgA deficiency, leaky gut, Inflammatory Bowel Syndrome(IBS), deficient methylation/failure of epigenetic regulation and cellular expression, autoimmunity: T/B cells get ‘loaded’ with Zoster and EBV respectively, T/B cells and endothelial cells cross react if they find common epitopes when cells come to expression, cross reaction of endothelial cells with B cells
5. (i)NOS and superoxide EBV B cells, biochemical reaction leads to elevated peroxynitrite, oxidative stress, microglia activation; as the ATP production of mitochondria becomes weaker the inflammatory component that gradually extinguishes over time gets a new chance which explains the second peak in the graph age of onset
: neurological trauma and ATP depletion causes stimulation of synaptic neurons, this increases levels of nitric oxide, two distinct positive feedback mechanisms stimulate NDMA receptor activity establishing vicious cycle of oxidative stress, via iNOS to increased NO and peroxynitrite, the longest nerve paths (legs, feet) show most weakness and exhibit earliest and most spasticity, the limps with most neurological trauma shows most progression, vanilloid receptor and temperature effects
6b. elevated peroxynitrite in turn will lower e.g. all reduced folates in the body as a scavenger of peroxynitrite, lowering methylation cycle activity; lowered methylation activity will lead to increased cellular expression, more superoxide from EBV B cells, and more peroxynitrite, further strengthening the vicious cycle [which initially starts and acts at the level of individual cells because NO, superoxide and peroxynitrite have quite limited diffusion distances]
7. lipid peroxidation and cellular metabolic defects, fats (saturated, trans) and inhibition of enzymatic antioxidant activity causes structural changes to Endoplasmic Reticulum, saturated fats help spread EBV across the genome, number of mitochondria (note vitamin D relation during growth) is key factor, damage of ER causes ever lower ATP production by mitochondria which results in ion pump failure (neuro deficiency) and muscular rigidity (failure to break muscular bonds), air pressure mitochondrial working ATP availability and mobility
8. breaking out of the self-reinforcing vicious cycle of oxidative stress could be done by managing the EBV B cell population by chemo (e.g. cyclophosphamide) with or without HSCT, Cladribine, or mabs, or -ultimately- by hoping that above 60 years of age the B cell population will drop down by itself anyhow, combined with antioxidant treatment (the Pall Protocol http://www.prohealth.com/library/showar ... ibid=17947
) and low saturated fat diet (as per Roy Swank's protocol https://overcomingms.org/recovery-program/diet/
). Incidently, Terry Wahls succesfully used the combination of chemo (mitoxantrone in her case) and an anti-oxidant diet to get out of the wheelchair.
Also antiviral (val-acyclovir or anti HIV) and anti-inflammatory treatment (addressing leaky gut and gut flora transplantation (Borody)) have shown to benefit or even cure MS patients.
9. [post-script] neuromuscular
/muscular blockage: a significant part of progression is an increasing muscular stiffness and rigidity caused by many years of neurodeficiency and diffuse muscular control signals; in parallel the oxidative stress cycle (NO/ONOO cycle) will detoriorate signal conduction; when mitochondria run closer to the edge, issues like oxygen homeostasis become issue. muscles will relearn/remodel, fire together wire together, fire apart wire apart, calcium homeostasis influences signal transfer, needs the right physiotherapy and muscular treatment to break tightened muscles. https://www.semmes-murphey.com/neuromuscular-disorders
When the neurons become unhealthy or die, communication between your nervous system and muscles breaks down. As a result, your muscles weaken and waste away (as I most clearly see in my own case when comparing my left and right leg..).
Here Dantrium is a medication on its own to help break muscle rigidity.
The skeleton is up for further discussion. And of course it now needs flesh around the bone. If there are experts or doctors reading here who want to help for instance by drafting a paper along these lines, please send me a PM. Confidentiality guaranteed.