Introduction
This section sets out what we now believe is the likely cause of Multiple Sclerosis (MS) and, once this cause is eventually accepted by the scientific and medical community, how its treatment might develop in the coming years.
This explanation has been prepared by pulling together evidence based on existing research and then applying logic and common-sense deductions to the current state of knowledge. We identify where we have made deductions and inferences and what is conjecture or supposition. We also highlight further areas of research to be undertaken, which should then complete the missing pieces of the MS jigsaw puzzle.
In essence, when one puts together all the evidence from a wide range of sources and combines it with logic and sensible deductions, it is increasingly likely that the trigger of MS is very small (possibly picomolar or nanomolar) quantities of a highly lethal toxin called epsilon toxin (ETX). Epsilon toxin is the third most lethal toxin known to man after botulinum and tetanus. It is also categorised as a Grade B bio-terrorism agent in USA and France.
Although MS was first recognised and documented in the 1860s, its cause has proved elusive. It has long been known that MS is a more common disease in northern, less sunny climates, which has given rise to the possible association of MS with a lack of vitamin D. MS was linked to sheep and sheep farming in the 1980s and, for instance, there was an unexplained sporadic outbreak of MS in the Faroe Islands in the 1940s.
MS has also been linked to the Epstein Barr Virus (EBV) because 99% of the MS population test positive for antibodies to EBV, compared with only 90% of the normal population. This link is also supported by some evidence of the persistent infection of brains of MS patients, which have been infiltrated by EBV memory B cells in MS patients, causing an auto-immune response. However unlike ETX, the potential link of EBV to MS does not explain how the blood brain barrier can be breached.
Many of the currently reasonably successful disease modifying drugs (DMDs) (taken both oral and intravenous) deplete or restrict the movement of B cells in patients with MS. There is therefore increasing evidence that B cells are associated with worsening MS symptoms but this does not prove the link with EBV. EBV infection also does not explain how the specific, initial damage to the blood brain barrier (BBB) occurs or how oligodendrocytes are damaged (see below).
What is Multiple Sclerosis?
Multiple Sclerosis (MS) is defined as a chronic condition that affects the brain and spinal cord (i.e. the central nervous system (CNS)) in humans. Oligodentrocytes produce the insulating coating (myelin) that protects the nerve cells (axons). In MS, the oligodentrocytes are damaged (demyelinated) and this causes a range of symptoms including problems with vision (such as Optic Neuritis), muscle weakness affecting arm or leg movement and trouble with sensation or balance.
MS takes several forms. The most common form of MS is Relapsing Remitting MS (RRMS), with which new symptoms occur in isolated attacks. Less common, but more severe, are the progressive forms of Secondary Progressive MS (SPMS) and Primary Progressive MS (PPMS), in which MS attacks build up over a shorter time. In RRMS, attacks may be months or years apart and symptoms may disappear completely. However, permanent neurological problems often remain, especially as the disease advances.
MS also involves an immune-mediated process in which an abnormal response (possibly caused by memory B cell lymphocytes) of the body’s immune system is directed against myelin in the CNS, which is why MS is frequently referred to as an “auto-immune” disease. See the Multiple Sclerosis Society (48) ( https://www.mssociety.org.uk ) for further information.
How is Epsilon Toxin produced and how does it get into the Bloodstream?
ETX is produced by a plasmid (a small self-replicating strand of DNA within a bacterial cell) and is hosted by a bacterium called C. perfringens, which inhabits the intestine. C. perfringens is ever-present in nature and can be found as a normal component of decaying vegetation and animals, marine sediment, the intestinal tract of humans and other vertebrates, insects, and soil. It has the shortest reported generation time of any organism at 6.3 minutes in thioglycolate medium. C. perfringens (type A) is one of the most common causes of food poisoning in the United States. C. perfringens is a gram-positive, spore-forming, anaerobic bacillus that is widely present; its spores can survive long periods (decades) in hostile environments and will germinate when favourable conditions arise.
C. perfringens comprises five different types of bacteria (A to E), which cause various ailments, but it is only types B and D which produce ETX. The plasmid in types B and D initially produces ETX as an inactive “prototoxin” in the gut, which is then activated by an enzyme (typically trypsin or chymotrypsin, which is prevalent in the gut). Once in its active state, the toxin can cross the intestine wall and thereby enter the bloodstream. To give an analogy, we could say that, if the prototoxin is represented as a “shirt and tie”, the trypsin rips off the “tie” to leave just the “shirt” as the active toxin.
ETX is known to react with cells in the blood brain barrier (BBB), which are CNS endothelial cells, and once in the brain ETX also binds with high affinity to white matter – attacking myelin in oligodendrocytes, the optic nerve, spinal tissue as well as the kidney and Schwann cells. In addition to its pore forming ability, there is also evidence that ETX can damage oligodendrocytes without having to form pores. Oligodendrocytes lose potassium and take in sodium and calcium through osmosis and this leads to cell death.
What does ETX do once in the Bloodstream?
ETX is known as a “pore-forming” toxin, whereby seven units of the toxin (“monomers”) bind together in certain cell walls of a host cell to form a heptameric (seven-sided) structure (“oligomer”). A good analogy would be that the monomers combine together in a cell wall to create a “funnel” between the cell and the blood vessel. This pore exposes the contents inside the cell to the outside, leading to rapid cell death (necrosis). There is an image of the ETX monomer, which consists of three “domains”, together with the pore:
The following is an extract from an article by MR Popoff (2011) (14) “Epsilon toxin: a fascinating pore‐forming toxin“ describing the impact of ETX:
“The brain is the second organ, after the kidneys, where ETX accumulates massively. By contrast to kidneys, ETX binds to brain in an exclusively specific manner and with high affinity… This indicates that ETX passes the blood–brain barrier and recognizes specific cells or sites in the brain. Indeed, ETX has been shown to alter the integrity of the blood–brain barrier, permitting not only its own passage, but also that of macromolecules …. Such a rapid decrease in blood–brain barrier permeability facilitates rapid ETX accumulation in the brain …. Endothelial cells then show macroscopic alterations including swelling, abundance of clear vacuoles and loss of intracellular organelles, as well as protrusions or blebbing of the luminal surface. Later, their cytoplasm is very thin and the nuclei pyknotic, leading to a very attenuated capillary endothelium….”
ETX is therefore known to react with cells in the Blood Brain Barrier (BBB), which are CNS endothelial cells, and once in the brain ETX also binds with high affinity to white matter – attacking myelin in oligodendrocytes, the optic nerve, spinal tissue as well as the kidney and Schwann cells. In addition to its pore forming ability, there is also evidence that ETX can damage oligodendrocytes without having to form pores. Oligodendrocytes lose potassium and take in sodium and calcium through osmosis and this leads to cell death.
Blood Brain Barrier
It is often thought that MS is an “auto-immune” disease and it does exhibit features, whereby host T effector cells and B cells attack the host’s myelin (myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG)) in the brains of MS patients. However, Barnett and Prineas (2004) (5) found no or little evidence of lymphocytes in newly forming lesions when examined in MS patients, who died of other causes shortly after a MS relapse. This demonstrated that the first damage in a newly forming lesion is inflicted by something else other than host lymphocytes, which would be consistent with an infection from a toxin such as ETX. It is known and accepted that MS in its early stages involves damage to oligodendrocytes within the brain (lesions), which first requires that the BBB must be breached. So, in the first place, we need to identify something, which is capable of breaching the BBB. Whilst it is clear that there are “auto-immune” features of MS, we believe these are consequences of the initial cause, being ETX.
The BBB is a highly selective semi-permeable border that separates the circulating blood from the brain and extracellular fluid in the CNS and originates from the endothelium during human embryonic development. The BBB is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of water, some gases, and lipid-soluble molecules as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function. The BBB restricts the diffusion of solutes in the blood (e.g. most bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of hydrophobic molecules (O2, CO2, hormones) and small polar molecules. The BBB is therefore not easily breached – indeed significant medical research has been, and is being, undertaken to facilitate the uptake of drugs by the brain but so far with limited success. The BBB is breached, for instance, from a haemorrhagic stroke, certain bacteria such as meningeal bacteria. The other blood body barriers (including the blood periphery nervous system barrier) have different embryonic origins to the BBB and are not affected by ETX.
Breaching the Blood Brain Barrier
It is often thought that MS is an “auto-immune” disease and it does exhibit features, whereby host T effector cells and B cells attack the host’s myelin (myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG)) in the brains of MS patients. However, Barnett and Prineas (2004) (5) found no or little evidence of lymphocytes in newly forming lesions when examined in MS patients, who died of other causes shortly after a MS relapse. This demonstrated that the first damage in a newly forming lesion is inflicted by something else other than host lymphocytes, which would be consistent with an infection from a toxin such as ETX. It is known and accepted that MS in its early stages involves damage to oligodendrocytes within the brain (lesions), which first requires that the BBB must be breached. So, in the first place, we need to identify something, which is capable of breaching the BBB. Whilst it is clear that there are “auto-immune” features of MS, we believe these are consequences of the initial cause, being ETX.
The BBB is a highly selective semi-permeable border that separates the circulating blood from the brain and extracellular fluid in the CNS and originates from the endothelium during human embryonic development. The BBB is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of water, some gases, and lipid-soluble molecules as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function.
The BBB restricts the diffusion of solutes in the blood (e.g. most bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of hydrophobic molecules (O2, CO2, hormones) and small polar molecules. The BBB is therefore not easily breached – indeed significant medical research has been, and is being, undertaken to facilitate the uptake of drugs by the brain but so far with limited success. The BBB is breached, for instance, from a haemorrhagic stroke, certain bacteria (such as meningeal bacteria). The other blood body barriers (including the blood periphery nervous system barrier) have different embryonic origins to the BBB and are not affected by ETX.