Multiple sclerosis remains a challenge for health professionals and the sufferers.

We need vigilance to detect MS as early as possible, to clarify any differential diagnosis, to understand mechanisms and to deliver safe and effective therapies.

The clinical presentations require us all to be good neurologists!

This is a disease that needs to be carefully followed at clinical and research levels.

With imaging, MRI is positive in about 95% of cases.

With established MS, MRI of the spinal cord will show changes in similarly high percentages.

In order to understand a major mechanism in MS, I provide the following basic information.

Immune cells are divided into thymus-derived cells (T lymphocytes) and bursa-derived (B lymphocytes) which respectively are involved in cell mediated and humoral (antibody) mediated immunity.
The body is patrolled by billions of T cells of which the majority appear to be dormant.

T cells must not launch attacks on the host's own cells.
In the development of T cells, mechanisms are set up that ensure that this does not happen. In some diseases there is a breakdown in these mechanisms.

ANTIGEN RECOGNITION AND T CELL ACTIVATION.

Antigens are generally peptide sequences, polysaccharides or nucleotides from outside the body (non-self)
T cells require 2 signals for activation.

(1) Signal 1 is antigen-receptor ligation.

(2) Signal 2 for B cells and cytotoxic T cells is delivered by helper T cells, and for helper T cells is delivered by the antigen presenting cell.

ANTIGEN-PRESENTING CELLS

T cells recognize antigens only on the surfaces of antigen-presenting cells (APCs).

2. Macrophages and dendritic cells.

These are the antigen processing and presenting cells. (Ephraim Fuchs 1997)
The ligand for the T cell receptor is generated by the APC through processing and presentation of the antigen.

Foreign proteins in intracellular compartments are degraded into peptide fragments and these peptides then associate with the specialized antigen-presenting molecules encoded by the highly polymorphic genes of the MHC.

The MHC-peptide complex is exported to the cell surface, and the T cell receptor is then ligated by a complex determinant .

Macrophages are thus crucial cells for the processing and presentation of antigens.

Some intracellular pathogens have the capacity to delay or prevent maturation of phagosomes in the macrophage.

Work by deCC Thilo L in Paris showed that after infection of macrophages with mycobacterium avium, phagosomes became depleted in membrane components and through interchange of constituents ,early endosomes also became depleted.

Ordinarily the phagosomes are microbicidal organelles

Numerous pathogens such as toxoplasma, coxiella burnetti, leishmania, mycobacteria, salmonella, and legionella species can thrive in macrophages, evading lysosomal degradation and even multiplying. (Amor and Swanson)

Dendritic cells

These cells have long arms or dendrites and are found in many sites including skin (here they are called Langerhans cells) and mucous membranes.
They have stem cell precursors in the monocyte line as do macrophages.
Some capture invading microorganisms, engulfing them in vacuoles.
They are highly efficient in capturing and presenting antigens, and activate T helper cells and cytotoxic cells.
Researchers are interested in the role of particular subsets of these cells in setting the type 1 and 2 (TH1 and TH2) T cell responses as described below.

Some dendritic cells can produce interferon..

A subset of dendritic cells make DC-SIGN, a molecule which can bind to the outer coat of the human immunodefiency virus.
Other infectious agents can alter dendritic cell responses.
Malarial parasites bind to dendritic cells and prevent them from maturing.
Some of the herpes virus family such as cytomegalovirus also interfere at this level.

MHC MOLECULES

The name MHC refers to the major histocompatibility complex consisting of the genes and the products discussed below.

HLA is the logo for human MHC.

The MHC, on human chromosome 6p21, is a principal susceptibility locus for many human autoimmune diseases. Susceptibility to a number of these diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS) and type 1 diabetes, is associated with particular alleles of HLA-DR and/or -DQ genes, providing strong evidence for a significant role of MHC class II restricted antigen presentation in these disease processes

MHC class 1 molecules are expressed on the surfaces of almost all nucleated cells, and present peptides consisting of mainly 8-11 amino acids. The MHC-peptide complex is formed in the endoplasmic reticulum and is brought to the cell surface for recognition by CD8+ T cells.

MHC class 2 molecules present mainly 12 -24 amino acid length fragments that have been taken in from outside the cell. The class 2 proteins are expressed on the surface of a limited number of cell types, thymic epithelium, B lymphocytes, activated macrophages and dendritic cells.
The peptides are generated in and associate with class 2 molecules in endocytic vesicles and are brought to the surface for recognition by CD4 +
T cells.

Susceptibility to MS is multifactorial, but some DR2 alleles and their corresponding haplotypes seem to be important, namely DRB1*1501,DQA1*0102, and DQB1*0602.

These genes and their products influence the way that antigens are presented to T cells.

TH1 and TH2 setting.

During the description of T cell transformations researchers describe T helper cells being set into TH1 or TH2 states.
This setting of T cells into the TH1 or TH2 states may turn out to be extremely important.

T helper cells termed TH1 cells appear to be involved in getting T cells to attack intracellular organisms ,but are also involved in diseases such as multiple sclerosis and juvenile onset diabetes, whereas T helper cells being set in TH2 forms appear to be involved in antibody production and in allergy.

Not only are there genetic markers in autoimmune diseases which influence the kind of immune response, but there appear to be factors evoking greater dendritic cell activity and a higher tendency to ingest DNA and result in varieties on anti nuclear antibodies. One such stimulus is increased production of interferon alpha

There are specific cytokines associated with these cells.

TH1 cells produce interleukin2 (IL2), IL6, tumour necrosis factor alpha (TNF alpha), and interferon gamma(IF gamma).
TH2 cells produce interleukin4 (IL4), interleukin10 (IL10), and in allergic disorders, interleukin5 (IL5).

If a dendritic cell provokes the wrong kind of response in T cell and cytokine profile, the outcome can be persistent disease.
With leprosy, a type 1 response leads to a mild tuberculoid form of the disease, but a TH2 response gives the more serious lepromatous disease.

Specific ratios of TH1/TH2 cells occur and the above associated cytokines are released. This TH1/TH2 description is probably over-simplified.

In clinical practice we need to be able to assess T cell activity and cytokine production, but at present it is not a routine form of testing.
We need to consider the likelihood that infectious viruses and bacteria have evolved defence molecules that divert the immune system, thus enabling them to keep a pathological process going..

This has implications beyond understanding MS.

In MS some of the episodes appear to be related to times of increased migration of activated T cells across the blood-brain barrier into plaques or injury sites.

Myelin basic protein(MBP) becomes an antigen to activated T cells in MS. The DR2 status includes molecules that bind with high affinity to an amino acid sequence in MBP.

To summarize the above, a crucial requirement is for immune cells to recognize and read specific antigens from microorganisms and other foreign materials. This recognition involves macrophages producing an antigen presenting protein which attaches to some peptide groups on the antigen and allows T cell receptors that are specific to other groups on the antigen to allow specific clones of T cells to be activated. As well the macrophage phagosomes are important in the lysis of microbes inside the cell.

Activated T cells can be characterized by laboratory measurement of surface markers.

Glycoproteins are a crucial component of the recognition mechanism. The arrangements of these glycoproteins give the specificity of the surface markers. CD means "cluster determinant" and from here on we can explain specificities of cells by their CD classification.

T helper and T cytotoxic cells.

T cells can be divided into T helper cells (CD4 cells), and cytotoxic T cells (some of these have CD8 surface markers.)
Cytotoxic T cells tend to shift into a TH1 state and are concerned with dealing with intracellular infections.

T suppressor cells

There are also T suppressor cells, with capacity to decrease the risk of immune reactions towards self. Sakaguchi at Kyoto university in Osaka found T cells with CD4 markers which also possessed CD25 molecules.

These cells can decrease activity of killer T cells possibly by their responses to TGF? and IL10.
T suppressor cells have a surface receptor called glucocorticoid-induced TNF receptor (GITR), Blocking this receptor has evoked tumour reduction in mice.
In some circumstances the activity of these suppressor cells may decrease the effectiveness of other T cells against intracellular infections and also malignant cells.
In mouse experiments antibodies that blocked TGF beta and IL10 blocked tumour /leukaemia induced by Friend leukaemia virus, and reduced CD25 cells.
(Also CD8 cells.)

T natural killer cells

Natural killer (NK) cells are large granular lymphocytes which kill target cells that express little or no HLA class1 molecules.
Such target cells are virally affected cells and malignant cells. NK cells express receptors that inhibit killer cell function when self MHC class1 is present.

Darryl See cites the T (NK) cells as improving in function, when CFS sufferers consume glyconutrient supplements.
I have no data on any role of this in MS

We can now link immune cell abnormalities, viral/cell interaction and cytokine release with the metabolic abnormalities in MS.

We are approaching the time where a capacity to stop a particular clone of T cells attacking myelin is becoming feasible and there may also be some advantages in substances that block the target effects of tumour necrosis factor alpha and other cytokines.

It has never been really demonstrated that any therapy alters the ultimate course of MS but interferon beta and glatiramer (copaxone) seem to decrease the number, and perhaps severity, of episodes while in the acute attack ACTH or steroids may modify that exacerbation.

At last new therapies are emerging.

Recent advances in (HMG Co A reductase inhibitor) ( Statin) actions

3-hydroxy-4methylglutarylCoA is a stepping stone in cholesterol synthesis as well as the synthesis of ubiquinone (Co-enzyme Q10)

Recently several researchers have reported regression of M S plaques and clinical improvement with statin drugs (HMG CoA reductase inhibitors) such as Simvastatin.

From Dr Timothy Vollmer at the Barrow Neurological Institute in Arizona, USA and Dr O Neuhaus MS Research group, Dept of Neurology, Karl-Franzens-Universitat,Graz., Austria there is clinical and research data to suggest that HMG CoA reductase inhibitors such as simvastatin can decrease mononuclear cell activity including migration into injury sites, and decrease molecular mechanisms of damage to myelin as well as allow improvement of MRI appearances over 2 years.

This will be ongoing research, but clearly a drug which has the profile of safety such that it is used widely in lipid disorders has a reasonable role here.

It may be useful alone or even in combination with copaxone or IF beta-1.

If statins are used I recommend a minimum of 50 mg of Coenzyme Q10 per day, since statins have been found to lower blood and tissue levels of this vital co-enzyme.
I cannot find data to determine the best dose of co-enzyme Q10,but it needs piperine in black pepper to increase absorption.

Mevalonic acid reverses the protective effects of statins in the mouse model.

If there is a trend for the metabolic products of omega 6 poly unsaturated fatty acids to be elevated, reducing the oils that contain them , such as sunflower, safflower and soya oils could be sensible and at the same time the provision of omega 3 poly unsaturated fatty acids such as alpha linolenic acid in flaxseed oil could be helpful.

Dr Bob Gibson has found that flaxseed oil does not elevate blood levels of EPA and DHA, so fish oils are desireable as well.

I tend to recommend the antioxidants vitamin E better as natural E, (mixed tocopherols) co enzyme Q10 and R alpha lipoic acid.

Gamma tocopherol and R alpha lipoic acid mop up peroxynitrite which is an active free radical which would be generated by inflammatory cytokines.

TNF alpha, peroxynitrite and NF kappa beta have all been found in the areas where myelin is being damaged.

In essence thecytokines above induce one form of nitric oxide synthase called inducible nitric oxide synthase (INOS). The nitric oxide which forms, reacts with superoxide in mitochondria to produce the peroxynitrite, a more reactive free radical.

Superoxides are also a product of oxidative injury in cells in circumstances of chemical and microbiological damage.

PEROXYNITRITE EFFECTS.

(1) The peroxynitrite inactivates superoxide dismutase in mitochondria increasing the levels of superoxide.

(2) But in addition the peroxynitrite activates a transcription factor called nuclear factor kappa beta (NF??) which stimulates gene transcription for ILI, IL6, TNF alpha and IF gamma, and also gene transcription for inducible nitric oxide synthase. (A self perpetuating cycle)

Thus both superoxide production (and decreased degradation) and nitric oxide production are kept high, perpetuating a higher level of peroxynitrite.

(note that TNFalpha, PON,NFKB have all been found along with antibody-binding domain of T cell receptors in the MS lesions.)

(3) Peroxynitrite contributes to a decrease in ATP pools in the following fashion (a further feed forward effect).

An enzyme called poly adenylate ribose synthase (PARS) is activated by breaks in DNA. Free radicals produce "nicks" in mitochondrial and nuclear DNA.

The PARS promotes polyribosylation of histones, and the substrate NAD
involved in all oxidative and energy metabolism conversion to NADH is depleted.

With depleted NAD+/NADH, ATP is also depleted. Hence mitochondrial and perhaps nuclear cell energetics are impaired.

As well peroxynitrite can injure pyruvate dehydrogenase, aconitase and ? keto gluterate dehydrogenase impairing Krebs cycle mechanisms.

(4) It is likely that increased peroxynitrite contributes to injury in other inflammatory states. The proximity of T cells, and other cells participating in pathological processes, to target cell sites shapes the risk of interleukin over-activity or oxidative injury.

It is clear that a number of factors are involved in the location of these specific injuries.

Now we have evidence that R-alpha lipoic acid also decreases migration of activated T cells across the blood-brain barrier.

(5) Chromosomal abnormalities are found in up to 90% of cases of scleroderma where peroxynitrite is likely to be active at endothelial and sub endothelial vascular locations. I have no definite evidence about local chromosomal damage in cells involved in MS.

(6) Dr Judy Ford has reported increased chromosomal abnormalities in people using pesticides.

(7) I believe that we need to be much more concerned than ever about the high level of environmental pollutants. Sufferers with MS may represent a more vulnerable sub group.

(8) PON increases intracellular calcium which is pertinent to 2 other NO synthases which are calcium dependent. Increased intracellular calcium could further disadvantage cell function.

(9) NO and PON might also facilitate rapid glutamate release in some neurological injury states but it would be speculative to know whether the" mind-fog" states of CFS and MS are related to this.


OTHER ASPECTS OF IMPAIRED ATP FUNCTION

(1) There may be decreased transfer of free fatty acids by carnitine across the mitochondrial membrane.
Acetyl l carnitine is needed to transport long chain fatty acids(C20 and greater) across mitochondrial membranes.
I am strongly supporting mitochondrial protection.

(2) If magnesium is low, ATPase cellular pumps may not work as well.

It is feasible, but not totally proven, that giving cobalamin as methyl cobalamin, provides the form which is used inside neurones and may be more effective than hydroxycobalamin or cyanocobalamin.

Now experimental data supports protection by PPAR agonists.(pioglitazone)
There is not enough to support ongoing therapy with this.

Other unrelated contributions to nerve susceptibility

I found five papers suggesting that serum homocysteine was higher in MS.

Some studies have shown low B12 levels.

This is important as protection require ser B12 > 400 pmol/L, and preferably higher.

I think it is a good idea to keep homocysteine levels(at 8 umol/L o rless )lower by being sure the person has adequate folate and trimethyl glycine or some similar methyl donor.

Incidentally, the prevalence of one genetic mutation is common enough to warrant testing in all MS patients.
The MTHFR gene writes the code for the synthesis of 5,10 methylene tetrahydrofolate reductase.
It is located on Chromosome1 (Cr 1 p 36.3)
A point mutation 677C->T results in a 50% reduction in the enzyme activity. This enzyme is described as thermolabile.
This is an autosomal recessive gene present in 15% of the caucasian population.

One study in France showed a 16.9% prevalence there.

People can be tested by having blood taken (fasting and kept cold ) for homocysteine, folic acid, B12 and the MTHFR gene status.

If we count heterozygotes for MTHFR polymorphisms thwe rate of high homocysteine is higher than 20%

If it is true that there is any other abnormality of fatty acid metabolism it would make sense to give evening primrose oil in small amounts and fish oil as well.

Vit D deficiency

Now evidence supports checking vitamin D3 levels, and bringing serum levels up to at least 80 nmol/L.

Vitamin D supplements are associated with lower risk of multiple sclerosis
In the first study of its kind, research published in the January 13 2004 issue of the journal Neurology, has found that women who take multinutrient supplements that contain vitamin D have a 40 percent reduction in the risk of developing multiple sclerosis (MS) compared to women who don’t take supplements.

The research team examined data obtained from the Nurses’ Health Study and the Nurses’ Health Study II, which lasted twenty and ten years, respectively, to include a total of 187,563 in the current analysis. Information on diet and supplement use was assessed at the beginning of the studies and every four years. One hundred seventy-three women developed multiple sclerosis during the period analyzed in the current research.

It was discovered that women whose vitamin D supplement intake was 400 international units or greater per day had a 40 percent reduction in the risk of developing MS compared to nonsupplement users.

Women whose intake of vitamin D from both supplements and food also had a reduced risk. Multiple sclerosis risk was not lower in those whose vitamin D source was food alone. None of the other multivitamin components was found to be associated with MS risk, following adjustment for total vitamin D intake or vitamin D from supplements.

Author Kassandra Munger, MSc, of Harvard School of Public Health in Boston, commented, "Because the number of cases of MS increases the farther you get from the equator, one hypothesis has been that sunlight exposure and high levels of vitamin D may reduce the risk of MS. These results need to be confirmed with additional research, but it's exciting to think that something as simple as taking a multivitamin could reduce your risk of developing MS."

These are some of the nutritional things which can be considered above and beyond the average sort of diet.

In the future transfer factors from colostrum may well have a place, and quercetin and DHEA are interesting. This is work in progress.
Considerable interest is being generated about low dose naltrexone (LDN) (Dr Burt Berkson).
There is a combination of R alpha lipoic acid 200mg tds with LDN at 3-4.5mg at bedtime. It appears to be very safe.

Minerals
It may emerge that mineral imbalances or toxicity from heavy metals increase the risk for some neurological diseases.
If anything high CSF copper may be found in MS and can be lessened by lowering copper intake and increasing zinc intake.

Curcumin

This ingredient of turmeric has powerful anti-inflammatory properties.

Again it needs piperine to be adequately absorbed.

Suggested curcumin dose is 200mg 3-4 times per day with 20mg of piperine per dose!

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