MULTIPLE
SCLEROSIS EPIDEMIOLOGY
New Ideas and Concepts in Multiple
Sclerosis from Epidemiology, Etiology to Epigenetics
IAGIM Drug Development
Institute have currently undertaken a 10 to 15 year global initiative
in the study of all five major types of Multiple Sclerosis covering
diverse interdisciplinary fields of thyroid lymphocyte B-, T-cell
selection, Virology (EBV, HH2-6-8 etc.), Blood CNS Barrier penetration,
MHC, Protein folding chemistry, Immuno-molecular chemistry, Chronic
and acute CNS inflammation sequence, Human Microbiota, Microbiota
and CNS Connectivity, Cytokines & Chemokines role, Autoimmune
scaring and lesion, in terms of neuro-immuno epidemiology, etiology,
genetics (human genome) and epigenetics.
THE
INTERNATIONAL GLIMER I, II & III MS STUDY (Ongoing 2010 -2025)
Prof. Jeremy D. BLOCK - Epidemiologist
- Chief Scientist IAGIM Association and CEO LIGroup, IAGIM Association
Chief Scientist, Head;
Department of Neurology & Neurological Research, Neuro-Immuno
Epidemiologist (N.I.E).
Multiple Sclerosis remains one of the most devastating illnesses of
young adults, the commonest cause of disability after trauma, and
one of the most enigmatic puzzles in Medicine. It is a complex and
heterogeneous disease, in which both inflammation, de-myelination
– removal of the ‘cables’ which insulate and increase speed of signal
transmission in nerves – and nerve fiber degeneration occur in the
brain and spinal cord. Repetitive immune attack against the myelin
sheaths and oligodendrocytes, the cells that produce myelin, mark
the first phase of disease in most patients. These events are termed
relapses and cause temporary disability in themselves. This may be
followed, or in some cases primarily established, by a slow cumulative
degeneration of nerve axons, which leads to slow accumulation of disability
– the secondary progressive phase. Bone marrow-derived
stem cell transplantation may eventually replace some apoptotic neurons
due to auto-immune exacerbation / attacks.
In Restorative Multiple Sclerosis Brain Repair has focused on attempts
to repair the myelin loss, and attempts to generate new neurons as
an assay to test reparative drugs, and possibly for transplantation.
Oligodendrocyte precursor cells (OPC), Schwann cells – the myelin
producing cells of peripheral nerves, olfactory ensheathing cells,
and neural stem cells are studied using in vitro cell culture techniques
and animal models. Various factors that prevent remyelination have
been identified and there are also several growth factors that can
stimulate the process. Further, has led the way in the trial of novel
therapies (Campath-1H: alemtuzumab) that may not only reduce relapses
in MS, but also prevent disability, and in the inception and development
of international genome-wide association studies to find new susceptibility
genes.
Prof. J. D. Block of IAGIM Drug Association and Founder and CEO of
Locum International (Research) Group are beginning, via the International
GLIMER I, II, and III MS epidemiological and epigenetic international
research study, to unravel the past epidemiology research and development
that could overturn the prevailing wisdom on the cause and progression
of multiple sclerosis (MS) in men and women . Multiple Sclerosis in
not only a debilitating neuro-degenerative disease that strikes
predominately females at the peak of their childbearing life, but
significantly, earlier in the lives, starting literally from birth
as their immature immune system starts to develop during the critical
pre-puberity ages of <1-3 and 3-6 years and onwards to puberty
and then to child bearing and final to menopause. Although this disease
strikes men as well, the incidence in men is significantly lower than
females which is generally 2.5:1 and as high as 3:1 in the Atlantic
Region of Canada (450+ per 100 000) compared to Cape Town or South
Florida which are well under 10 or 50:100 000. Men normally get MS
later (39-40 years) but more severely as PPMS (Primary Progressive
MS). Well over 2.5+ million people worldwide, suffer from MS .
The question is why are the Canadian's and South New-Zealand numbers
so high, when compared to the rest of the world. That conundrum is
being unraveled by the intensive epidemiological epigenetics and geographical
study covering most countries of the world. The answers are slowly
unraveling and the results are both surprising, unexpected and require
a total rethink of just exactly what multiple sclerosis, really is,
today in 2018... Most of us got it wrong in the past. Highlighting
a series of cascading effects and sequential serial triggers from
birth - MS is a lifelong disease. It starts (postpartum) in very early
child hood age with the developing immune system at birth and remains
unseen and benign for close to less than two and sometimes as long
as three decades before a detectable and recognizable exacerbation
(attack).
This displays, as a two or three decade, cascade of triggering events
that eventually culminate in the mid-twenties and early thirties in
women with the second significant clinical event of MS. The
first significant clinical event of MS is difficult to detect and
identify as positive MS, as it is brief (only about 24+ hours) and
the etiology is not clearly understood by the patient and equally
poorly by the treating physician, who generally would not recognize
the clinical event (exacerbation /attack) as RRMS. This first attack,
at early child bearing age, will pass unnoticed as possibly an optical
neuritis (remember the optic nerve is part of the CNS) not the PNS
as the other 11 cranial nerves are classified. Alternatively, the
young female in her prime will suffer a 24 hour gait or muscle problem,
which could start as young as 18 - which few physicians are able to
recognize as a clinical significant event. It is only at the second
significant clinical event that both the patient, now in the early
stages of MS can recognize that something serious is wrong, and an
astute physician would concur.
The dormant or sub-clinical phase of MS has now passed, all the triggers
have all fallen, and the neuro-degenerative CNS brain, optic nerve
and spinal cord disease has displayed its "first, but really second"
clinical life long debilitating symptoms. All the triggers in the
two to three decade process or cascade have now tripped and the patient
is truly sclerotic as per MRI/MRS normal white and gray matter scans
show and oligoclonal bodies in the spinal fluid... So the question
remains; What are these triggers and how do they fit into the almost
two to three decade cascade or "domino effect" to use a well understood
cliché'. There are several triggers in this early stage, but
really it's mid to late stage RRMS that will, with added decades i.e.
as time progresses, progress to SMS (Secondary MS) while PPMS (Primary
Progressive) develop from onset mainly or predominantly in men, but
luckily just less than 15% of RRMS will progress upwards - unlike
in men. Their fate, when it starts, is significantly worse. It generally
is faster, quicker and it is diagnosed as PPMS at age 40 or a smidgen
later. This PPMS goes upwards, it's fairly constant and degeneration
is faster and much more problematic. The International (ZAR-ISRAEL-USA-CANADIAN)
GLIMER STUDY has separated the triggers over the life long decades
up to the seventh or eight decade into a series of tipping points,
such as, and in no particular order here - that comes later - the
layered autoimmune development, GIT (70%) Lympho-leucocyte production,
the critical GIT microbiota patient lifelong cycle and homeostatic
role, (this microbiota homeostatic profile is really of critical importance),
Bone Marrow B-Cells and Thyroid gland T-cells, The faulty thyroid
quality control (TQC) producing a subset tiered range of passing and
'just passing' B- and T-cells (the whole group of them CD4+ CD8+ NKS
and discussion of a further differentiating group of additional white
blood cells and phagocytes (macrophages) that we will come to later).
The bottom line is that the thyroid gland rejects on or about 90%
of the lymphocytes and leukocytes that the TQC examines.
Most of them are faulty, in fact almost all of them are, they are
layered, flawed and have different faults - and the question really
is, why?
That's a big question to answer and it has a lot of epigenetic background
as highlighted by a 150 years of epidemiology especially unwrapping,
teasing out and sorting the confounding conclusions reached,
over the many decades of wrong or inaccurate conclusions. Confounding
statistics, here too, plays an important role. In net effect, the
thyroid only passes 10% of the presented white cells from the bone
thyroid GIT and spleen etc. The approximate 10% of leuco-lymphocytes
that pass the TQC are much layered.
Now that's an unusual medical term - these lymphocytes and leukocyte,
white cells, have varying recognition and flagging abilities - all
passing lymphocytes and leukocyte are not equal, they have different
precognition abilities and some of them are poor and they flag badly,
in fact some flag proteins very poorly indeed. These blood cells are
improperly trained - really the equivalent 'dropouts' of the thyroid
gland and these immature leuco-lymphocytes cannot
really recognize own body protein - and that can cause an auto-immune
disease, first inflammation and subsequent own-protein attack and
the lymphocytes and leukocyte can't help it - they are not physiologically
trained to do their job of recognizing own protein, effectively. They
are kind of protein blind, in specific cases. (More of this later).
Where the protein has a slight flaw due to a probable indel insertion
then a 'pregnant protein' with a (bump) arises due to a one line or
more than one line purine-pyrimidine miscoding. From here on a special
CNS scenario is set up when a subset of leuco-lymphocytes (graded
and layered) cross the CNS BBB by squeezing through the arteriole
junction gaps and backing foot cells and enter randomly into the CNS
NAWM (normal appearing white matter and also later the NAGM, normal
appearing gray matter (detected by MRS - Magnetic Resonance Spectroscopy).
At this moment of time it is a statistical entry (that is just a random
entrance) but it soon progresses into a 'directed attack' concentrating
in the pregnant (bumped) protein environment. The onset of a full
scale, full blown autoimmune attack progresses in the classical style
and sequence, i.e. B-cells, -> T-cell -> Mast cells -> Macrophages,
CD4+, CD8+, and NK cells (inflammation, cellular disruption, myelin
auto-immune attack, axon exposure and degradation with eventual scarring
(sclerosed plaques) and finally lesions)
Now the question arises why are some of these lymphocytes and leukocyte
(say 10% of those who pass, that's about 1%) are so poorly trained
via the TQC system and how did they get to this point and why do they
do their job so poorly i.e. attack normal basic myelin protein and
other lipoprotein in MS as well as in a host of other autoimmune diseases
(+/-81). Diseases such as RA, SLE, JD and MG (Rheumatoid arthritis,
Systemic Lupus Erythematosis, Juvenile onset Diabetes (Type 1) and
Myasthenia Gravis) all the way down to Stiff Persons Syndrome (Stickman's
disease ) to mention a few. In order to answer this question we need
to look at epigenetic, epidemiology, etiology and a smidgen of genetics
and a large portion of the GIT Microbiota over an extended period
of time (the early and second childhood decades) and later to mid
childbearing and finally up to menopause. Men don't really have menopause,
but mid-life crisis's - However, they have all the other tipping points
in this extended, developing, ongoing persistent cascade with all
the same sequential triggers.
Now the balance of the triggers that cause the cascade must be highlighted
- early child viral immunization by mother (EBV and others), glandular
fever, mononucleosis (kissing's disease), ancient adhesion proteins,
(crossing the BBB), NAWM casual proximity, Oligodendrites and "their
40 feet" (one podium/many podia), DNA indels, (insertions deletions
and repetitions, are mutation types), default protein folding small
errors (affecting basic myelin protein in MS i.e. the pregnant {bump}
protein ) -alternatively "the pea in the bed" or "pregnant
proteins" analogy, MHC, random wrong site inflammation, B- and T-cells
literally 'gone wild', (by analogy a hypothetical dog called 'Trigger'
"digging up the garden (i.e. NAWM"), chemokines and cytokines production,
messenger proteins - "don't kill the messenger syndrome", scaring
and lesions, nodes of ranvier, axon degradation and eventual cleavage,
and finally comparative autopsies of MS and non-MS patients and their
surprising findings. The GLIMER STUDY has specifically excluded brain
repair mechanisms and neuronal repair as in-depth epidemiology show
this field is decades away (see foot notes below:)
This end Part One Part two of this ongoing review - will deal with
the epigenetics and epidemiology triggers, such as early (a) EBV immunization,
(b) Vit. D3 (24-25 dihydroxycholcalciferol), (c) Normal
sunlight exposure, (d) combination of
a food symbiosis containing Vit. D3 and natural Sunlight to produce
not less than 2000 IU's of equivalent D3 every day. Ingesting the
right foods fully balanced and proportional. Not 400IU's per day but
on average 2000 IU's of intrinsic and extrinsic Vit. D3 daily and
in the proper daily ratios. The number of minutes of sunshine a young
immune developing child and adult must be exposed to, is in the region
of 22-35 min at day (weather depending), but certainly not 8 min.
a day as is normal in Canada and much less in the Canadian Atlantic
Region - eventually we will end with (e) Oligodendrites
and their fatal unavoidable mutational mistakes (indels, insertions
deletions and repetitions are simply a statistics numbers game) together
with the (f) DNA indels and the (g)
statistical probability of DNA mutations in
synthesizing the amino-acids in basic myelin protein (and their surprising
causes) affecting the 3.2+ and counting, billion lines of DNA code
(purine and pyrimidine line CG/GC and AT/TA) and the global geographic
regions variations as a function of epigenetic's and neuro-immuno
epidemiology.
MS like polio is eventually a preventable disease, not quite
yet at this time through vaccination, (i.e. via Retrospective-Prospective
Didactic Vaccines (R.P.D.Vaccines) which are coming quite soon around
the year 2020), but currently controllable through healthy lifestyles
and careful and proper nutrition. The epigenics and etiology are becoming
clearer, as the epidemiology dust over the past decades begins to
settle. We need to take care of the developing first six years of
life, in graded periods or age blocks, and develop a healthy immune
system and keep it balanced and in a healthy homeostasis for future
decades. Diet, sunlight and very early EBV inoculating by "Mom (viral
and bacterial) Transfer Method" are three early trigger safeguards
out of a possible twelve triggers, we need to protect and fully understand.
Education in this parenting domain is important and critical - essential
for a healthy life from cradle to grave. We are now understanding
the basic underlying etiology, how and when MS all starts - so many
years ago in very early days of childhood (in-fact it's really immediate
postnatal), even C-Sections are discouraged as they affect the gastric
human microbiota and other 'all-orifice-human-microbiota' and thus
affecting the immune developing system significantly (As said 'about
Vegas' what happens in the GIT Human Microbiota does not stay
in the Human GI Tract [i.e. colon etc.]) and for sometime now, we
know - how it (MS) all ends...
Prof. Jeremy David Block B.Sc., (Engineering, ZAR.
SANA.), M.Sc. (Micro/Stats (U. of WC), D. Pharm., (Wits ZAR), (Neuro-Immuno
Epidemiologist (N.I.E.) (LIG-IAGIM)
Part Two
2018. - Total Parts 20 - Pages 210).
Background: Prof. Jeremy D. Block served for the duration of the development
of COP 1 as a senior medical/pharmaceutical researcher and part of
the Teva COP 1 innovative research team in the early nineties that
rapidly developed Teva's first MS immuno-modulating drug Glatiramer
Acetate (CopaxoneTM). As Chief Scientist as well as Teva Group Scientific
Research Auditor, and by touching each and every part of Teva's overall
global scientific team, Teva rapidly attained New Drug Registration
with the FDA under Prof. J. D. Block scientific and technical guidance
and regulatory department training and systemic overviews and audits.
Note * ISRAEL Israeli Jews have a prevalence of up to 62 per 100,000,
but Christians (35 per 100,000), Moslem Arabs (15), Druze (11), and
Bedouins (17) have lower rates (Alter et al 2006). Genetically similar
immigrants have half the rate of native-born Jews, suggesting an environmental
factor. Other groups also have a significantly lower incidence of
multiple sclerosis (Caucasians) Hispanics Latino's black African Americans,
Asians African Natives, Inuits, SWA bushman, and Romani Gypsies (almost
zero)).
FOOTNOTES
Brain Repair mechanisms - Why does the brain
need repairing?
Most types of neurological damage lead to permanent disability. People
with spinal injuries never recover from their paralysis and loss of
sensation, as an example those suffering from Parkinson’s disease
will never recover from the condition and always be reliant on medicines.
Patients with multiple sclerosis never recover fully from their lesions.
This is because the brain and spinal cord lack the ability to heal
themselves after injury. Many nerve fibers in the brain and spinal
cord are insulated by myelin, which is a sheath formed by glial cells
called oligodendrocytes. If this insulating sheath is removed, the
nerve fibers cannot conduct nervous impulses.
This happens particularly in multiple sclerosis. In this disease an
autoimmune process kills oligodendrocytes (myelin-forming cells) in
small patches of the brain and spinal cord, leaving the exposed nerve
fibers uninsulated and therefore poor- or non-conducting. These patches,
known as plaques, are usually only a few millimeters in size, but
they can occur frequently anywhere in the brain or spinal cord. The
plaques do not generally repair themselves. The result is small regions
in which the nerve fibers do not conduct. These give symptoms which
depend on where they are, and the function of the nerve fibers that
are affected.
BRAIN REPAIR
Repairing the structure of the brain
and spinal cord Replacing lost neurons (1) Where neurons are permanently
lost, there are two potential ways of replacing them. The first is
to transplant equivalent neurons taken from a donor brain or spinal
cord. The second is to persuade primitive stem cells, which are present
in the adult brain or can be transplanted, to turn into new neurons.
Neural transplantation. If a group of neurons are lost, an obvious
possibility is to transplant new neurons in their place. This is particularly
attractive in diseases such as Parkinson’s disease, in which the lost
neurons are all in a small restricted site.
Successful neuronal transplantation has not been achieved using neurons
from adult donors. However, if neurons are taken from embryos of just
the right age, they will survive transplantation. In addition they
will grow nerve fibers into the host brain and make functional synaptic
connections. In animal models of Parkinson’s disease this cures most
of the symptoms of the disease. This has led to several trials of
neuronal transplantation using embryonic tissue for human patients
with Parkinson’s disease. In almost all these trials the patients
have had their disease partially corrected, but in no case has there
been complete recovery.
Methods for improving the results of these operations are ongoing.
Normal Status. - The substantia nigra is intact, and its nerve fibers
connect to the striatum.
Parkinson’s disease. - Most of the neurons in the substantia nigra
have died, and few nerve fibers remain to connect to the striatum.
A graft of embryonic substantia nigra has been placed in the striatum.
It sends out nerve fibers that innervate the striatum and bring back
lost neurological function.
BLOCKING SIGNAL TRANSMISSION
-
How is nerve fiber conduction blocked? Many nerve fibers
in the brain and spinal cord are insulated by myelin, which is a sheath
formed by glial cells called oligodendrocytes. If this insulating
sheath is removed, the nerve fibers cannot conduct nervous impulses.
This happens particularly in multiple sclerosis. In this disease an
autoimmune process kills oligodendrocytes (myelin-forming cells) in
small patches of the brain and spinal cord, leaving the nerve fibers
uninsulated and therefore non-conducting.
PLAQUES
These patches, known as plaques, are usually only a
few millimeters in size, but they can occur frequently anywhere in
the brain or spinal cord. The plaques do not generally repair themselves.
The result is small regions in which the nerve fibers do not conduct.
These give symptoms which depend on where they are, and the function
of the nerve fibers that are affected.
NEURONAL DAMAGE
Recall that the three main causes of loss of function
after damage to the nervous systems are: (a) loss of neurons, (b)
cutting of axons and (c) loss of insulation on axons. None of these
deficits heals spontaneously. Lost neurons are not replaced. Neurons
are created during embryonic development, but after that time we have
almost no ability to make new ones. Thus, when large numbers of neurons
are killed they cannot be replaced, and the disability that results
from their loss is permanent.
Cut nerve fibers also cannot regenerate. In order to restore the function
of cut nerve fibers, they need to be able to re-grow from the site
of the cut back to their original connection site. Nerve fibers in
the brain and spinal cord are completely unable to regenerate. Therefore
nerve fibers cut in the spinal cord as a result of a cord injury will
never redraw, and people with cord injuries will be paralyzed for
life. Lost insulating myelin is not fully replaced.
Oligodendrocytes Apoptosis
When the oligodendrocytes that form myelin are lost
(die) as a result of multiple sclerosis, the brain and spinal cord
have a very limited ability to replace them. Therefore many of the
multiple sclerosis plaques never become re-myelinated. This means
that the nerve fibers that pass through these plaques can never conduct
nerve impulses normally, and eventually many of these demyelinated
nerve fibers will die.
Multiple Sclerosis remains one of the most devastating illnesses of
young adults, the commonest cause of disability after trauma, and
one of the most enigmatic puzzles in Medicine. It is a complex and
heterogeneous disease, in which both inflammation, demyelination –
removal of the ‘cables’ which insulate and increase speed of signal
transmission in nerves – and nerve fiber degeneration occur in the
brain and spinal cord. Repetitive immune attack against the myelin
sheaths and oligodendrocytes, the cells that produce myelin, mark
the first phase of disease in most patients. These events are termed
relapses and cause temporary disability in themselves. This may be
followed, or in some cases primarily established, by a slow cumulative
degeneration of nerve axons, which leads to slow accumulation of disability
– the secondary progressive phase.
Work at brain repair is decades away, has focused on attempts to repair
the myelin loss, and attempts to generate new neurons as an assay
to test reparative drugs, and possibly for transplantation. Oligodendrocyte
precursor cells (OPC), Schwann cells – the myelin producing cells
of peripheral nerves, olfactory ensheathing cells, and neural stem
cells are studied using in vitro cell culture techniques and animal
models. Various factors that prevent remyelination have been identified
and there are also several growth factors that can stimulate the process.
Further, trials of novel therapies (Campath-1H: alemtuzumab) that
may not only reduce
relapses in MS, but also prevent disability, and in the inception
and development of international genome-wide association studies to
find new susceptibility genes.
The
complete article of the month is available at the

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