Title:
Autoimmune Cross-targeting Hypothesis.
The "ins and outs" of the immune system.
Abstract:
The trigger of autoimmunity has
remained elusive. Genetic susceptibility and infections contribute to the
development of autoimmunity but the pathogenesis has not been clear. This
Cross-targeting hypothesis suggests that simultaneous infections on one target
triggers autoimmunity. One infection exists on the outside of the target
cell and one infection exists on the inside of the target.
Introduction:
Paul Ehrlich called it Horror
autotoxicus when the immune system attacks self tissue, we call it autoimmunity.
Under normal healthy conditions our immune system does not attack self
tissue because the immune system has built up a tolerance to self proteins by
educating it's B cells and T cells. T cells are educated to recognize the
inside of cells while B cells are educated to recognize the outside of our own
cells. Both of these "educations" must be compromised for the
immune system to attack self.
Hypothesis:
It is my contention that in order
for autoimmune disease to occur two different infections must be attacking the
same target tissue. Cross-targeting is a military term for when a target
is attacked from 2 different platforms. I will use this term for the 2 branches
of the immune system attacking at the same time on the same target. Those immune
cells attacking the outside of a cell to kill large infections and those
attacking viruses on the inside. It is this state of both B cell and T
cell educations uncoupling and attacking at the same time that causes
autoimmunity. There is nothing to hold the immune system back from killing the
entire cell thus autoimmunity develops.
Evaluation of Hypothesis:
The pathogenesis of autoimmune disease
can be elucidated if autoimmune diseases are analyzed as a group and the
overlapping characteristics are established as key. Think of autoimmune
diseases in terms of the target tissue and infections.
Most autoimmune diseases can have
multiple infection triggers and they don't have specific time tables until
looked at in terms of infection. One virus on the inside and one larger
infection marking the outside exists. Typically the larger infection takes hold
first and for some reason has not been eradicated before the second infection
appears. Then the virus can mark the inside of the target cell but you
only need one virus to mark the inside. The autoimmune disease is not triggered
unless infections are marking both the inside and the outside at the same time.
When autoimmune diseases appear linked
together it is because they share an infection. For example they could all have
E.coli as the larger infection marking the outside. E.coli has been found
in the bladder, in the intestine, in the pancreas, and in the liver. This
could explain bladder infections, celiac disease, type one diabetes and autoimmune
liver disease coexisting. ( 1,
2, 3, 4, 5, 6, 7)
Some autoimmune diseases have
associations to gluten sensitivity but this is not a digestion issue or needed
for autoimmunity to develop rather an indication of the type of infection
involved in the disease. Different infections cause gluten sensitivity
because they are barrier breaking infections with the ability to cross the
intestine or the blood brain barrier.
The pathogenesis of autoimmunity
can be elucidated if we just look at the areas of overlap we can see the
significance of the autoimmune target, of the infection’s similar abilities,
and of the autoimmune diseases having shared infection triggers. Think of
autoimmunity in terms of target and infections.
The significance
of the target in autoimmune disease
Autoimmune disease
is when the immune system has decided to attack self tissue. Each
autoimmune disease has a core target tissue that is being attacked. The
hypothesis is that cross-targeting is occurring at this target. This pattern
can be found in all autoimmune diseases.
For example, in type one
diabetes the immune system has decided to attack the pancreas. The
development of the autoimmunity on this target is not random but selected by
the infections. Two viruses have been associated with the development of type
one diabetes the Coxsackie virus and the Flu virus. Both of these viruses
can and do replicate inside of pancreatic cells but it only takes one virus to
mark the inside. (8)
Viruses do not infect all body
cells rather they only gain entry into target cells by using specific receptors
as door knobs. Flu viruses have a tendency to infect dopamine-2 receptor organs
which makes me suspect this receptor. The pancreas has the D2 receptor which
might explain how the flu viruses replicate there. (9, 10)
Larger infections have also
been found infecting pancreatic cells from the outside: mycoplasmas, e.coli,
and candida. So which infection is responsible for the development of
autoimmune type one diabetes? All of them and yet only one of them on the
outside at a time is needed to trigger type one diabetes. (8, 11, 12)
The trick is that the
outside and the inside of the pancreas cell must be under attack simultaneously
for autoimmunity to result. Imagine a pancreatic cell having a flu virus
on the inside and the outside infected at the same time by mycoplasmas.
It is this state of cross-targeting that I believe causes the immune system to
go into an autoimmune attack and destroy the entire target tissue. The
immune system has lost it's tolerance education. Normally if the immune
system is attacking an infection on the outside the immune system's education
of the inside protects the cell from complete destruction and vice a versa.
Remember B cells have been educated to know all of the outside self
proteins and Tcells have been educated to know all of the inner cell
proteins. If the immune system decides that both of these areas
need destruction what would save the target tissue?
Most autoimmune diseases
appear to fit this inside and outside cross-targeting problem. Multiple
sclerosis for example has been found to appear after shingles but not everyone
with shingles develops it. People with psoriasis also have higher rates
of multiple sclerosis but not everyone with psoriasis gets it. Now put into place
the cross-targeting hypothesis. Shingles is the herpes zoster virus that
would mark the inside of the nerves while psoriasis if it is a mycobacteria
infection which likes the myelin sheath marks the outside of the nerve.
The inside and the outside of the nerve would be marked to the immune system at
the same time. Are people who have shingles while they have mycobacterial
infections the ones at risk for multiple sclerosis? (13, 14, 15, 16, 17)
What about the vaccine induced
autoimmunity? This cross-targeting hypothesis can be applied to vaccine
reactions. Looking at the list of what has been accused of causing autism then
listing the targets they infect reveals patterns which reflect distinctively
different forms of autism. Autism appears to be an autoimmune disease.
The DTP vaccine has three bacterial
infections that it inoculates for : diphtheria, pertussis, and tetanus.
Only one of these bacterial infections exists in the temporal lobe of the brain
and that is tetanus. When the vaccine is given even if the disease is
prevented a small amount of antibodies would end up at the temporal lobe
because those virus pieces bind there. Why pick tetanus out of this list
? Some autism patients have HHV6 with the neural autoantibodies. This 6th disease
known for it’s rash Roseola is a virus that replicates in the temporal lobe of
the brain. Applying the cross-targeting hypothesis on the temporal lobe
suggest that if a child with 6th disease gets the dtp
vaccine they could develop an autoimmune attack of the temporal lobe thus
developing an autism disease of this part of the brain. (18, 19, 20, 21)
What about the infamous MMR
vaccine? Autoantibodies for the measles part of that vaccine have been
seen in a group of autistic kids and the measles virus pieces migrate to the
cerebellum. Clusters of autistic kids have been found to have sutterella
bacteria in their system too. Sutterella is closely related to
campylobacteria which can infect the cerebellum. Does the cross-targeting of
the measles vaccine and sutterella cause an autoimmune attack of the
cerebellum? Is this possible? Does campylobacteria do the same thing?
(18, 22, 23)
What about the children
born with autism that were not induced by vaccines? Pregnant women with
Rheumatoid arthritis are more likely to have autistic children. Women who
catch the flu during pregnancy are more likely to have autistic kids. If we
apply the cross-targeting hypothesis and look for a specific target we find the
frontal lobe in this form of autism. Antibodies to the frontal lobe have been
found in mother's with rheumatoid arthritis. The flu (H1N1) when it has
infected the brain of the young children has been found in the frontal lobe
region. It is possible that an unborn fetus develops an autoimmune form
of autism on the frontal lobe when both of these infections occur at the same
time in a pregnant woman.
Are children the only ones
susceptible to autoimmune brain disease? I don't think so. Parkinson's
disease has been associated with psoriasis' mycobacteria and nocardia which are
infections capable of crossing the blood brain barrier. Parkinson's has
also been connected to the flu H5N1, west nile, and dengue viruses. These
infections like the basal ganglia area of the brain specifically the Substantia
Nigra area. Parkinson's could very likely be cross-targeting autoimmunity of
the substantia nigra. (30-35)
The key theme here is knowing the core
target tissue of the autoimmune disease. If one knows the target tissue
and what can infect this tissue then once can be careful not to cross-target.
Prevention would be to kill the current infection as quickly as possible or
only vaccinating when healthy.
Preventing acute flaccid paralysis from
d68 could be possible. What if the d68 virus is cross-targeting with staph on
the nerves causing the paralysis? Staph once inside the body can infect nerves.
We know that there is a strong association of eczema with staph and we know
what group of children are vulnerable to paralysis: those with asthma. A few with
septic staph died which indicates a strong immune reaction between staph and
d68 exists. Since eczema and asthma can be linked maybe we should be
treating kids with eczema and asthma for staph during outbreaks of d68.
We could prevent more cases of acute flaccid paralysis. (36-42)
The exception to this infection driven
hypothesis is the drug-induced autoimmunity. Cross-targeting is still
occurring triggering when drugs are triggering the immune system but a drug
replaces an infection.
Drug induced lupus can be triggered by
monocycline and hydralazine. Hydralazine is a muscle relaxer and works
inside the muscles cells. Monocycline which is an acne medication is
known to penetrate muscles and cause severe muscle cramping. Either of
these drugs could replace the viral infection which marks the inside of the
cell. A patient with autoimmune liver disease makes anti-muscle
antibodies which would mark the outside of muscle cells. They are the
vulnerable group. If the outside and the inside of the muscle appears
marked or foreign to the immune system cross-targeting autoimmunity could
result. (43, 44, 45)
Halothane hepatitis could be caused by
cross-targeting too. The Halothane would replace the virus on the inside of
liver cells. A child with a pre-existing issues of e.coli might have the
liver already marked on the outside. A young girl developed hepatitis
after using the anesthetic. This particular girl also went on to develop
type one diabetes. Does the girl have celiac too? Is celiac a risk factor for
halothane hepatitis? (46)
The reverse scenario can also occur.
Hemolytic anemia is triggered when a drug like penicillin coats the
outside of the red blood cells. Normally this would not be an issue but if the
person had recently had the RSV virus which replicates in bone marrow or had
chronic hepatitis C which might try to infect red blood cells and the virus was
still visible in the red blood cells thus it might trigger autoimmunity. (47)
This leads us to the next autoimmune
issue of recognizing and diagnosing what you are infected with. People who host
parasites like t.gondii, yeasts, mycobacterias or mycoplasmas will find this
hard to accept and it is still hard to diagnose. Very little is known
about the good verse the bad microbes in our digestive system but we must
learn what is there in the body and what they can do.
The significance
of similar infection abilities
Gluten sensitivity
has appeared in multiple autoimmune diseases. Autism, schizophrenia,
celiac disease, pandas, parkinson's, and psoriasis to name a few . The
infections associated with these diseases are e.coli, sutterella, strep,
candida, and mycobacterias. The associations are unproven but suggestive
because they all have the ability to cross the intestine and the blood brain
barrier. Gluten is a macromolecule. It is huge. The sensitivity to gluten
could be because these infections have made a huge hole in the barrier which
then allows the gluten across to interact with the immune system at the other
side. Obviously these infections attack differently but all of them break
barriers by crossing them leaving a hole behind.
The notorious t.gondii which first
crosses the intestine then crosses into the brain where it nests around the
amygdala is probably the easiest to study. Days after infection with
t.gondii, mice become gluten sensitive and will show an antibody response to
gluten. T.gondii and the herpes virus have been suspects of schizophrenia.
Schizophrenia has also been documented to be gluten sensitive.
Schizophrenic patients who removed gluten from their diet were able to
lower their medications. It could be that Schizophrenia is an autoimmune
cross-targeting of the amygdala with gluten increasing the response. This could
be showing that the gluten sensitivity has an effect on the area of the blood
brain barrier not just the intestine. (48-51)
I believe Celiac
disease has a magnified reaction to gluten compared to the other autoimmune
diseases only because of the location of this autoimmune disease target at the
intestinal lining where the barrier is broken and gluten can be seen. An
autoimmune reaction on top of barrier breaking. Gluten has been
considered to be “the trigger” of celiac disease causing the immune
system attacks upon the intestinal lining. This is indirectly true
because gluten has been demonstrated to ramp up the immune system. Gliadin
has been shown to interact with the immune system ramping up macrophages.
The immune system becomes hyper right where the cross-targeting
autoimmunity is occurring at the intestine with e.coli thus the reaction
to gluten will be stronger because of the location getting mixed up with the
autoimmune reaction. (52)
Patients of celiac disease often
have a history of bladder infections. E.coli is the most common culprit
of bladder infections. If the infection spreads to the intestine E.coli
would cling in a feather like attachment all over the intestinal lining.
At first the patient would only have gluten sensitivity. Then, in
time, a stomach virus like the adenovirus or hepatitis C could infect the
lining. Gluten would hype up the immune system when it leaks
across the barrier hole made by e.coli making the autoimmune reaction even
worse. Other bacterial infections might cause autoimmunity but the intestine is
filled with bacteria that normally don't set off the immune system.
Understanding how the immune system discriminates here will be key to figuring
out the cause of celiac disease. (3)
Think of gluten as potentiating the
immune reaction once it gets to the other side of the barrier. Gluten has
been shown to inflame the immune system after crossing the barriers. Eating
gluten with a barrier hole heightens the inflammatory immune response.
If we say that
Gluten sensitivity occurs at both the barriers: the brain and the intestine and
that gluten sensitivity occurs by breaking the barrier we can now predict other
gluten sensitive infections.. Strep for instance is suspected for it's
ability to cross the blood brain barrier and for triggering the Panda's
autoimmune reaction called Sydenham's chorea. Suspiciously gluten sensitivity
has also been associated with chlorea. Would a strep infection of the
intestine eventually lead to gluten sensitivity? Strep does break the barriers.
(53)
Gluten sensitivity, I
believe, can warn us when we are vulnerable. When we are sensitive to
gluten we have "holes". Normally our immune system and
any viruses we have do not normally have access to the brain. Many of us have
different forms of herpes viruses hiding out in our body. Once a hole has
been created in the blood brain barrier mental issues may result not just
from the entering infections, not just from gluten, but from the viruses
seeping in the hole after these infections. In other words gluten
sensitivity should not just be about avoiding gluten but figuring out what
infection is there as quickly as you can before you catch a virus. My
hypothesis is the autoimmune disease will only appear when a virus triggers
cross-targeting with a larger infection.
Allergies can also help us determine
what infections we have. Autoimmune diseases tend to have associated allergies.
The staph of eczema makes a pigment with egg and milk which ironically
are the allergies associated with eczema. Is the immune system reacting
to a pigment change of the infection? What of other allergies? Bee venom
has been found to kill t.cruzi and t.gondii. Could people with t.gondii
or t.cruzi allergies be the ones with bee allergies? Allergists should
compare the family autoimmune histories of their patients with the known
allergies. Patterns will appear.
The significance
of shared infection triggers
It has become accepted that some
autoimmune diseases have associated autoimmune disease families. If you have
one autoimmune disease your risk for another autoimmune disease goes up, but
specific ones. If you start looking for shared possible infections in
these families you realize that although an individual autoimmune disease has
several culprits only one suspect is common for the group.
Looking at the outer larger infection we
can see families form. Parkinson’s, psoriasis, crohn’s, and multiple
sclerosis are all mycobacteria associated. Celiac disease, type one
diabetes, and autoimmune liver disease can all be associated with e.coli.
Sjogren's, Hashimoto's, Microscopic colitis, and Vitiligo have all been
associated with various fungal infections. (yeasts and molds) RA,
graves, and type one diabetes have all been connected with mycoplasmas. Each
autoimmune disease has a different virus associated but the large infections
match. (55-63)
Looking at the inner viral
infections we see patterns linked to receptors. The Herpes viruses seem
to use estrogen receptors which in nerves cycle to the mitochondria. The
autoimmune diseases associated with the herpes viruses tend to involve the
central nervous system: Multiple sclerosis, schizophrenia, Guillian Barre, and
Encephalitis. As mentioned earlier flu viruses possibly uses the D2
dopamine receptors which not all tissues have but the pancreas does.
Seizures often have associations with
enteroviruses. Enteroviruses may, no evidence to prove yet, be using
nicotinic acetylcholine receptors. The hypothalamus has multiple nicotinic
acetylcholine receptors. Seizures could be caused by autoimmune cross-targeting
on the hypothalamus. Enteroviruses could be infecting the hypothalamus where it
can cross-target with whatever parasite appears there. Is there an
enterovirus causing the seizures with t.gonidii, with pertussis in dtp
vaccines, and with a parasite in Africa? The nodding disease of
Africa, which is a type of seizure, could be the black fly parasitic worm cross-targeting with the live polio vaccine which as an enterovirus
replicates in the hypothalamus. Schizophrenic patients can develop
seizures but it is unknown why. Febrile seizures fit in here too. The
pertussis of the DTP vaccine goes to the hypothalamus. Enteroviruses have
already been found with febrile seizures too. If an infant had an enterovirus
right before the DTP cross-targeting autoimmunity could occur.
Understanding how one infection family works lead to the ability to
predict others. The malaria seizures could be similar with autoimmune
cross-targeting because severity of the seizure increases when both the parasite
and virus are detected there. (64-70)
Considering malaria, outside of
seizures, cross-targeting could help explain Central America's Chronic kidney
disease. A mysterious disease of sugar cane workers who we know are
constantly infected with the malaria parasite. One of the organs infected by
the malaria parasite is the kidney. If chronic kidney disease is
autoimmune we need a virus marking the inside of the kidney cells. In this case
enteroviruses don't infect kidneys. Adenoviruses on the other hand can
infect the kidney. If a sugar cane worker with a malaria parasite catches
an adenovirus then cross-targeting could occur on the kidney and result in an
autoimmune chronic kidney disease. If we look maybe we will find this
adenovirus or something even more likely: glyphosate marking the inside of
kidney cells. Glyphosate has been associated with higher rates of chronic
kidney disease. It is used as a pesticide in these areas. (71, 72)
Conclusion:
The pathogenesis of autoimmune disease
can be elucidated if autoimmune diseases are analyzed as targets and
infections. The overlapping characteristics are key to understanding
what we are really looking at, which infections we are looking at. Think
of the immune system cross-targeting on one target as the trigger for
autoimmune disease. What infections are shared among autoimmune disease
families, what is the target tissue, and what these infections have in
common can give us not just insight into how autoimmune disease is triggered
but how to prevent them and maybe even cure them.
I
need to respectfully identify Dr. Andrew Church and Dr. Russel Dale who work on
Encephalitis Lethargia.
Everyone
remembers the 1990 Awakenings movie with Robin Williams as Dr. Oliver who in
1918 dealt with a cluster of encephalitis lethargia patients. In 1993 Dr.
Andrew Church found himself with another Encephalitis cluster and he discovered
that 2 infections were there not just the flu. Dr. Andrew discovered that
a high number of his patients had a rare form of strep called Diplococcus along
with the spanish flu. He has spent a life time trying to piece together
this disease. In 2011 Dr. Andrew and Dr. Russel came out with a
paper proving Encelpalitis lethargia was an autoimmune disease with antibodies
directed at the Basal Ganglia. This is possibly the first paper
supporting cross-targeting as the trigger for autoimmune disease. (73)
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