rewriting the cross-targeting autoimmune hypothesis

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 and one infection exists on the inside. 

Introduction:

Paul Ehrlich called the immune system attack on self tissue Horror autotoxicus; today it is called 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.  Both the inside and the outside of a tissue must be infected. 

Hypothesis:

  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. The 2 branches of the immune system attacking at the same time on the same target but from different systems fits.  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:

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 Encephalitis 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.

 The concept of the simultaneous activation of the immune system's inside and outside pathways triggering autoimmune disease and not the infections themselves becomes obvious with this autoimmune disease mouse model,  NOD.  The NOD, non obese diabetic, mouse model has now been shown to be caused by a mutation in the TCR,  the T cell receptor.  The TCR activates when it encounters an infected cell's HLA mailbox with foreign, typically viral, pieces in it.

Here is a simplified summary: TCR activation causes the T regulator cell to secrete il-10 and remove FoxP3.   Il-10 suppresses the T helper cells of the "outer" infection pathways.  Foxp3 suppresses the viral response of T cells so when this Foxp3 disappears the "inner" immune pathway against viruses is favored.  If there are not enough T regular cells with TCR as the case appears to be with NOD mice there is a weak response to viral infections and an incomplete suppression of the "outer" immune pathway.  The autoimmunity occurs because both inner and outer immune systems are "on" at the same time.

NOD mice are triggered into autoimmunity because of incomplete il-10 suppression during viral infections.  Normal, real life not model, autoimmune disease would be the result of simultaneous infections inside and outside. 

Most autoimmune diseases have dual infections triggering them and they don't have specific time tables until looked at in terms of cross-targeting infections. Typically the larger infection takes hold first and for some reason has not been eradicated before the second viral infection appears.  The autoimmune disease is not triggered unless infections are marking both the inside and the outside at the same time. Which virus does not matter. Which outer infections does not matter. It is the mere coincidence of layered infections on one target. This inside-outside pattern can be found in all autoimmune diseases.  An immune attack against a viral infection during an immune attack on an outer infection can be implicated in all cases.

The collection of genetic susceptibilities of autoimmune diseases, specifically the HLAs, can identify which viral infections are involved.  Each HLA mailbox is responsible for a specific zone within the cell. Viruses infect specific zones and often match up with a particular HLA mailbox.

 The overlapping of autoimmune diseases can reveal which larger infections cause the outer infections.  Often the infectious suspect appears in each of the autoimmune diseases but the viral trigger companions are different. An infection may have taken root on several organs but it is only when that organ becomes infected with a virus that autoimmunity results.  Hence the lack of order to autoimmune disease family development.  One autoimmune disease does not lead specifically to another thus autoimmune disease. Autoimmune disease development is random upon viral exposure once the larger infection has taken hold.

Analysis of the autoimmune diseases:

Narcolepsy

Similar to encephalitis lethargia, narcolepsy has been associated with a flu virus, H1N1, and strep but in this case inducing an autoimmune attack on the the hypocretin cells of the hypothalamus.  A group of children in England developed narcolepsy after receiving vaccinations against the flu suggesting that it is not the virus directly rather the immune system itself causing the narcolepsy.  All the children who developed narcolepsy after the vaccine had recently had a strep infection supporting the notion of an autoimmune cross-targeting even triggering the narcolepsy.

Encephalitis is almost always associated with a type strep infection seems to have different viral triggers. Encephalitis has been associated with the flu, enteroviruses, and flaviviruses.

Rheumatic fever

There is a high incidence of co-infection in Rheumatic fever. Coxsackie B virus antibodies  have been found along side streptococcus antibodies in children with rheumatic fever.  Is this evidence of autoimmune cross-targeting? If a child with untreated strep encounters the coxsackie virus do they develop Rheumatic fever? Can any enterovirus cause this?

PANS (formerly PANDAS)

 PANS is considered an autoimmune disorder of the Basal Ganglia area of the brain with the development of anti-basal ganglia antibodies following strep infections. Originally believed to be triggered primary by strep it was called "Pediatric Associated Neuropsychiatric Disorder Associated with Strep"

 Specifically Sydenham's chorea, a condition of jerky movements occurs in 30 percent of rheumatic fever cases.  Sydenham's chorea tics have also been connected to enteroviruses. Is this autoimmune cross-targeting of strep and enteroviruses like coxsackie how rheumatic fever becomes Sydenham's chorea; the strep just has to move to the brain? In order for the virus to reach the brain the strep has to create a hole in the blood brain barrier first.  

Tourettes has long been suggested to be triggered by multiple strep infections but the how and why of verbal tics that appear under stress has been a mystery and the fact even after the strep has been eradicated the symptoms remain still puzzles.

It has now become accepted that other infections can cross over the barrier and infect the basal ganglia area.  Spirochetes like lyme could cross-target too.  The genetic form of tourettes has been found to involve a damaged histamine gene. Is tourettes caused by too low a level of histamine?  If spirochetes make cortisol that could suppress histamine causing a similar tourette effect.  How Tourettes is autoimmune needs to be elucidated but because stress and anxiety can play a role this relationship of cortisol and histamine should be examined. It could be that a virus triggers the autoimmune disease but the severity of the condition changes with the histamine level.

Most PANDAS have been found to develop after common H1N1flu infections or flu vaccines when the children have preexisting strep infections.  Eradication of the strep should stop the symptoms because the flu virus does not stay in the body long.

Alzheimer's can involve tics and tourrette like symptoms because a herpes virus can infect the basal ganglia too. Current research has connected rosacea and alzheimer's with herpes zoster virus infections. If an alzheimer's patient develops a strep infection then cross-targeting of the basal ganglia can occur because the herpes virus has already moved into to the brain.

Remember the exact viruses or large infections are not as important as the target.  The target brain cells upon which the autoimmune cross-targeting occurs determines the disease.  Infections such as mycobacterias or spirochetes as well as strep could cause the cross-targeting of the basal ganglia.

OCD

Looking at brain scans OCD appears to involve the frontal lobe. The D2 receptors which the flu uses are there as well as both of the estrogen receptors used by herpes viruses.  So if the infections, like strep, of the basal ganglia reach the frontal lobe then OCD along with memory recall issues could result.

OCD could also develop completely independent of PANDAS.  Rheumatoid arthritis has high incidents of OCD which could be a flu cross-targeting with mycoplasmas in the brain. Mycoplasmas prefer the frontal lobe and have strong associations with Rheumatoid arthritis.

Dyslexia which may involve the CMV virus could also have OCD traits. Again this would be completely different from the pandas groups but involve cross-targeting of the frontal lobe with CMV and mycoplasmas.

(note that hoarding is no longer considered to be OCD because it involves a different area of the brain and may involve spirochetes with cortisone levels rising which means it is not an autoimmune disorder. Hoarder's MRI revealed issues with the anterior cingular cortes and insula)

Parkinson’s 

Children are not the only ones susceptible to autoimmune brain disease causing tics.  Adults tend to develop the basal ganglia jerky movement disorder of parkinson's disease.  Parkinson's disease has been associated with psoriasis' mycobacteria and nocardia.  These mycobacterias are capable of crossing the blood brain barrier.

Parkinson's disease  has also been connected to the flu H5N and flaviviruses. These viral infections target the Substantia Nigra area of the ganglia. Parkinson's could very likely be cross-targeting autoimmunity of the substantia nigra specifically.

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 and only vaccinating when healthy.

Type 1 diabetes 

   In type one diabetes the immune system has decided to attack the pancreas. Two viruses have been associated with the development of type one diabetes the Coxsackie virus (an enterovirus) and the Flu viruses.  Both of these viruses can and do replicate inside of pancreatic cells but it only takes one virus to mark the inside. 

   Larger infections have  been found infecting pancreatic cells from the outside: mycoplasmas, e.coli, campylobactera, 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.

Note that the e.coli and campylobacter infections attach to intestinal cells using the blood type antigens.  Like the epithelial tissues, the pancreas has expressed the blood type antigens which means that E.coli or campylobacter will be drawn to this organ if they cross from the intestine into the body.

How do you know which infection could possibly be infecting the pancreas? E.coli is involved with bladder infections and intestinal infections.  Fungal infections tend to trigger Hashimoto's thyroid disease. (how is unknown) Mycoplasmas have been linked to rheumatoid arthritis.  You only need one of these to infect the outside of the pancreas. 

 The trick for triggering autoimmune cross-targeting 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 T cells 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?

Multiple sclerosis and the myelin of nerves

   Most autoimmune diseases appear to fit this inside and outside cross-targeting problem.  Multiple sclerosis for example has been found to appear after a shingles outbreak but not everyone with shingles develops it.  People with psoriasis 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 myelin because the oligodendrocytes and schwann cells have estrogen receptors, the receptors used by the herpes virus to infect.  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's myelin would be marked to the immune system at the same time.  The immune system would be triggered to destroy all myelin.  Are people who have shingles while they have mycobacterial infections the ones at risk for multiple sclerosis?

Autism the 3 types

  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 bacterial pieces bind there.  Why pick tetanus out of this list ? Some autism patients have HHV6 with the neural autoantibodies.  This 6^th 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 6^th 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. The CMV herpes virus could be implicated here too.  C. tetanus has been found in the guts of some children with autism.  These kids may have developed autism not because of a vaccine rather from catching a herpes virus while dealing with the C. tetanus in their system.  The key autism feature of the temporal lobe is the involvement of the senses.  Visual and hearing decoding including dyslexia has been associated with the temporal lobe.  

   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? Can the coxsackie virus replace the measles virus because it too infects the cerebellum?

    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.

Acute flaccid paralysis 

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 d68 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.  (note the d68 is an enterovirus like polio).

 Another viral family that can trigger acute flaccid paralysis is the flavivirus family. West nile has already been connect with cases of flaccid paralysis and it is only a matter of time before other flaviviruses are connected to it. Note that zika has been shown to cause acute myelitis, inflammation of the spinal cord, so it is quite possible that it too can cause flaccid paralysis in those with staph infections.

Herpes zoster infects these nerves too and on rare occasions has triggered acute flaccid paralysis. Have we not seen more of these in children because of the chicken pox vaccine which has become standard?

Rheumatoid arthritis ????

Guillain Barre

In Guillain barre the bacterial suspect is Campylobacteria Jejuni.  This infection begins in the gut but can trigger the autoimmune paralysis of the legs by triggering autoimmune cross-targeting of the peripheral nervous system after it has moved into the body from the intestine and taken residence with the nerves. Several of the flaviviruses and herpes zoster have been implicated as the viral trigger.  As the Zika virus hits Hawaii with it's sutterella issues there could be adults becoming paralyzed because Sutterella is a bacteria closely related to campylobacteria.

Bell's palsy

Two infections have been associated with Bell's palsy: herpes virus simplex and the spirochete family. Spirochetes include Borrelia, Syphilis, and Leptospira. Not everyone who has lyme disease will develop the facial numbness only those with preexisting herpes infections. Although anti-viral drugs have been found to help this condition is likely to reoccur as the herpes virus comes in and out of dormancy. 

2 types of Myasthenia gravis

 There are two types of Myasthenia gravis and based on the viruses involved drastically different symptoms along with the thymus autoimmune attack. One involves the conjunctivitis and ACTH antibodies.  This type is associated with flaviviruses like west nile which use ACTH receptors.  The other type of myasthenia gravis has muscle weakness of the arms and legs.  The enteroviruses, the polio family viruses, use acetylcholine receptors. Close association with rheumatoid arthritis suggests that the outer infections are the mycoplasmas.

Alopecia

 There could be 2 or 3 types of autoimmune cross-targeting but this will focus on the most common one

Is vitiligo associated with Alopecia more often because some type of skin infection is one of the triggers? Trichophyton violaceum has been associated with discord lupus and vitiligo.  If trichophyton makes tyrosol as it's quorum that could explain the pigment loss. Tyrosol inhibits tyrosinase a step in melanogenesis. Note that autoimmune antibodies to tyrosine have been found in vitiligo patients.

For the cross-targeting autoimmune attack to be started a virus must mark the inside of the hair follicle.  Alopecia precedes both herpes zoster infections and epstein barr infections by 6 months. Any virus that can infect the hair follicle cells could trigger the cross-targeting. Can alopecia be prevented if these viruses are stopped?

Nodding disease and epilepsy

Nodding disease and epilepsy are closely related.  Nodding disease, the zombie like state of those in Africa that has been connected to the black fly blindness could be due to cross-targeting of Trypanosoma brucei and polio or even the live polio vaccine because it is an enterovirus.  Epilepsy has an strong link with schizophrenia a T.gondii disease.  Epilepsy could be autoimmune cross-targeting of t.gondii, t.cruzi, or malaria with enteroviruses. The pattern here is trypanosoma and enterovirus and the medial temporal lobe.

Febrile seizures

There is also evidence of enteroviruses and the pertussis vaccine in Febrile seizures . Does the pertussis bacteria go to the same medial temporal lobe region as malaria and trypanosoma?  Could this be cross-targeting autoimmunity in a baby triggered by vaccine virus particles? Note that the specific region of the medial temporal lobe has been studied with pertussis and the hypothalamus was key.  Could the hypothalamus be what is attacked in nodding disease and epilepsy too by the immune system?

Kikuchi-Fujimoto 

Kikuchi-Fujimoto disease is an autoimmune disease of the lymph nodes. In Japan Aspergillus oryzae is used for making miso, soy sauce, and sake. Exposure rates for aspergillus are high there. The key here is that only one virus and not a specific virus can trigger the autoimmune attack as long as the virus infects the lymph glands.  Herpes viruses and parvoviruses have been suspected but large case studies have failed to prove a direct connection.  It is suspicious that the rare acute disseminated encephalitis, an autoimmune disease of  brain and spinal cord, has been known to overlap Kikuchi-fujimoto.  Unlike multiple sclerosis this autoimmune attack on the nerves does not wax and wane, perhaps it is triggered by the parvoviruse B19.

Hashimoto's thyroid

Hashimoto's thyroid disease has antibodies to thyroid peroxidase (TPO).  All fungal infections secrete peroxidases in order to digest their surroundings.  Logically antibody cross-reactivity can occur between the fungal peroxidase and the thyroid's peroxidase. Sjoren's has strong associations with candida and Hashimoto's. Discord lupus and vitiligo has strong associations with trichophyton and Hashimoto's.  If these autoantigens to the thyroid are started by fungal infections then the inside of the thyroid still needs to be marked as foreign. Multiple viruses have been linked to triggering thyroid disease.  Any of the viruses that infect a thyroid can trigger the autoimmune attack.  Flaviviruses, enteroviruses, and even parvoviruses can infect thyroid cells.  The key to autoimmune cross-targeting is that the inside and the outside must be simultaneously marked as foreign to trigger the immune system to attack and destroy self tissue.

Graves thyroid

Graves disease is not an autoimmune cross-targeting disease; the tissue is not attacked. Antibodies generated by yersinia infections cross react, bind, and activate the TSH receptors.  The thyroid activity is stimulated. The thyroid tissue is not attacked by the immune system.  Now Graves can turn into an autoimmune variety through cross-targeting but the antibody binding the receptor is not on the cells surface very long and a virus or medication must also be marking the inside as foreign.  The window of opportunity for graves disease to become autoimmune is small because the antibody quicky cycles in with the receptor and doesn't have much of a chance to do it's job.

Celiac disease

Celiac disease is an autoimmune disease of the intestine.  Patients tend to have histories of bladder infections or Dermatitis Herpetiformis both of which are associated with e.coli infections.  Campylobacteria was also found in high concentrations in celiac patients. Either of these infections could be the larger mark on the outside of intestinal cells.

 Astroviruses have been isolated from newly diagnosed celiac disease patients.  Other intestinal lining viruses could logically trigger the cross-targeting of e.coli feathered intestinal cells.  Hepatitis B was once considered and so was rotavirus. The specific virus is not as important as the layering of inside and outside infections.

Gluten sensitivity occurs because e.coli is a membrane barrier crosser like T.gondii.  The hole created in the intestine allows gluten to pass through and heighten the immune response.  Celiac disease is an autoimmune cross-targeting on top of a membrane crossing which is why gluten seems to inflame the situation. Gluten does not cause the autoimmune cross-targeting. It has guilt by association with e.coli. 

Drug induced

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. 

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? 

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. 

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.

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 as the first to recognize the coexistance of two infections.