POIS Cause/Treatment Discussions > Auto-Immune Causes and Treatments

New ideas about POIS and review of excitotoxicity

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trusttheprocess:
I know everyone has been a little depressed lately about the POIS study, so I would like to share some progress I made recently reading some very interesting medical articles that have made me rethink the role of histamine and genetic factors in POIS.  If these factors are implicated in POIS like I believe, then this will explains the symptoms pretty well and even points to some possible treaments.  But it will also mean POIS is still very complicated, which it why this post is long.  Also what I've read lately changes my opinion on the promise of VNS stimulation as a cure, and shows why there might be some possible underlying medical issues in POIS.

Overview
I think POIS is caused by genetic factors, and the complex immune reaction in POIS involves systemic inflammation due to dysfunctional immune cells and environmental facotrs, mast cell activation and neuroinflammation from microglia activation (which causes a breakdown of the blood brain barrier), and production of the enzyme Indoleamine 2,3- Dioxygenase (or IDO).  IDO also depletes Tryptophan (which is eventually converted to Serotonin and Melatonin) and causes dysfunctions in the Kynurenine Pathway (KP), which seems to cause a large portion of POIS symptoms.  This is induced by IDO for two reasons.  First, to produce Kynurenine, as it is strongly neuroprotective and immunosupressive (although later on it leads to neurotoxicity and vagus nerve-blocking inflammation).  Second, IDO causes Tryptophan depletion to prevent T cell responses against your body.  This suggests POIS triggers some strong neurotoxic and autoimmune response, and the IDO and Kynurenine helps in the short run buts leads to many days of recovery.  Furthermore, the IDO depletion of Tryptophan leads to a temporary state of Pellegra, and at the same time the Kynurenine Pathway shifts from NAD+ to Kynurenine.  This is important because niacin is rapidly converted to NAD+.  NAD+ declines with aging and is associated with mitochrondrial dysfunction.  This can lead to free radical production and excitotoxicity, as energy is needed to pump Calcium ions out of neurons to prevent excitotoxic damage.  The neural tissue is the main energy consumer of the human body, and imbalance in energy homeostasis can lead to neuronal deficit and, eventually, to neuronal death.  The very same immune dysfunctions that caused the autoimmune reaction leads to various antibodies being produced in a desperate attempt by the body to restore homeostasis. 

This final stage of POIS would be much like lupus (with the production of multiple antibodies), with the main difference being that POIS flares are triggered by orgasm instead of sunlight, infections, or stress like in lupus.  Anything the body could possibly interpret as causing this cascade could be targeted, especially sperm cells (antibody causes IBS symptoms), tryptase (and possibly even histamine as both chemicals activate microglia causing brain fog and neuroinflammation), chymase, CRH and other mast cell products, glutamate and glutamate receptors, acetylcholine receptors, calcium and potassium channels, anti-basal ganglia antibodies, anti-nuclear antibodies, and possibly even mitochondrial antibodies (is a target in Sj?gren's syndrome, because mitochrondria produce many damaging free radicals).

trusttheprocess:
Causes of POIS

I. Lack of Immune Tolerance:  Immune Tolerance is a complex series of mechanisms that impairs the immune systems ability to mount responses against self antigens.  Failure or breakdown of immunological tolerance leads to autoimmune disease, while high tolerance can lead to cancers and infections that avoid elimnation.  Certain parts of the body such as the brain and testes have evolved immune priveledge, meaning they are able to tolerate the introuduction of antigens without an inflammatory immune response. (Wikipedia)

2. Molecular Mimicry: "Molecular mimicry can be a mechanism for instigating an autoimmune disease.  Certain antibodies and T cells can interact with dissimilar antigens found in microbes and in host cells. More than 5% of over 800 monoclonal antibodies derived from multiple RNA and DNA viruses, as well as from a large number of T cell clones, engage in such interactions.  Molecular mimicry provides an explanation for the genetic observation that identical twins rarely manifest the same autoimmune disease and the documented epidemiologic evidence that microbial and/or viral infections often precede autoimmune disorders." (Check out this article for a good description and pictures explaining this.  Pubmed ID: 24694269)

While there are many factors that can lead to failed immune tolerance and the body being fooled by molecuar mimicry, I'd like to focus on the dsyfunction of Regulatory T Cells and Dendritic Cells, as they've been implicated in systemic inflammation.

"While systemic inflammation may be induced by multiple external factors, research suggests that a lack of control by tolerogenic dendritic cells and T-regulatory cells (Treg) is possibly the primary risk factor for the development of system inflammation. In functioning immune responses, T-helper and T-cytotoxic cells are activated by presentation of antigens by antigen-presenting cells (APCs). Chief among these are dendritic cells (DCs).  When a DC presents an antigen to a Treg cell, a signal is then sent to the nucleus of the DC, resulting in the production of IDO. IDO inhibits T cell responses by depleting tryptophan and producing kynurenine.  Individuals susceptible to developing chronic systemic inflammation appear to lack proper functioning of Treg cells and TDCs. In these individuals, a lack of control of inflammatory processes results in multiple chemical and food intolerances, autoimmune diseases and many other symptoms and diseases." (Wikipedia)

In an attempt to try and confirm the involvement of DC's, T reg cells and the possibility of immune priveledge-related disease, I used three genome analysis tools (23andMe, Promethease, and LiveWello) to check my results for all DC's and Treg associated genes.  Results are attached, gene frequency is listed, and statistically significant genes are colored. I had one rare mutation in the gene Foxp3, considered to be the master regulator of the regulatory T cells, and could cause a disease called IPEX syndrome.  All of my TNF receptor-associated factor 1 genes (TRAF1) were yellow.  For my Dendritic cells, I had 4 red SNPs and 3 yellow SNPs which could I'd imagine could lead to molecular mimicry. There's a lot more info in two images I've attached to this post, including the 23andMe data, population data and an explanation of what DC and Treg Cells do and what each gene is responsible for.

Often times genes need to be triggered by environmental factors, and the same is true for autoimmune diseases.  One bacteria that could activate microglia (cause neuroinflammation) and fool the body with Molecular Mimicry at the same time is  Streptococcus pneumoniae.  Streptococcus pneumoniae is both a frequent colonizer of the upper respiratory tract and a leading cause of life-threatening infections such as pneumonia, meningitis and sepsis.  It is commonly found in the nasopharynx of asymptomatic carriers, and, under certain still unknown conditions, can invade the brain.  The organism also causes many types of pneumococcal infections other than pneumonia. These invasive pneumococcal diseases include bronchitis, rhinitis, acute sinusitis, otitis media, conjunctivitis, meningitis, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscess.  It is toxic to microglia and astrocytes and may be in part responsible for brain injury during meningitis.  One study investigated it's effect on brain injury:

"S. pneumoniae infection triggered atherogenesis, led to systemic induction of interleukin (IL) 1, and profoundly exacerbated (50-90%) ischemic brain injury in rats and mice, a response that was more severe in combination with old age and atherosclerosis. Systemic blockade of IL-1 with IL-1 receptor antagonist (IL-1Ra) fully reversed infection-induced exacerbation of brain injury and functional impairment caused by cerebral ischemia."

One signifcant way that it does this is by blocking phagocytosis in the brain, preventing the clearing of dead cell debris and possibly triggering the production of anti nuclear antigens.  Along with Streptococcus pneumoniaes toxicity to microglia and astrocytes, histamine induced neuroinflammation could combine to break down the blood brain barrier and expose the brain to this bacteria.  This could be happening in the 20% of POIS sufferers who suffer from fever, a sign of meningitis, as they exhibit worse symptoms than most POIS sufferers.  I think this is the environmental factor that led to my POIS because I had many strep infections as a kid, which led to the movement disorders tics and chorea, and Tourette's and psychiatric disturbance starting right after one of the strep infections.  These are all symptoms of an Anti-basal ganglia antibody, suggesting that the strep had invaded my brain and I was fighting it.  It eventually went away, but I've had a history of chronic bronchitis so it might have just moved to my lungs, and if it can get in my brain once I don't see why it can't again.

This is not the only environmental factor that could trigger POIS though.  Herpes simplex virus (HSV) can cause herpes encephalitis, and studies have shown that long-term neuroimmune activation persists after the herpes infection in patients.  I believe these factors could explain a lot about why we are vulnerable to autoimmune diseases, why strict diets are necessary with POIS (due to the huge number of inflammatory additives in foods), and could even relate POIS to dysfunctions of immune priveledge. This also sets up the body for Kynurenine pathway dysfunction with IDO activation, and this is bad as Kynurenine is found in aging and in neurodegenerative diseases (ex. Physchiatric disorders and Encephalopathies).

trusttheprocess:
Review of Kynurenine Pathway shift in POIS
Kynurenine is useful as an emergency neuroprotective molecule (through it's NMDA, AMPA and kainate receptor antagonism it strongly prevents excitotoxicity) and it scavenges reactive oxygen species.  This is  just my theory but I think it's used by the body to raise the tolerance to increased intracranial pressure and excess Glutamate and Quinolinic acid activity.  I think this because AMPA is used for fast synaptic transition and NMDA is used for learning and memory.  Both seem to be inhibited during POIS, both are activated by Glutamate and Quinolinic acid, and both targeted by Epsilepsy drugs.  If glutamate excitotoxicty (which also happens in encephalitis) is so great to reach levels close to cause a seizure or a Cushing response, I'd imagine the body would release a lot of IDO, which leads to the production of Kynurenine that will counteract the over excitement and slow your brain down.  The release of IDO must be triggered by a serious immune event though, as this will lower tryptophan, serotonin, and melatonin levels, will lead to the prodution of the potent neurotoxin Quinolinic acid, impairs learning and memory, and leads to slower synaptic transmission.

Kynurenine also has significant immunosuppressant effects such as, "Inhibition of T cell functions, activation of the regulatory T cells, and the inhibition of Natural Killer cells are among the important factors in the immunosuppressive effects of IDO and kynurenines. There is a close connection between cytokines (IFN-α, IFN-γ, TNF-α, TGF-β, IL-4 and IL-23) and the kynurenine system, and an imbalance in the TH1/TH2 cytokine profile may possibly lead to neurologic or psychiatric disorders. As the tryptophan metabolic pathway is activated by pro-inflammatory stimuli, the anti-inflammatory effect of kynurenic acid provides a further feedback mechanism in modulating the immune responses." (https://link.springer.com/article/10.1007%2Fs00702-011-0681-y)

Although Kynurenine seems to have many upsides, it has equally as many downsides, making it only useful as an emergency measure.  The first downside is that it blocks α7-nicotinic acetylcholine receptors (non-competitive antagonistic effect).  What this does is block an incredibly important process from performing it's anti-inflammatory effects. This response to excess inflammation is known as the Cholinergic Anti-Inflammatory Pathway (CAP), and it is how the Vagus Nerve is able to reduce inflammation.  It does this specifically by activating the efferent (from the CNS) portion of the Vagus Nerve, causing the release and the binding of acetycholine to the α7-nACh receptors.  This blocking of the CAP by Kynurenine explains the prolonged inflammatory response in POIS, as the bond between Kynurenine and the α7-nAChr is non-competitive, meaning it completely blocks many receptor sites that acetycholine should be activating.  The body produces more acetycholine to compensate for this, explaining lowered heart rate in POIS.  Even VNS devices will probably have some but limited effect (reported by Colm_2), as VNS stimulation releases serotonin and acetylcholine by firing the same nerve as the CAP (Although there is the possiblity that this just means we need a stronger or higher frequency VNS device).

At the same time as IDO is triggering the shift to the KP, it has also been shown to cause temporary pellegra (studies find N1-methylnicotinamide in blood, a marker for pellegra) because it oxidizes tryptophan molecules to impair T cell responses against your body (Pubmed ID: 25933499).  This makes sense, as a deficiency in either niacin or tryptophan can lead to pellegra.  The shift from Tryptophan to Kynurenine is so important that it is commonly used as an indicator for IDO actvity, as the ratio of Kynurenine/Tryptophan in the body, some disorders with changes to this ratio include inflammation, stress, release of gluocorticoids, arthritis, HIV/AIDS, pyschiatric disorders, and cancer. 

The problem of excessive IDO enzyme activity and depleted tryptophan becomes a very serious when you consider that mast activation can also deplete serotonin.

"It is known that mast cells can synthesize and store serotonin...The specific mediator content of mast cell granules however, depends on the local microenvironment in which they reside...As much as 20-40% of serotonin may originate from mast cells. Determination of the role of this immune cell in hippocampal physiology and function is especially interesting given evidence for other immune system effects on an array of hippocampal functions.  The hippocampus is important in the regulation of anxiety and depressive behaviors as well as in spatial learning and memory (PMC ID: PMC3721752)."

Mast cells are located in many areas between the outside world and the body such as connective tissues, skin, lungs, digestive tract, mouth, nose, conjunctiva or lining of the eyelid, and the brain in areas such as the pituitary stalk, the pineal gland, the area postrema, the choroid plexus, thalamus, hypothalamus, hippocampus and the median eminence.  These tissues are the most directly affected due to the inflammatory effects of mast cell activation as well as the release of dozens of other chemicals.  Mast cell activation and depletion of serotonin in the GI tract is unhealthy and underlies many disorders.

This systemic depletion of serotonin and tryptophan is an immunosuppressive mechanism used by the body in order to prevent autoimmune damage, as a tryptophan defiency prevents damaging T cell responses.  Although combined with the depletion of serotonin by mast cells, it leads to anxiety, depression and insomnia.  This is because instead of producing neurotransmitters that it needs to prevent these changes, the body produces Kynurenine.  This is good in the short term, but in the long run it leads to toxic byproducts.

The first notable toxic byproduct of Kynurenine is anthranilic acid (AA).  "AA has been shown to inhibit citric acid cycle and the respiratory chain complexes I?III [46], interfering with mitochondrial function. It may have an anti-inflammatory effect by forming a complex with copper."  This will worsen excitotoxicity and energy levels.  Another neurotoxic byproduct of Kynurenine is "3-hydroxykynurenin (3-HK), which is generally considered as a neurotoxic agent in vivo, causing convulsive attacks when administered intraventricularly [54] or leading to tissue damage when administered intrastriatally [55]. 3-HK is also present in eye lens, and it has been connected with cataract formation [56].  The toxicity of 3-HK can be attributable to its capability to produce free radicals during its auto-oxidation. The next step in the metabolism of Kynurenine is the generation of 3-HA from either 3-HK  or from AA. 3-HA is also prone to auto-oxidation, generating superoxide radicals, H2O2, and cinnabarinic acid [59]. Cinnabarinic acid is a ligand for the type 4 metabotropic glutamate receptor and also for AHR [60,61]. 3-HA can induce apoptosis in monocytes/macrophages [62], and it can inhibit the mitochondrial respiratory chain [46,63]. Furthermore, it has important immunoregulatory functions by interfering with T-cell survival.

Next, Quinolinic acid, under normal conditions is present in the brain in nanomolar concentrations and metabolized for the synthesis of NAD+. In vitro, QUIN is toxic for brain cells from above 150 nM [73]. QUIN is a weak endogenous agonist on NMDA receptors [74], the action of which is selective, involving the receptor subtypes containing the NR2A and NR2B subunits [75]. QUIN causes the greatest excitotoxic damage in brain areas rich in NMDA receptors containing NR2A and NR2B subunits, mainly in the striatum and in the hippocampus [76]. Furthermore, it can increase glutamate release by neurons and inhibit glutamate uptake by astrocytes, maintaining an elevated level to constantly stimulate NMDA receptors, resulting in excitotoxicity [77]. Lipid peroxidation also contributes to QUIN toxicity [78]; results suggest that QUIN forms a complex with iron, and this complex can contribute to the formation of ROS [79,80]. The toxicity of QUIN on brain cells is exerted mainly through NMDA-mediated excitotoxicity [73,81].  Quinolinic acid phosphoribosyltransferase converts QUIN to NAD+, finishing the metabolic process. NAD+ is thereafter utilized by different intracellular processes, serving as an electron transfer molecule" (PMC ID: PMC4463617).

The shift towards Kynurenine production also causes a shift away from the end product of the pathway, Nicotinamide adenine dinucleotide (NAD).  If NAD sounds a little familiar, it's because its health benefits have been in the news lately as having an even more direct anti-aging supplement than resveratrol, and thats what niacin is turned into when it enters the body (this happens very rapidly, with a half life of 20-60 minutes).  Although something about the flushing response does help greatly, I think a large part of niacins benefit may come from the microchrondrial effects of NAD.

"NAD has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response (Pubmed ID: 26118927).  NAD, as well as its phosphorylated form, NADP, are best known as electron carriers and co-substrates of various redox reactions. As such they participate in approximately one quarter of all reactions listed in the reaction database KEGG" (Pubmed ID: 26614649).

I believe NAD plays a large part of the benefits of niacin because it maintains the microchrondria, an absolutely critical benefit.  This is critical because the mitochrondrial theory of aging states that mitochondria are the chief targets of free radical damage, since it is known that they can produce reactive oxygen species.  Also, Mitochrondrial DNA demonstrates higher levels of free radical damage than nuclear DNA.  Electrons might be able to escape from mitochrondrial processes and react with water to form reactive oxyen species (ROS).  NAD works as an electron transfer molecule, so its possible this is what NAD prevents.  These free radicals can then damage the DNA, damaging mitochondrial components and leading to impaired mitochrondrial function.

"Impaired mitochondrial function causes the uncontrolled generation of ROS and nitrogen species (RNS) which can attack macromolecules, resulting in misfolded proteins, lipid peroxidation or nitrosylation and nucleic acid damage. The excess amount of reactive species, i.e., oxidative stress, is closely related to neurodegenerative diseases.   The theory proposes that a positive feedback loop of this process leads to deteoriation of the cells in the entire body and this is why aging occurs."

Temporary Mitochondrial dysfunction is incredibly releveant to POIS for the following reason, "The neural tissue is the main energy consumer of the human body, and imbalance in energy homeostasis can lead to neuronal deficit and, eventually, to neuronal death. The energy, in the form of ATP, is provided by the mitochondria. These organelles are the scenes of the citric acid cycle, fatty acid oxidation, the urea cycle and oxidative phosphorylation. Impaired mitochondrial function leads to energy deficit (lack of ATP), which, in turn, leads to the disruption of Na+/K+-ATP-ase, Ca2+/H+-ATP-ase and the reversion of the Na+/Ca2+ transporter [5]. Under these circumstances, the cells are not able to maintain their normal membrane potential, resulting in depolarization. Cells with disrupted membrane potential are more prone to excitotoxic and oxidative damage. 

Excitotoxicity is the neuronal death caused by excessive or prolonged activation of excitatory amino acid receptors. The main participant in this process is glutamate, acting on ionotropic N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors and on metabotropic glutamate receptors [3]. An excessive amount of glutamate in the synaptic cleft can result in the dysregulation of Ca2+ homeostasis, mitochondrial dysfunction and the generation of ROS and RNS. Under normal conditions, the presence and amount of glutamate is highly regulated, but in neurodegenerative diseases, this regulation is often disrupted, contributing to neuronal damage" (PMC ID: PMC4463617).

Glutamate is not the only cause of excitotoxicity in POIS though, so is something called Ischemia, which is a restriction in blood supply to tissues causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive).  This is caused by lowered heart rate due to excess acetylcholine production, along with inflammation (especially in the brain), and could be made worse by iron deficiency.  This combined with NAD depletion leads to serious mitochrondrial dysfunction and results in excitotoxicity.

I think POIS is also related to lupus because lupus is associated with defects in clearing dead cells, which can be very damaging if not cleared.  This is because when they are not removed by phagocytes they are captured instead by antigen presenting cells, which leads to the production of antinuclear antibodies.  I think this aspect of lupus links it to POIS, as someone a few months back had a positive ANA result.  Furthermore, the primary reason the body has immune priveledged sites is because of physical structures that cause a lack of lymphatic drainage and limit the immune system's ability to enter the site.  This explains why POIS manifests strongly for days, as what is supposed to prevent this autoimmune reaction is instead now a roadblock in clearing antigens.

When POIS does not start at puberty, I think defects in the blood-testes barrier (caused by injury or surgery) along with reduced immune tolerance leads to POIS in this subgroup.  I think these POIS sufferers will have antisperm antibodies more often than the rest of POIS sufferers and will tend to exhibit worse IBS symptoms as a result of the antibody.  Effects not explained by the cascade above can be explained by neurotransmitter disruption inherent with an orgasm (called the honeymoon effect), as well as abnormally high levels of glutmate and histamine present in POIS sufferers after orgasm (and these chemical's whole brain modulating effects).

Going forward I'm going to focus on researching which antibodies are present in POIS, the overlap between POIS and lupus, and what this could mean for treating POIS with the variety of lupus treatments.  I'm also going to start taking Hydrangea root to support regulatory T cell production, Neuroproteck to prevent mast cell activation, Zyrtec and Benedryl to prevent the immune response, Basis by Elysium Health to support mitochrondria function and prevent pellegra, supplements that support lymphatic drainage, and some IDO and TDO inhibitors.

note: any PubMed ID references an article on the joint National Center for Bioinformatics-US National Library of Medicine-National Institudes of Health website, which can be accessed by appending the ID to the end of the following URLS:
Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/
PMC: https://www.ncbi.nlm.nih.gov/pmc/articles/

Quantum:
Hi TTP,

You have worked a lot on these posts, thanks for sharing your hypothesis on the forum.

I have came to very similar conclusions, in particular about the kynurenine pathways "hacking" the tryptophan metabolism through immune upregulation of the IDO enzyme, and TDO enzyme too in the liver, this ultimately producing toxic metabolites that causes excitotoxicity in the brain ( I have written a lot about this on the forum 2 years ago, for example here: http://poiscenter.com/forums/index.php?topic=1988.msg15559#msg15559 and here: http://poiscenter.com/forums/index.php?topic=2078.msg16431#msg16431 .

If you have never seen any of my posts about this, it means that we independently came to the same kind of conclusions, which is very interesting :-)

The most part of my current relief method is largely based on those hypothesis I made then, and has been efficient since that time.  I have included in my pre-pack some IDO inhibitor ( for example, turmeric, and also sources of rosmarinic acid, like rosemary essential oil, Holy Basil, ....) and TDO inhibitors ( my favorite is quercetin, because it is also a mast cell stabilizer)), to lower the effect of upregulated IDO and TDO,  and also including in this pack NMDAr inhibitors, to protect neurons form excitotoxicity ( neuroprotective substances), like magnesium, flaxseed ( the lignan in it) and L-theanine. ( See complete composition of my pre-pack at http://poiscenter.com/forums/index.php?topic=2090.msg16604#msg16604 )

I think you may enjoy looking at this diagram, too:  http://fr.slideshare.net/adonissfera/tryptophan-and-madness/17-Cytokines_Come_in_Two_FlavorsProInflammatory .  It helped me understand how it could be possible that a POIS sufferer can have some clusters of symptoms and not others  ( I don't have any cognitive symptoms, no memory or speech or concentration problems, but much emotional problems... and most have a mix of both, more or less severe on one side or the other.... not to mention other clusters, like the pellagra-like symptoms ).

Keep on diggin, TTP,, and don't hesitate to post about your hypothesis and what you will come up with, in continuing your huge research effort.  :)

certainlypois2:
good stuff from both you.

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