POIS Cause/Treatment Discussions > General Alternative Causes and Treatments of POIS

Transiently Induced Immune Deficiency and Therapy

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nanna1:
  The following post describe an immune therapy that I designed and administered to myself. This therapy is patterned after immune therapies that have been studied for the treatment of cancers and viral diseases. It has been tailored to improve the typical experience of POIS sufferers based on the work of N. Jiang, et. al. (2015) and P. Haake et. al. (2004) as well as medical test posted to Medical Test Results and discussions (public and private) from POIScenter forum.

* Normal immune sexual response
* Aberrant Immune Suppression and Immune Tolerance
* Immune Suppression model of POIS
* Therapy Targets
* Possible solution: Immune Competence Therapy

nanna1:
1. Normal immune sexual response:

  In the paper, "Effects of Sexual Arousal on Lymphocyte Subset Circulation and Cytokine Production in Man" they found that of the most common lymphocytes, natural killer (NK, CD56, CD57) cells experience the greatest increase in the blood circulation by sexual activity and appear to peak around the time of orgasm. While a small increase in (CD8) T cells was measured, (CD4) T cells and B cells do not change significantly during coital behavior.

--- Quote from: nanna1 on January 19, 2019, 09:10:59 PM ---"the orgasm induced a moderate but statistically significant transient elevation of the cytotoxic/suppressor T cell (CD3+CD8+) numbers (Fig. 2). In contrast, the absolute numbers of T cells (CD3+), T helper cells (CD3+CD4+), and B cells (CD3-CD20+) were not affected by sexual stimulation...the levels of LPS-induced proinflammatory cytokines (IL-6, TNF-alpha) remained unaffected by masturbation-induced orgasm...The effects of orgasm on peripheral lymphocyte subsets were restricted to NK cells and had minor or no effects on T or B cell subsets and showed no effects on (IL-6, TNF-alpha) cytokine production, indicating limited and selective effects of orgasm on immune system functions in parallel with its selective and short-lived neuroendocrine effects." -Effects of Sexual Arousal on Lymphocyte Subset Circulation and Cytokine Production in Man (P Haake, U Hartmann, et al., 2004)
--- End quote ---
  During sex, the immune system is enhanced because beta-endorphins block the immune suppression effects of adrenaline/noradrenaline. Beta-endorphin also stimulates the innate immune response to viruses and inhibits viral replication. See: Ref1, Ref2
For example:
"We found that beta-endorphin but not dynorphin could stimulate NK cell activity... beta-endorphin appears to be one of the signals that is induced in the brain at the CS recall step of the conditioned response to trigger the elevation of NK cell activity."
-Expression of the conditioned NK cell activity is beta-endorphin dependent
The activity of, NK cells are believed to be upregulated by endorphins, dopamine, serotonin and nitric oxide in the following way:
Ultimately, serotonin and nitric oxide participate in a complex sequence of immune signaling where by melatonin, IL-12, IL-2 and prolactin produce an expansion in the number and activity of NK cells.

  The most "successful" pathogens remain latent (hidden) in the body and selectively reactivate their replication whenever bodily fluids are being exchanged from person-to-person. Some sexually transmitted infections (STIs, STDs) trigger reactivation from the same neurotransmitters that trigger semen ejaculation (epinephrine and norepinephrine) (post1, post2, post3, post4). So the pathogen replication is syncronized to the exchange of bodily fluids (saliva, sweat, semen).
  The increase in NK cells during sex is needed to suppress these STDs and prevent the spread of infections during sexual fluid exchange. These immune cells are one of the bodies most efficient killers of pathogens (earning the name Natural Killer cells).   

nanna1:
2. Immune Suppression and Immune Tolerance:

  The female genital tract is highly dense with immune cells that aggressively kill any thing with foreign DNA (including harmful bacteria, viruses and sperm). So semen contains a high density immune signalling molecules such as prostaglandins (prostate-gland-in), spermidine and spermine. These signalling molecules increase the likelihood that his sperm will fertilize her eggs by suppressing the immune system (including NK cells) in her genital/vaginal tract. Over time her immune system learns (through spermadine/spermine signalling) to tolerate the man's DNA and sperm without forming an immune response. This is called immune tolerance.

  However, if these immunosupressing molecules (PGE2, spermidine, spermine, etc...) increase in other parts of the body during sexual activity, they could suppress the protective NK cell function and ultimately allow pathogens to reactivate. Certain viruses such as HSV-1, HSV-2, VZV and CMV encourage this scenerio by upregulating the COX-2 arachidonic acid enzyme in their latent host cells. So these viruses modify the cellular enzymes (i.e. COX) to make their own replication favorable.

  Note that PGE2 induced upregulation of arginase leads to L-arginine and nitric oxide depletion. This is because arginase decreases the available pool of L-arginine for Nitric Oxide Synthase (NOS). As a result, high arginase levels are associated with epithelia and endothelial dysfuction.   The PGE2 induced upregulation of IDO1 leads to the depletion of Tryptophan and serotonin. Decreases in serotonin leads to a decrease in melatonin (sleep quality) and N-acetylserotonin (antidepressant). While increases in kynurenine contribute to immune tolerance.

  When NK cell function is suppressed, it can lead to an increase in inflammatory chemokines and a dependence on CD8 T cells to perform the anti-viral (or anti-bacterial) functions of NK cells. Relative to NK cells, CD8 T cells have a slower pathogen-killing response which delays the clearance of the pathogen. (click image to get full size)
Figure 4 from: "Deciphering the role of DC subsets in MCMV infection to better understand immune protection against viral infections"
  A suppression of NK cells (low NK) causes inflammatory pathogen-based disease (CD8 w/o NK), while a healthy NK response (NK) prevents symptoms (CD8 w NK: grey):
Abstract Figure from: "Human Natural Killer Cells Prevent Infectious Mononucleosis Features by Targeting Lytic Epstein-Barr Virus Infection"

nanna1:
3. Immune Suppression/Immune Tolerance model of POIS

  Many theories of POIS center around an assumption that the immune cells are too active and need to be suppressed or stabilized. Here, I present the exact opposite theory, namely that cytotoxic innate immune cells, such as natural killer (NK, CD56 or CD57) cells are not active enough and need to be increased. NK cells are protective against the reactivation of latent infection. It is the absence of a competent innate (NK) immune response that causes increased inflammatory chemokine release due to uncontrolled pathogen replication. In other words, POISers experience a temporary immuno-compromised state triggered by certain neurohormones (adrenaline, PGE2, etc...) of the sexual response cycle.

  In the paper "Immunophenotypical Characterization of a Brazilian POIS patient", the POIS patient was found to be deficient in cytotoxic natural killer (NK) cells and B lymphocyte cells, and an over expression of monocytes. The aurthors of this paper also note that:
"Some studies have shown a decrease of NK cell percentage in association with a reduction of activity of these cells in peripheral blood of patients with depression. Other mental disorders such as mental stress, autism and obsessive-compulsive disorder have also been reported to present lower NK cell activity."

  The deficiency in Natural Killers indicates that immune suppression could be preventing this patient from forming a competent immune response. The deficiency in B cells may indicate that immune tolerance is preventing humoral immunity from correcting the problem associated with POIS. Without a competent humoral/memory immunity, the immune system treats the reactivation of latent infections as if it is a new/acute infection. One of the main signaling roles of spermine and kynurenine is to induce immune tolerance to foreign substances and DNA. This immune tolerance can inhibit the formation of cytotoxic T cell memory of pathogens and prevent a competent humoral response.
 
  Since, most POISers recover from POIS in the 5 to 7 day range. The time kinetics of NK, T, B cells seems to suggest that, in the absence of an immunocompetent NK response, POIS recovery is correlated with the time-dependent expansion of non-memory CD8+ T cells.
Figure 7 from: Global Transcriptome Analysis in Influenza-Infected Mouse Lungs Reveals the Kinetics of Innate and Adaptive Host Immune Responses 
  This time-dependent increase in CD8 T cells occurs during sleep (How Sleep Fights Infection: Snoozing Makes Killer Immune Cells More Sticky). So, the sooner sleep occurs following orgasm, the sooner CD8 T cells can start replacing the function of NK cells in the immune response. Moreover, sleep deprivation has been shown to suppress NK cells in humans (Ref1, Ref2, Ref3). So good sleep is vital for immune function and recovery from POIS.

  So this immune suppression model predicts that normal (non-POIS) people rely upon a transient increase in NK cell activity to suppress latent infections, while POISers rely upon the slower CD8 T cell increase to control those same latent infections. This means that POISers should experience a (days-long) elevation in chemokines due to the delay in time that it takes the adaptive (non-memory) T cells to respond. Transient PGE2 release induces the arginase-1 and IDO1 mediated suppression of innate cells (namely Natural Killers).

nanna1:
4. Therapy Targets

Adenylyl cyclase
  Adenylyl cyclase is an enzyme that produces cyclic AMP (cAMP) from the basic energy substrate ATP. Norepinephrine (norepinephrine) and epinephrine (adrenaline) bind to beta-adrenergic receptors to activate adenylyl cyclase. Prostaglandin E2 (PGE2) also activates adenylyl cyclase. This adenylyl cyclase activation causes an increase in cAMP. Herpes viruses reactivate when rising cAMP levels induce arginase activity in infected cells (see Ideas on Herpes Induced POIS). Cyclic AMP stimulates the up-regulation of arginase-1, while cyclic GMP does not stimulate arginase-1. There are direct and indirect inhibitors of adenylyl cyclase. Flush niacin, acetylcholine, dopamine and beta-endorphins inhibit adenylyl cyclase indirectly through Gi coupled protein receptors.
From: Cardiac Muscle Contraction
"The addition of exogenous nicotinamide adenine dinucleotide (NAD) to isolated rat fat cells at concentrations between 1 and 10 μmol markedly inhibited the rise in cyclic AMP accumulation due to norepinephrine...NMN was as potent as nicotinamide while nicotinic acid (flush niacin) was 100- to 500fold more effective than either compound as an inhibitor of cyclic AMP accumulation."
-Effect of NAD, nicotinamide and nicotinic acid on cyclic AMP accumulation by fat cells
* Caffeine directly inhibits adenylyl cyclase by competitive binding to the location (active site) where ATP interacts.
* Nicotinic acid (flush-niacin) inhibits adenylyl cyclase through the GPR109A receptor (Ref1)
* Dopamine inhibits adenylyl cyclase through the D2 dopamine receptor
* Endorphins inhibits adenylyl cyclase through the opioid receptors
* acetylcholine inhibits adenylyl cyclase through the (M2, M4) Muscarinic acetylcholine receptor  Not every cell-type expresses these receptors and the corresponding neurohormones are only effective in localized portions of the body expressing these receptors. So an infected cell that does not express the opioid receptors will not be affected by beta-endorphin. While reactivation of infections in cells expressing these receptors may be suppress by beta-endorphin. However, the inhibition of adenylyl cyclase by caffeine is direct and does not depend on a Gi based receptor. So caffeine can act more universally across all cell types to block cyclic AMP production from beta-adrenergic and prostaglandin signalling.
  N Jiang suggested that a lack of endorphin signaling is a necessary feature of POIS manifestation. The endorphin receptors are adenylyl cyclase inhibitors.

Arginase
  Arginase produces the polyamines spermidine and spermine from L-arginine. Spermine suppresses the immune system and prevents immune cells from killing pathogens. Spermine also increases the rate that viral DNA can be replicated. Some viruses (like herpes) chronically up-regulate arginase through COX-2 and other genetic signaling (Ref1, Ref2).
"Many viruses have been shown to require polyamines for one or more aspects of their replication cycle, including DNA and RNA polymerization, nucleic acid packaging, and protein synthesis...Inhibition of polyamine synthesis with difluoromethylornithine (DFMO) results in a block of both HSV and HCMV replication." -Polyamines and Their Role in Virus Infection

Arginase also disrupts endothelial (blood vessel) barrier function:
"...Putrescine, spermidine and spermine, given individually, were found to disrupt Blood Brain Barrier (BBB) integrity within 15 min of i.c.v. administration...When injected into the carotid artery, rapid increase in BBB permeability was found 1 min after putrescine and spermidine..." -Polyamines induce blood-brain barrier disruption and edema formation in the rat (1996)
Arginase activity produces urea as a waste product so urea in the blood and may be a relevant biomarker of POIS.

cyclooxygenase-2 (COX-2)
  COX activity can increase protaglandin E2 (PGE2) production. PGE2 activates adenylyl cyclase leading to cyclic AMP increases. This process then induces immune suppression of NK and T (CD8) cells. Inhibiting COX and PGE2 activity has be shown to increase NK cell numbers and activity (Ref1, Ref2, Ref3). It has also been shown that inhibiting COX has the effect of increasing beta-endorphin stimulating activity.

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