Regulatory T Cell investigation in POIS

[Muon]

T-regulatory cells play a role in immunological tolerance in particular self/non-self discrimination. ''The immune system must be able to discriminate between self and non-self. When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases''. https://en.wikipedia.org/wiki/Regulatory_T_cell

Tregs are subsets of CD4+ T cells. Some Treg subsets cover only a few percent of the total number of CD4+ and probably won't affect total CD4+ numbers much when they are low.

I've seen that some Treg cell types contain peptide specific receptors, with other words these Treg cells can be modulated by peptides:

https://www.ncbi.nlm.nih.gov/pubmed/15520851
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128373
https://www.sciencedirect.com/science/article/pii/S0092867408006247

Now this got me thinking. Some POIS patients are reacting on food, peptides could be responsible for this, for example in wheat:
https://www.jacionline.org/article/S0091-6749(17)30343-3/fulltext

Now I remember Waldinger mentioning peptides in his paper:
''The lack of a local genital skin reaction after ejaculation, but the occurrence of multiple complaints after ejaculation, and the findings of the hyposensitization treatment suggest that in POIS immunologic reactions occur due to repeated close contact during ejaculation between seminal peptides and circulating T-lymphcytes. This leads to a systemic reaction with multiple physical and cognitive complaints.''

So Waldinger, Meinardi, Zwinderman and Schweitzer speculated about the involvement of seminal peptides in POIS. So I'm wondering whether these seminal peptides are activating TCR peptide-specific Tregs (Treg dysfunction?).

From the mayoclinic website which I found interesting:
''The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 am and noon, with no change between noon and afternoon. Natural killer cell counts, on the other hand, are constant throughout the day.(9) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(10-12) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(10) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening,(13) and during summer compared to winter.(14) These data, therefore, indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.'' https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/89318

Please consider testing Tregs when you, as a POIS patient, living near a Mayo Clinic medical center even if your CD4 T-Cell count is normal. https://www.mayocliniclabs.com/test-catalog/Overview/89318

Abnormal sample report: https://www.mayocliniclabs.com/test-updates/attachment.php?id=30514

Last orgasm prior to the one below was 4/5 days back in time. Values below are refering to the same orgasm.

Parameter	Time	Value in pg/ml	Reference range in pg/ml
IL-10 (T-reg)	~10 min before orgasm	774	760-1900
IL-10 (T-reg)	~15 min after orgasm	638	760-1900
IL-10 (T-reg)	~45 min after orgasm	542	760-1900
IL-10 (T-reg)	~24 hour after orgasm	1045	760-1900

There is probably a minimum somewhere within the (45 min - 24 hour) interval after orgasm.

Click on the picture below to zoom in.


The SNS, Catecholamines & Tregs

I wrote a thread about possible ANS involvement in POIS: Is POIS associated with an Autonomic Nervous System Dysfunction?
The SNS is capable of regulating Tregs by targeting β2AR or D1/D2-like receptors on Tregs.
Habibou's results show elevated Noradrenaline 2 hours post orgasm. Catecholamine-dependent down-regulation inhibits IL-10 production in Tregs and could be responsible for the decrease in IL-10 values I have posted: Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop.

During this time, we have learned that T and B lymphocytes express almost exclusively the β2AR
The Beta2-Adrenergic Receptor on T and B Lymphocytes: Do We Understand It Yet?

Androgens, TRT & Tregs

There are a few members with normal testosterone levels reporting positive effects by applying testosterone therapy. I find that remarkable since POIS is relatively rare in respect to the amount of people with a normal testosterone level but close to the lower limit. Some tried boosting their levels with non-TRT methods but these weren't effective. If we speculate and assume that POIS is associated with lower levels of Tregs, then one explanation could be that these people are increasing their Treg numbers by applying testosterone which binds to androgen receptors on Tregs:

We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro:
Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells.

Influence of Testosterone on Inflammatory Response in Testicular Cells and Expression of Transcription Factor Foxp3 in T Cells.

Testosterone Replacement Effectively Inhibits the Development of Experimental Autoimmune Orchitis in Rats: Evidence for a Direct Role of Testosterone on Regulatory T Cell Expansion

Testosterone therapy in POIS patients might be beneficial despite showing a normal level. (if Tregs are low of course)

Vit D & Tregs

It is tempting to speculate that our results may not only hold for MS, but also for other autoimmune diseases
Vitamin D Status Is Positively Correlated with Regulatory T Cell Function in Patients with Multiple Sclerosis

Impaired Treg function in children of allergic mothers (I got a mother with allergies)

Impaired function of regulatory T cells in cord blood of children of allergic mothers

Tregs and muscle inflammation

Th1 Response and Systemic Treg Deficiency in Inclusion Body Myositis

[Nas]

This is indeed excellent Muon, doing tests on this matter will be very important. I'm also wondering potential methods of treating Treg dysfunction. Good job Muon.

[Muon]

better delete that quote Nas I'm updating the thread. About your questions, no I don't know yet what they mean. Yes they are mine.

[Nas]

better delete that quote Nas I'm updating the thread. About your questions, no I don't know yet what they mean. Yes they are mine.

God you're so OCD. Fine.

[Nas]

''The lack of a local genital skin reaction after ejaculation, but the occurrence of multiple complaints after ejaculation, and the findings of the hyposensitization treatment suggest that in POIS immunologic reactions occur due to repeated close contact during ejaculation between seminal peptides and circulating T-lymphcytes. This leads to a systemic reaction with multiple physical and cognitive complaints.''

I'm also very curious about this, doesn't this pretty much explain POIS? I don't I understand it though, how does it exactly lead to systematic reaction?

[Muon]

Click on the picture and scroll down to the bottom left corner. I wonder if seminal peptides couple to the TCR receptors, but what this has to do with POIS I don't know. Does this inhibit IL-10 or does it produce IL-10? Questions...

[demografx]

better delete that quote Nas I'm updating the thread. About your questions, no I don't know yet what they mean. Yes they are mine.

God you're so OCD. Fine.

[demografx]

Spectacular graphics, Muon!

[Nas]

better delete that quote Nas I'm updating the thread. About your questions, no I don't know yet what they mean. Yes they are mine.

What I find interesting in your results, is that IL-10 drops after ejaculation/orgasm; so you're not only low on IL-10 in general. Then you also regain IL-10 in time. You should look at hormones released in orgasm where the timing of their replenishment correlates with IL-10 replenishment time.   

[Nas]

''The lack of a local genital skin reaction after ejaculation, but the occurrence of multiple complaints after ejaculation, and the findings of the hyposensitization treatment suggest that in POIS immunologic reactions occur due to repeated close contact during ejaculation between seminal peptides and circulating T-lymphcytes. This leads to a systemic reaction with multiple physical and cognitive complaints.''

I'm also very curious about this, doesn't this pretty much explain POIS? I don't I understand it though, how does it exactly lead to systematic reaction?

What I interpret here is that, T-Lymphocytes that are circulating in the blood, they get close contact with seminal peptides, but they don't attach, so they keep circulating but in active state, thus producing systematic symptoms all over the body. I'm I wrong? Please correct me if I am. 

[Muon]

better delete that quote Nas I'm updating the thread. About your questions, no I don't know yet what they mean. Yes they are mine.

What I find interesting in your results, is that IL-10 drops after ejaculation/orgasm; so you're not only low on IL-10 in general. Then you also regain IL-10 in time. You should look at hormones released in orgasm where the timing of their replenishment correlates with IL-10 replenishment time.

What you can do is finding the time point which is related to the minimum of IL-10. If you pinpoint that you will have an idea when to test for other parameters close to that point and see if they correlate. I have placed some new ideas below the picture. Treg function could be impaired or Treg populations are temporarily down (no idea what their half life or replenishment rate is btw). Catecholamines could inhibit IL-10 production in Tregs, is this normal behaviour? Androgen receptors could be blocked or there could be a decrease of androgens.

[Nas]

better delete that quote Nas I'm updating the thread. About your questions, no I don't know yet what they mean. Yes they are mine.

What I find interesting in your results, is that IL-10 drops after ejaculation/orgasm; so you're not only low on IL-10 in general. Then you also regain IL-10 in time. You should look at hormones released in orgasm where the timing of their replenishment correlates with IL-10 replenishment time.

What you can do is finding the time point which is related to the minimum of IL-10. If you pinpoint that you will have an idea when to test for other parameters close to that point and see if they correlate. I have placed some new ideas below the picture. Treg function could be impaired or Treg populations are temporarily down (no idea what their half life or replenishment rate is btw). Catecholamines could inhibit IL-10 production in Tregs, is this normal behaviour? Androgen receptors could be blocked or there could be a decrease of androgens.

Well if you take Habibou's tests into consideration, he has low levels of catecholamines, which either means that them binding to Treg is actually beneficial, or that they are not involved in the whole Treg thing.   

[Nas]

I also must say, that today after I tried to masturbate without really much libido, I started noticing huge pressure in kidney region, as if my kidney is struggling to pull its weight back up again. And I still feel right now that my kidney is somewhat exhausted. I could potentially be catecholamines deficient. I've also noticed that me regaining my libido and sex drive is also correlated with my symptoms improving. It could be just the fact that a week is what it takes the testicles to replenish. Who knows.

[Nas]

I just had a thought Muon. I don't think IL-10 is necessarily responsible for the immune reaction, if low levels of IL-10 Treg are what triggers the auto-immune reaction then why were you having a reaction during prick tests? Technically the process of Orgasm is not present to down regulate IL-10. I think the down regulation of IL-10 is only natural during a general immune reaction, it's not directly responsible.

[Muon]

I never questioned whether IL-10 itself is responsible for the immune reaction but argued whether abnormal Tregs or dysfunctional Tregs could play a role in POIS. Tregs suppress the immune system, they downregulate inflammation by upregulating IL-10. So you would expect an increase in IL-10 during POIS but here we have the opposite. IL-10 is also able to penetrate cells like macrophages and stop those cells from releasing inflammatory cytokines. It doesn't make any sense. It's a bummer Simon's IL-10 test had a different timing. 24 hours later I still got POIS but levels seem to be normal again. If I'm going to do some blood tests in the future, I will make sure Tregs are included.

One other thing I'm thinking of is that when allergen specific immunotherapy in general is succesful or partial succesful then you will see an Ig class switch from IgE to IgG4. My IgG4 is elevated, is that due to immunotherapy? There wasn't any elevated IgE present before the treatment. Or is IgE production in B-cells actively being suppressed in POIS? Tregs are able to induce IgG4 and suppress IgE in B-cells. There are other mechanisms:

Dendritic cells suppress IgE production in B cells.

The level of IgE produced by a B cell is regulated by norepinephrine in a p38 MAPK- and CD23-dependent manner.

[nanna1]

Hi Muon,

This is an interesting thread. Also, great work on timing your IL-10 (and other cytokines)! I just had a few questions:

  My first question is: How do you distinguish between cytokines from Tregs and cytokines from macrophages. For example, the primary source of IL-10 in normal people comes from differentiated monocytes (M2 macrophages and dendritic cells) (wiki 1 and depiction 1). And the primary source of IL-8 comes from M1 macrophages (wiki 2 and depiction 2). These depictions come from: Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: Preliminary results (DM Hasan, 2012)

  My second question is: Do you know how cytokine levels change in normal non-POISers when they orgasm? Semen contains polyamines (spermine and spermadine), prostaglandins and cytokines. I could be wrong, but my understanding is that these signaling molecules are produced by the males immune system to tell the woman's immune system not to attack his sperm. So our immune system is regulating her immune system (using immune signaling molecules) so that our sperm have a chance to fertilize her eggs. Prostaglandins also help her uterus contract to draw the semen into her Fallopian tubes. Maybe there is a difference between male POISers and male non-POISers in which signaling molecules are produced during sex/orgasm. Getting a female POISer to do time-point cytokine test like you have, may help to eliminate the sperm production variable.

  Also, is there any place for innate immune deficiency in your hypothesis? I seem to remember you had low NK cell count (CD16+CD56+CD57+) which is a rare immunodeficiency (Natural killer cell deficiency (JS Orange, 2013)).

I like that you incorporate the autonomic nervous system into the hypothesis. Nice!

[Muon]

How do you distinguish between cytokines from Tregs and cytokines from macrophages.

I have asked myself the same question, I have no idea.

My second question is: Do you know how cytokine levels change in normal non-POISers when they orgasm?

A few years ago I stumbled upon a paper which did investigate the behaviour of interferon gamma in women post orgasm. If I remember correctly it dipped after orgasm. So decrease of IFN-g after orgasm might be normal behaviour. I have lost that article and couldn't find it again. As far as the other cytokines are concerned I have no idea.

Semen contains polyamines (spermine and spermadine), prostaglandins and cytokines. I could be wrong, but my understanding is that these signaling molecules are produced by the males immune system to tell the woman's immune system not to attack his sperm. So our immune system is regulating her immune system (using immune signaling molecules) so that our sperm have a chance to fertilize her eggs. Prostaglandins also help her uterus contract to draw the semen into her Fallopian tubes. Maybe there is a difference between male POISers and male non-POISers in which signaling molecules are produced during sex/orgasm. Getting a female POISer to do time-point cytokine test like you have, may help to eliminate the sperm production variable.

No you are not wrong. A certain prostaglandin plays a major role in this mechanism, forgot which one it was. I have thought about this but I never went deep into this matter. Now that you mention it, I do remember vaguely my mother telling me she gets a burning sensation upon intravaginal contact with male sperm. After reading your comment today this popped up into my mind, but wasn't sure so I called her today and asked her this question. She did confirm it.

I can have a burning sensation in my penile uterus when seminal fluid is being released, it's not a standard reaction but it happens when there is high frequency/long duration of exposure and/or when sperm is sticky after an orgasm and some of it is left behind in the uterus. When I get this burning sensation it might induce a burning sensation at my rectum as well, while nothing has happened over that area. Could be a signaling problem.

Third, when I received subcutanous injections it burned like hell. I asked my doc the question why it doesn't give me that reaction when you drop it on skin. He told me it's probably a big molecule, like a protein, that is not able to penetrate the skin due to its size.

POIS could be a signaling defect. Maybe it's something as simple as blocking or rerouting a signal to fix the issue. Perhaps you should start a new thread about this subject, there could be something wrong with this mechanism in poisers. Spermine and spermadine are present in food as well, that could explain food sensitivities, it could be part of the same signaling problem.

Now one other thing, before I forget to mention it, it's probably unrelated but since I'm rambling anyway, when I received a subcutane shot most of the time I felt great right after leaving the clinic. It's like my immune system is temporarily stronger/stable, having less intens food reaction, stronger muscles, My dry mouth is being reversed. I have to look up the exact timing, dunno whether I have wrote it down somewhere. Maybe it peaks around 40 min or so, rough estimate, could be a bit later. Most of the time I used samples which were frozen though, so no orgasm was involved. So that's another thing, the molecule(s) in question is able to stay stable when it's enduring low temperatures and it's relatively large in size.

Also, is there any place for innate immune deficiency in your hypothesis? I seem to remember you had low NK cell count (CD16+CD56+CD57+) which is a rare immunodeficiency (Natural killer cell deficiency (JS Orange, 2013)).

I have not thought about that yet.

[Nas]

POIS could be a signaling defect. Maybe it's something as simple as blocking or rerouting a signal to fix the issue. Perhaps you should start a new thread about this subject, there could be something wrong with this mechanism in poisers. Spermine and spermadine are present in food as well, that could explain food sensitivities, it could be part of the same signaling problem.

I'd be very interested to hear this one.

[Vandemolen]

Third, when I received subcutanous injections it burned like hell. I asked my doc the question why it doesn't give me that reaction when you drop it on skin. He told me it's probably a big molecule, like a protein, that is not able to penetrate the skin due to its size.

A few years ago I tested this. I let my pre ejac 10 hours on my hands. My hands became very red with dots. I think I posted a pic here or on the previous forum.

[Muon]

Third, when I received subcutanous injections it burned like hell. I asked my doc the question why it doesn't give me that reaction when you drop it on skin. He told me it's probably a big molecule, like a protein, that is not able to penetrate the skin due to its size.

A few years ago I tested this. I let my pre ejac 10 hours on my hands. My hands became very red with dots. I think I posted a pic here or on the previous forum.

When skin is being exposed to water for that long, it undergoes structural changes. You also degrade the sebum layer in this way.

Hey Muon, when you were injected by your own semen, did you get POIS? I mean did you get the usual symptoms like brain fog, etc.?

Good question, from what I remember it did not induce the typical cascade of POIS symptoms. Maybe there was a symptom present I can't remember every occasion (5 year period), I probably have written it down somewhere, but generally speaking no. It was also very diluted btw, I started with, I believe, a concentration of 1:40.000 (parts sperm/parts water). Sperm contains at least 1000 different proteins, all kinds of immunological parameters etc, so it's possible this could have nothing to do with allergen specific immunotherapy. You could potentially and theoretically affect all kinds of different systems with this huge diverse soup of molecules.