Author Topic: Regulatory T Cell investigation in POIS  (Read 2594 times)

Muon

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Regulatory T Cell investigation in POIS
« on: January 13, 2019, 11:45:24 AM »
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.

ParameterTimeValue in pg/mlReference range in pg/ml
IL-10 (T-reg)~10 min before orgasm774 760-1900
IL-10 (T-reg)~15 min after orgasm638760-1900
IL-10 (T-reg)~45 min after orgasm542760-1900
IL-10 (T-reg)~24 hour after orgasm1045 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
« Last Edit: April 23, 2019, 10:33:24 AM by Muon »

Nas

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Re: Regulatory T Cell investigation in POIS
« Reply #1 on: January 13, 2019, 01:36:05 PM »
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

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Re: Regulatory T Cell investigation in POIS
« Reply #2 on: January 13, 2019, 03:04:10 PM »
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

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Re: Regulatory T Cell investigation in POIS
« Reply #3 on: January 13, 2019, 03:05:29 PM »
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.


Muon

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Re: Regulatory T Cell investigation in POIS
« Reply #5 on: January 13, 2019, 03:18:33 PM »
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

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Re: Regulatory T Cell investigation in POIS
« Reply #6 on: January 13, 2019, 03:29:24 PM »
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.
« Last Edit: January 13, 2019, 03:32:12 PM by demografx »
10 years of significant POIS-reduction, treatment consisting of daily (365 days/year) testosterone patches.

TRT must be checked out carefully with your doctor due to fertility, cardiac and other risks.

40+ years of severe 4-days-POIS, married, raised a family, started/ran a business

demografx

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Re: Regulatory T Cell investigation in POIS
« Reply #7 on: January 13, 2019, 04:25:39 PM »

Spectacular graphics, Muon!
10 years of significant POIS-reduction, treatment consisting of daily (365 days/year) testosterone patches.

TRT must be checked out carefully with your doctor due to fertility, cardiac and other risks.

40+ years of severe 4-days-POIS, married, raised a family, started/ran a business

Nas

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Re: Regulatory T Cell investigation in POIS
« Reply #8 on: January 14, 2019, 08:50:17 PM »
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

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Re: Regulatory T Cell investigation in POIS
« Reply #9 on: January 14, 2019, 09:02:50 PM »
''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

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Re: Regulatory T Cell investigation in POIS
« Reply #10 on: January 16, 2019, 08:30:11 PM »
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.
« Last Edit: January 16, 2019, 09:08:51 PM by Muon »

Nas

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Re: Regulatory T Cell investigation in POIS
« Reply #11 on: January 17, 2019, 10:39:45 AM »
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

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Re: Regulatory T Cell investigation in POIS
« Reply #12 on: January 17, 2019, 10:47:16 AM »
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

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Re: Regulatory T Cell investigation in POIS
« Reply #13 on: January 22, 2019, 03:34:19 PM »
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

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Re: Regulatory T Cell investigation in POIS
« Reply #14 on: January 23, 2019, 11:04:20 AM »
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.