T3 intracellular calcium and caffeine

[Inara]

I also had my whole genome sequenced a while back but my geneticist only looked for Ehlers-Danlos genes at the time so he probably missed my calcium aberrations or didn't know what to look for. If you find any researchers who study calcium genetics, I'd like to get in on that!

Maybe your genetist is willing to re-check?

I was meaning researchers with a medical background, but why shouldn't I contact people that really must know?

 

[Wonkmonk]

So caffeine, a typical activator of sarcoplasmic reticulum Ca2+-release channel, doesn't work well if cells are T3 deprived, but the association is working!

Does coffee and/or T3 increase intracellular calcium? Could be a reason why I can't tolerate both.

Intracellular calcium influx also plays an important role in the spread and multiplication of Herpes Simplex virus (and possibly other herpes viruses) via Akt activation. Maybe that's somehow related?

 

[drob31]

I don't know if this is related to pyruvate and calcium, but I can't seem to tolerate eating fats.

Weather that's because an unrelated issue or it's because fatty acid oxidation and pyruvate require more calcium, I'm not sure.

 

[pattismith]

Does coffee and/or T3 increase intracellular calcium? Could be a reason why I can't tolerate both.

Intracellular calcium influx also plays an important role in the spread and multiplication of Herpes Simplex virus (and possibly other herpes viruses) via Akt activation. Maybe that's somehow related?

Herpes virus cell invasion follows activation of IP3 by the herpesvirus, which induces calcium influx from the reticulum to the cytoplasm and allows the virus to penetrate.

On the other hand, T3 is needed to keep control on Herpesvirus, so you can't consider just cytosolic calcium on it"s own.

When I was low T3, Herpes was a chronic issue for me until I started Lysine supplementation. Then I kept my Herpes sumplex under control with daily Lysine intake, but if I was forgetting to take it only a few days, or if I was taking some corticoids, Herpes was showing up again.

When I started T3, I no longer needed lysine, I never had again any Herpes simplex relapse, even when I was taking corticoids.

 

[Iritu1021]

Herpes virus cell invasion follows activation of IP3 by the herpesvirus, which induces calcium influx from the reticulum to the cytoplasm and allows the virus to penetrate.

On the other hand, T3 is needed to keep control on Herpesvirus, so you can't consider just cytosolic calcium on it"s own.

When I was low T3, Herpes was a chronic issue for me until I started Lysine supplementation. Then I kept my Herpes sumplex under control with daily Lysine intake, but if I was forgetting to take it only a few days, or if I was taking some corticoids, Herpes was showing up again.

When I started T3, I no longer needed lysine, I never had again any Herpes simplex relapse, even when I was taking corticoids.

EBV virus also affects calcium release from ER.
I wonder if the combination of hypothyroidism and stress leads to virus activation which eventually leads to cellular calcium depletion.

 

[Gingergrrl]

EBV virus also affects calcium release from ER. I wonder if the combination of hypothyroidism and stress leads to virus activation which eventually leads to cellular calcium depletion.

I was curious @Iritu1021 @Inara @pattismith @drob31 (and all the other smart people out there ), since you mentioned the EBV virus affecting calcium release, do you think that EBV (what started my entire illness) could lead to the specific shift to autoimmunity that could cause the calcium channel autoantibody/LEMS that I have to develop?

I had severe mono from EBV in 2012, then second virus in 2013 (possibly the reactivation of EBV) and then I developed POTS, Hashimoto's/ hypothyroid, and in 2015 & 2016 everything shifted from viral to autoimmunity with the calcium channel autoantibody (and other autoantibodies). My doctor explained how EBV can shift into autoimmunity but we never discussed the calcium channel/LEMS autoantibody specifically in relation to EBV.

 

[Iritu1021]

I was curious @Iritu1021 @Inara @pattismith @drob31 (and all the other smart people out there ), since you mentioned the EBV virus affecting calcium release, do you think that EBV (what started my entire illness) could lead to the specific shift to autoimmunity that could cause the calcium channel autoantibody/LEMS that I have to develop?

I had severe mono from EBV in 2012, then second virus in 2013 (possibly the reactivation of EBV) and then I developed POTS, Hashimoto's/ hypothyroid, and in 2015 & 2016 everything shifted from viral to autoimmunity with the calcium channel autoantibody (and other autoantibodies). My doctor explained how EBV can shift into autoimmunity but we never discussed the calcium channel/LEMS autoantibody specifically in relation to EBV.

@Gingergrrl There is definitely some good evidence to believe that almost all autoimmune diseases have their root in viral infections. Hashimoto's for example has been shown closely linked to EBV infection of thyroid gland.
On other hand POTS is a chronic sympathetic overstimulation which is also known to lead to autoimmunity.
But how would EBV virus specifically cause antibody to calcium channel is not clear. Is it for a fact a blocking antibody or do they not know it's function? Perhaps it was an attempt on the part of the body to lower calcium entry to prevent the virus from replicating. Or if it's an agonistic antibody, then the virus DNA might have hijacked your cellular machinery to better serve its needs.

 

[Iritu1021]

So lithium has a very unique effect on calcium - it seems like it can increase it yet stabilize it at the same time.

Chronic lithium treatment attenuates intracellular calcium mobilization.
Wasserman MJ1, Corson TW, Sibony D, Cooke RG, Parikh SV, Pennefather PS, Li PP, Warsh JJ.
Author information

Abstract
Elevated basal intracellular calcium (Ca(2+)) levels ([Ca(2+)](B)) in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) patients implicate altered Ca(2+) homeostasis in this illness. Chronic lithium treatment affects key proteins modulating intracellular Ca(2+) signaling. Thus, we sought to determine if chronic exposure to therapeutic lithium concentrations also modifies intracellular Ca(2+) homeostasis in this surrogate cellular model of signal transduction disturbances in BD. BLCLs from BD-I (N=26) and healthy subjects (N=17) were regrown from frozen stock and incubated with 0.75 mM lithium or vehicle for 24 h (acute) or 7 days (chronic). [Ca(2+)](B), lysophosphatidic acid (LPA)-stimulated Ca(2+) mobilization ([Ca(2+)](S)), and thapsigargin-induced store-operated Ca(2+) entry (SOCE) were determined using ratiometric fluorometry with Fura-2. Compared with vehicle, chronic lithium exposure resulted in significantly higher [Ca(2+)](B) (F=8.47; p=0.006) in BLCLs from BD-I and healthy subjects. However, peak LPA-stimulated [Ca(2+)](S) and SOCE were significantly reduced (F=11.1, p=0.002 and F=8.36, p=0.007, respectively). Acute lithium exposure did not significantly affect measured parameters. In summary, the effect of chronic lithium to elevate [Ca(2+)](B) in BLCLs while attenuating both receptor-stimulated and SOCE components of intracellular Ca(2+) mobilization in BLCLs suggests that modulation of intracellular Ca(2+) homeostasis may be important to the therapeutic action of

 

[Iritu1021]

@Gingergrrl I updated my reply with some more thoughts. Do they know for a fact that the antibody you have blocks calcium entry?
By the way, I had super high antibodies to EBV too.

 

[drob31]

I had EBV occur two times in a row about 2 years ago. Never recall having it reactivate like that before.

So I wonder if that's what's causing the thyroiditis that is causing the heterogenous echotexture. EBV could trigger autoimmunity in the form of those calcium receptor antibodies?

 

[drob31]

I was curious @Iritu1021 @Inara @pattismith @drob31 (and all the other smart people out there ), since you mentioned the EBV virus affecting calcium release, do you think that EBV (what started my entire illness) could lead to the specific shift to autoimmunity that could cause the calcium channel autoantibody/LEMS that I have to develop?

I had severe mono from EBV in 2012, then second virus in 2013 (possibly the reactivation of EBV) and then I developed POTS, Hashimoto's/ hypothyroid, and in 2015 & 2016 everything shifted from viral to autoimmunity with the calcium channel autoantibody (and other autoantibodies). My doctor explained how EBV can shift into autoimmunity but we never discussed the calcium channel/LEMS autoantibody specifically in relation to EBV.

I had EBV infection occur twice within about 6 months of eachother, 2 years ago. My antibodies are never high enough to be considered hashitmotos, but my ultrasound shows a heterogenous echotexture which could be suggestive of some sort of thyroiditis. So maybe I'm hashimoto's, seronegative.

 

[Iritu1021]

I had EBV infection occur twice within about 6 months of eachother, 2 years ago. My antibodies are never high enough to be considered hashitmotos, but my ultrasound shows a heterogenous echotexture which could be suggestive of some sort of thyroiditis. So maybe I'm hashimoto's, seronegative.

That's semantics but Hashimoto's implies autoimmune thyroiditis. You may just have viral thyroiditis. I think most of my thyroid damage is due to viral thyroiditis too since my antibody levels are not all that high. True Hashimoto cases have antibodies >1000.

I suspect that the importance of the antibodies in CFS and POTS has been overrated. It gives doctors some diagnostic test to fall back on when they don't know what's going on. Then they can prescribe treatments like IVIG and Rituximab which may work for completely different reasons - such as changing calcium homeostasis or killing EBV virus - but the fact that they often do work might be just perpetuating the false belief that antibodies are the problem.

Back when I had POTS, I tested positive for antibodies to about 50% of the foods that I normally eat. I decided to disregard that to continue eating them anyway in order not to risk malnutrition. And I still got better which tells me that those antibodies were essentially harmless.

 

[Iritu1021]

Going back to your questions @Gingergrrl here's what we learned so far:

a) many cases of CFS appear to be related to EBV which infects B cells
b) EBV relies on intracellular calcium flux in order to be able to enter the cell and replicate
c) rituximab cuts off intracellular calcium flux in B cells

Therefore, it would be plausible to assume that rituximab is a drug perfectly designed for killing EBV.

 

[Iritu1021]

@pattismith Some researchers believe that bipolar disorder is linked to CNS Herpesviridae infection and that the reason lithium works in bipolar might be due to its anti-viral and immunomodulating properties.

 

[Gingergrrl]

I'm breaking this into two posts so it is not too long!

@Gingergrrl There is definitely some good evidence to believe that almost all autoimmune diseases have their root in viral infections. Hashimoto's for example has been shown closely linked to EBV infection of thyroid gland.

Thanks for confirming that @Iritu1021 and my doctor feels the same as you re: viral infections triggering autoimmunity. I had heard of Hashimoto's being triggered by HHV-6 but was not sure if it could also be triggered by EBV. My Endo who treats my thyroid said there is no way to know for sure which virus triggered my Hashimoto's.

On other hand POTS is a chronic sympathetic overstimulation which is also known to lead to autoimmunity.

So, POTS alone can trigger autoimmunity? My POTS was virally triggered but then shifted and my main doctor said that I have "Autoimmune POTS".

But how would EBV virus specifically cause antibody to calcium channel is not clear. Is it for a fact a blocking antibody or do they not know it's function? Perhaps it was an attempt on the part of the body to lower calcium entry to prevent the virus from replicating. Or if it's an agonistic antibody, then the virus DNA might have hijacked your cellular machinery to better serve its needs.

I was not sure if EBV itself could cause an autoantibody against the calcium channel? I know that EBV links to MS and several cancers, and the calcium channel autoantibody links to LEMS and also to several cancers (with the main one being small cell lung cancer). But I was not sure if EBV linked to the CA+ Channel autoantibody itself.

Three Neuro's (one at Stanford who first found I had this autoantibody) told me that they block the calcium channel and not to take meds that were calcium channel blockers. I accepted it at face value and have not researched how or why it blocks the CA+ Channel (vs. acting as an agonist/opening the CA+ Channel).

So you are saying that if it acts as an antagonist (as I was told by Neuros) it could be an attempt to lower calcium entry into the cell to prevent the EBV virus from replicating? I think I never heard before that EBV virus needs calcium to replicate. Can you confirm that I am understanding this correctly?

@Gingergrrl I updated my reply with some more thoughts. Do they know for a fact that the antibody you have blocks calcium entry? By the way, I had super high antibodies to EBV too.

I saw it and bookmarked that post. Thank you again. Interesting that you had super high EBV antibodies, too. Mine were off the charts high for 3-4 yrs post Mono.

I had EBV occur two times in a row about 2 years ago. Never recall having it reactivate like that before. So I wonder if that's what's causing the thyroiditis that is causing the heterogenous echotexture. EBV could trigger autoimmunity in the form of those calcium receptor antibodies?

Does heterogeneous echotexture mean that the outer layer of the thyroid appears rough and fibrous on ultrasound (like mine does)? Your last sentence (which I bolded) has a question mark at the end so I was not sure if you were making a statement that EBV can trigger autoimmunity in the form of CA+ receptor autoantibodies or if you were also asking the same question as me?!

I had EBV infection occur twice within about 6 months of eachother, 2 years ago. My antibodies are never high enough to be considered hashitmotos, but my ultrasound shows a heterogenous echotexture which could be suggestive of some sort of thyroiditis. So maybe I'm hashimoto's, seronegative.

I did not realize that someone could be seronegative Hashimoto's. Is your TSH level hypothyroid without thyroid med?

 

[Gingergrrl]

Post #2

That's semantics but Hashimoto's implies autoimmune thyroiditis. You may just have viral thyroiditis. I think most of my thyroid damage is due to viral thyroiditis too since my antibody levels are not all that high. True Hashimoto cases have antibodies >1000.

When my Endo tests me, there are cut-off ranges on the lab tests for each Hashi's autoantibody. I am always well above the range for both but you do not have to be in the thousands for it to be Hashi's. All lab ranges are different but looking at my last tests, one of my Hashi's Abs was 35 and anything above 0.9 was considered positive. I used to be in the hundreds on that one so it has come down but it still positive.

I suspect that the importance of the antibodies in CFS and POTS has been overrated. It gives doctors some diagnostic test to fall back on when they don't know what's going on. Then they can prescribe treatments like IVIG and Rituximab which may work for completely different reasons - such as changing calcium homeostasis or killing EBV virus - but the fact that they often do work might be just perpetuating the false belief that antibodies are the problem.

Do you mean antibodies (to viruses like EBV) or autoantibodies (like the calcium channel/LEMS autoantibody) just as an example? I believe there are sub-groups and it is not one monolithic illness. My illness morphed into severe autoimmunity but it started out viral (whatever name it ultimately gets). My Endo said that he would never prescribe IVIG or Ritux for Hashi's but he fully supports my other doctors prescribing them for my other illnesses.

I also agree that we have no idea how the mechanism of these things work and did I get better b/c it killed residual EBV virus, it eliminated autoantibodies, or it changed calcium homeostasis (or some other mechanism)? I wish I knew (or I wish the doctors knew)!

Back when I had POTS, I tested positive for antibodies to about 50% of the foods that I normally eat. I decided to disregard that to continue eating them anyway in order not to risk malnutrition. And I still got better which tells me that those antibodies were essentially harmless.

Do you also have MCAS (mast cell disease)? What kind of testing did you have? Was it for IgE allergies or something else? When my MCAS was severe in 2015 & half of 2016 (until I started IVIG), I was having anaphylaxis to all food but the only thing that showed up as an IgE allergy was certain fish/clams. But MCAS is not IgE mediated (if this is what you mean)? POTS and MCAS very often go together (although I still cannot remember why)!

Going back to your questions @Gingergrrl here's what we learned so far:

a) many cases of CFS appear to be related to EBV which infects B cells
b) EBV relies on intracellular calcium flux in order to be able to enter the cell and replicate
c) rituximab cuts off intracellular calcium flux in B cells

Therefore, it would be plausible to assume that rituximab is a drug perfectly designed for killing EBV.

Do you mean that Rituximab acts as a Calcium Channel blocker or am I totally misunderstanding?

 

[Iritu1021]

@Gingergrrl

I only know what I read on Wikipedia about rituximab mechanism of action:
The antibody binds to the cell surface protein CD20. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.

Then after @pattismith mentioned about herpesvirus, I looked up calcium influx and EBV and found this:
J Biol Chem. 2011 May 27; 286(21): 18583–18592.
Published online 2011 Mar 30. doi: 10.1074/jbc.M111.222257
PMCID: PMC3099674
PMID: 21454636
Epstein-Barr Virus Latent Membrane Protein 1 Increases Calcium Influx through Store-operated Channels in B Lymphoid Cells*

And yes, there can be activating calcium channel antibodies:
https://www.gastrojournal.org/article/S0016-5085(03)02056-0/pdf

Conclusions: A novel functional autoantibody that activates smooth muscle L-type calcium channels at the dihydropyridine binding site is produced specifically by patients with type 1 diabetes and may mediate gastrointestinal and autonomic dysfunction in these patients.

Antibodies are ubiquitous in chronic illness. For example, as it was mentioned earlier in this thread, patients with schizophrenia also have antibodies to muscarinic receptors. There are reports of severe OCD cases that responded to IVIG. Does that mean that psychiatric illness is autoimmune or does that mean dysfunction of nervous system (perhaps in combination with a certain virus) leads to increase in autoimmunity? I don't think anyone really knows for sure at this point.

 

[Gingergrrl]

@Gingergrrl I only know what I read on Wikipedia about rituximab mechanism of action: The antibody binds to the cell surface protein CD20. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.

I apologize for my slow reply @Iritu1021 and I knew about the mechanism re: binding to the CD20 proteins but I don't think I realized about the calcium connection (and still not sure I understand if it is blocking or activating re: Rituximab)?

Conclusions: A novel functional autoantibody that activates smooth muscle L-type calcium channels at the dihydropyridine binding site is produced specifically by patients with type 1 diabetes

I didn't know about the connection of the L-type autoantibodies in diabetes but I have been researching anesthesias (b/c some day I will have to get a colonoscopy) and it appears that Propofol can block the L-type calcium channels (although this should not affect me since my autoantibody is to the N-type, not the L-type).

For example, as it was mentioned earlier in this thread, patients with schizophrenia also have antibodies to muscarinic receptors. There are reports of severe OCD cases that responded to IVIG. Does that mean that psychiatric illness is autoimmune or does that mean dysfunction of nervous system (perhaps in combination with a certain virus) leads to increase in autoimmunity? I don't think anyone really knows for sure at this point.

I have read about some cases of schizophrenia being autoimmune and often wondered why high dose IVIG is not tried in (certain) cases of acute onset psychosis or OCD cases in children like PANDAS following strep? I think there should be lots more studies and research on all of this. I believe a lot of diseases are autoimmune in nature but we don't know it yet (or it is not proven yet).

 

[Iritu1021]

@Gingergrrl
Which of your symptoms got better with IVIG and which ones got better with rituximab? Which one do you think had more effect on autoimmunity and which one on fatigue and brain fog?

I wonder if being on IVIG made rituximab work for you since it didn't do all the great in the study but maybe it's because the other patients weren't on IVIG?

 

[Iritu1021]

@pattismith @drob31 @Hip