Severe COVID may be caused by 'autoantibodies'

[sometexan84]

Severe COVID may be caused by 'autoantibodies' – here is what that means

Note: Unfortunately, we can't test for most of these. It really really sucks. Only thing we can do is test for levels of a given protein, or cytokine. Many times, it's lower if there are auto-antibodies against it (not always).

Yale University study found the following antibodies....

COVID
Cytokine autoantibody targets
Type 1 interferons
IL-1α/β
IL-6
GM-CSF (CSF2)
IL-18Rβ (IL18RAP)
Leptin (LEP)
Chemokine autoantibody targets
CXCL1
CXCL7 (PPBP)
CCL2
CCL15
CCL16
Chemokine decoy receptor ACKR1 (Duffy blood group antigen)
Immunomodulatory cell surface autoantibody targets
NKG2D ligands (RAET1E/L, ULBP1/2)
NK cell receptors NKG2A/C/E (KLRC1/2/3)
B cell expressed proteins (CD38, FCMR, FCRL3, CXCR5)
T cell expressed proteins (CD3E, CXCR3, CCR4)
Myeloid expressed proteins (CCR2, CD300E)
CNS compartment autoantibodies
Orexin receptor HCRT2R
Metabotropic glutamate receptor GRM5
Neuronal injury marker NINJ1
Vascular cell type autoantibodies
Endothelial adhesion molecule PLVAP
Regulator of angiogenesis RSPO3
Connective tissue and extracellular matrix autoantibody targets
Suspected regulator of cartilage maintenance OTOR
Matrix metalloproteinases MMP7 and MMP9


https://www.medrxiv.org/content/10.1101/2020.12.10.20247205v4.full-text

"autoantibodies that target immune cell surface proteins are associated with depletion of particular immune cell populations and may negatively impact the immune response"

"patients with autoantibodies against antigens expressed on B cells (CD38, FcμR, and FcRL3) had significantly lower frequencies of circulating B-cells"

"patient with anti-CD38 autoantibodies and found that they also exhibited a lower frequency of NK cells, activated CD4+ T cells, and activated CD8+ T cells, all of which also express CD38"

"With respect to monocytes, we identified five autoantibody targets (CCR2, CCRL2, FFAR4, SYND4, and CPAMD8). patients with these autoantibodies had significantly lower frequencies of classical and intermediate monocytes as well as increased frequencies of nonclassical monocytes"

"patient with autoantibodies against CD3E (a component of the T cell receptor complex) who had intact B and NK cell compartments but dramatically reduced levels of CD4 T cells, CD8+ T cells, and NKT cells in the blood"

 

[Learner1]

And those were just the antibodies they tested for. Perhaps they should look for the antibodies that cause this:

"The possible association between COVID-19 and postural orthostatic tachycardia syndrome" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729277/

 

[sometexan84]

No, that's the thing. They tested for 2,770 antibodies at once using a new technique called Rapid Extracellular Antigen Profiling (REAP). That's how they were able to find so many.

 

[Rufous McKinney]

there are auto-antibodies

could these auto antibodies be...possible Somethings In the Blood?

 

[sometexan84]

A lot of these are fairly obscure, which limits information available. But here are a couple of associations...

GM-CSF - Mycobacteria, Cryptococcus, Norcardia, Aspergillus infection
IL-6 - Recurrent staphylococcal infections

Also, it's likely COVID was the cause of some of the antibodies.

 

[Learner1]

No, that's the thing. They tested for 2,770 antibodies at once using a new technique called Rapid Extracellular Antigen Profiling (REAP). That's how they were able to find so many.

But, were the antibodies on the CellTrend test on that list of 2770?

 

[Wishful]

No, that's the thing. They tested for 2,770 antibodies at once using a new technique called Rapid Extracellular Antigen Profiling (REAP). That's how they were able to find so many.

My first thought is that this is just another example of a new, more sensitive lab technique revealing something that exists in everyone, but just wasn't noticed before. The real question is: do these autoantibodies have a noticeable effect on health at the levels at which they are measured? Theoretical effects and in vitro experiments may not be valid in vivo, because there might be other factors that keep the autoantibodies from causing noticeable effects.

 

[joshualevy]

Just to remind everyone of the obvious, if you test for 2770 antibodies, and you use a p value of 5% (the standard), you will send up with 139 false positives. If you use a much higher standard (like 1% or even 0.1%) you will still end up with 27 or 3 false positives. This study used all of those different p values for different analysis that they did, so it is very unclear to me if any of this has meaning outside of p value hacking.

Additionally, I agree with Wishful: new techniques always leads to new observations, but that does not mean they are important.

 

[sometexan84]

But, were the antibodies on the CellTrend test on that list of 2770?

Good question. I'd assume so, since a couple of the positives mentioned include neurotransmitter receptors.

So, looking at the supplemental material, it looks like a bunch of those were tested.....

Beta 1 and Beta 3 adrenergic receptor?

This might be Angiotensin II receptor

This is Endothelin-Receptor-A

Muscarinic receptor 3... looks like just 3, and not 1, 2, 4, or 5...

Alpha adrenergic receptors, alpha 1 and alpha 2 w/ subtypes

 

[sometexan84]

Just to remind everyone of the obvious, if you test for 2770 antibodies, and you use a p value of 5% (the standard), you will send up with 139 false positives. If you use a much higher standard (like 1% or even 0.1%) you will still end up with 27 or 3 false positives. This study used all of those different p values for different analysis that they did, so it is very unclear to me if any of this has meaning outside of p value hacking.

Additionally, I agree with Wishful: new techniques always leads to new observations, but that does not mean they are important.

Maybe. Would probably take a lot more digging to know for sure how relevant the data is.

But from what I can tell, the data seems to show significance. The "severe" group had the most (immune-targeting) auto-antibodies, with a P value of 0.01% (****P ≤; 0.0001)

"Significance was determined using a Kruskal-Wallis test followed by a Dunn’s test. Longitudinal samples from the same patient were included in all analyses in this figure. *P ≤; 0.05, **P ≤; 0.01, ***P ≤; 0.001, ****P ≤; 0.0001 "

 

[Learner1]

Good question. I'd assume so, since a couple of the positives mentioned include neurotransmitter receptors.

So, looking at the supplemental material, it looks like a bunch of those were tested.....

Beta 1 and Beta 3 adrenergic receptor?

View attachment 41129

This might be Angiotensin II receptor

View attachment 41130

This is Endothelin-Receptor-A

View attachment 41131

Muscarinic receptor 3... looks like just 3, and not 1, 2, 4, or 5...

View attachment 41132

Alpha adrenergic receptors, alpha 1 and alpha 2 w/ subtypes

View attachment 41133

Thanks for looking. On their list: ngiotensin-II-Receptor-1 (AT1R) IgG-auto-antibodies.

Wonder why they left out M1, 4, and 5.

 

[sometexan84]

Wonder why they left out M1, 4, and 5.

Because that's how this young fellow developed it?

But apparently Long COVID patients do have the CellTrends antibodies...

https://www.healthrising.org/blog/2...y-fire-autoimmunity-chronic-fatigue-syndrome/

"Speaking of autoimmunity, a German company called “Berlin Cures” reportedly offered to screen the German long COVID group, “Covid 19 Langzeitbeschwerden”, for their autoantibodies to the adrenergic and muscarinic receptors that Carmen Scheibenbogen first found. In November, a doctor with the group reported that they were finding these antibodies in all long COVID patients tested so far… "

 

[Learner1]

Because that's how this young fellow developed it?

View attachment 41149


But apparently Long COVID patients do have the CellTrends antibodies...

https://www.healthrising.org/blog/2...y-fire-autoimmunity-chronic-fatigue-syndrome/

"Speaking of autoimmunity, a German company called “Berlin Cures” reportedly offered to screen the German long COVID group, “Covid 19 Langzeitbeschwerden”, for their autoantibodies to the adrenergic and muscarinic receptors that Carmen Scheibenbogen first found. In November, a doctor with the group reported that they were finding these antibodies in all long COVID patients tested so far… "

Exactly....

 

[Wishful]

The control was covid negative. What would be interesting is a control group that is covid negative but with active infection from other viruses, even the common cold. Maybe the increase in autoantibodies is just a general 'immune system is active' response. Are the autoantibodies a unique signature for a particular virus, or fairly useless information? More work to be done.

 

[sometexan84]

The control was covid negative. What would be interesting is a control group that is covid negative but with active infection from other viruses, even the common cold. Maybe the increase in autoantibodies is just a general 'immune system is active' response. Are the autoantibodies a unique signature for a particular virus, or fairly useless information? More work to be done.

They showed correlation between disease severity and number of (immune system related) auto-antibodies.

You're not going to want to hear this, but this means now there's more work to be done regarding the pathogenesis of autoimmunity and perpetuation of immune dysfunction. Just identifying and treating infections isn't enough.

For instance, say you get a Parvovirus B19 infection, and during your acute B19 infection you have severe psychological stress, weakening the immune system, (combined w/ a specific genetic predisposition) and allowing B19 to produce auto-antibodies to cytotoxic lymphocytes. After clearance of the acute B19 infection, these antibodies persist.

Now you have antibodies attacking your own (infection-fighting) cytotoxic lymphocytes. As time passes, you get more infections, but your immune system is having a hard time fighting them off because your Cytotoxic CD8+ or NK cells are down, and maybe the cytotoxicity levels in those cells are down as well. So infections persist.

You get more infections, more re-activated latent infections, more immune dysregulation, more auto-antibodies created, more epigenetic modifications being made, and decreased sleep efficiency making it even harder to fight infections. It just keeps getting more and more out of control.

What are you going to do, treat the B19 infection? No, because it's gone. There's nothing to treat. Current infections should try and be treated of course. But it's a never-ending uphill battle if immune dysfunction persists.

Tracing auto-antibodies to an infection is only slightly helpful. Also they're not all produced directly from an infection. Plus some are helpful. Finding these auto-antibodies is not useless. It demonstrates an "immune system is broken" response.

 

[mitoMAN]

I just posted about this on our CFS Treatment discord.


https://berlincures.de/pipeline/
Pipeline and BC007
Mode of Action Our candidate BC007 is a non-modified DNA aptamer out of a family of aptamers that bind to and lead to the neutralization of autoantibodies that are directed against G-protein-coupled receptors (GPCR-AABs). BC007 binds to ß1-adrenergic-receptor-autoantibodies. BC 007 was successfully tested in a Phase-1 clinical trial. This study included a sub-group of subjects that are tested positive for GPCR-autoantibodies and which are otherwise healthy. The study design allowed for the proof that BC007 can neutralize GPCR-autoantibodies in humans. The full study design is published on clinicaltrials.gov After successful completion of Phase 1/1b, we initiated a multi-center, randomised, controlled Phase 2 study in heart failure patients.

Berlin Cures
Pipeline – BC007



They had planned a ME/CFS trial but sadly it was closed due to money shortage.
BC007 is able to completly neutralize B-adrenergic-receptor autoantibodies as well as alpha-AR and muscarinic-AR https://berlincures.de/wp-content/uploads/2016/12/pipeline-2016.jpg