I have been re-reading this series of postings and have derived a lot of benefit from them.
However, I watched the Pillai video (because you insisted I do so) and one thing struck me.
He tells us that the wiruses go through a Darvinian process and damage to our innate immune system can prevent the ewolution of our development of the appropriate antibodies.
However, you have made a strong case, and I find it persuasive for a number of reasons, that the virus cannot mutate much and remain functional. Sure, it can change its Spike protein (possibly the S1 most) but it will not be able to do much to the N protein, and if you have ever been exposed to a Corona Wirus in the past then you likely have memory T cells that recognize it and can cleanup cells infected with SARS-CoV-2 as well.
So, is that a good explanation or is it simply that, as you seem to point out, it just shuts down the adaptive immune system for a period of time?
One thing I was confused about was the use of ADE in this post as it seemed atypical to its normal use.
I took ADE to refer to effector function as a method of mediating the enhancement, and strangely ADE appears to be found mostly with infection of effector cells. So would the case of IgG4 be appropriately termed as ADE or more like kooky "I don't see anything" immune tolerance.
Right, but ADE can't exclude novel ways that antibodies enhance disease, because, well, someone went and named it "antibodies enhancing disease." *edit: wait a minute the D is for dependent, anyway imagine I used that in the sentence and it still works. I added a footnote on Sunday acknowledging that this wouldn't be one of the traditional applications. But if IgG4 eventually results in severe disease / pneumonia there's no way to not call it ADE.
Great series of posts Brian! It's probably tough catching flak from both sides, but ultimately I think this process is producing the strongest arguments.
Regarding testing, especially in the US, almost all testing is nasal swabs which is of the mucus membranes. My understanding is IgM dominates the response there. It seems that response will be identical in both Vaccinated and Unvaccinated. If the immune tolerancing theory is correct and the Vaccinated start having persistent infections, would it continue to show up in the nasal swab tests or would anal swab tests or blood serum tests be more accurate?
Anecdotally, I have seen a case where a "vaccinated"19 year old healthy BMI female has had a persistent cough for 1.5 months. Tests "negative" for Covid with a nasal swab and has no other symptoms. I also see plenty of anecdotes about persistent viral infections "but it's not covid". Is it possible that we are already seeing persistent infections but our testing regime is failing us? Keeping in mind of course that there really are other viruses out there that we routinely do not test for.
In general, at least a trace amount of persistent infections seem to be reflected by PCR (for example .5% or 1 in 200 of all sequenced infections when using near-same-sequence on multiple days to define persistent infection vs reinfections in https://www.medrxiv.org/content/10.1101/2023.01.29.23285160v1 )
But there is a larger "iceberg" of persistent infections that are still almost hypothetical, because PCR / swab testing doesn't reveal anything. Plasma/stool/urine testing maybe reveals some of this iceberg (https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07153-4 - but that is only four weeks after infection, when even nasal PCR will still often be positive for "residual" virus) but there still seems to be more that we can only see indirectly (i.e. spike S1 lingering in monocytes in Long Covid, and tissue histology and PCR in autopsies https://onlinelibrary.wiley.com/doi/10.1002/path.6035). We would have to be able to chop people up and test every tissue and put them back together again to get a full look.
So even without the question of antibody masking in the nasal cavity, I think it safe to presume that persistent infections won't show on nasal PCR , plasma/stool/urine might give a better look, might not (I'll see if there are any studies with longer time-points). If it's coughing all the time, I don't think antibody masking should mess up PCR, maybe antigen assay - my guess would be generic immune suppression from the shots leading to an opportunistic infection, i.e. some degree of "VAIDS" at work.
It's very weird to me that current events have made amateur immunologists out of every thinking person in the world. Very weird.
But what I took away from that, is that when the virus and the immune system reach their stalemate, this is worse than is obvious. Even if the virus is not rapidly infecting and destroying cells there is a baseline load of spike that is still proinflammatory and still doing random vascular damage possibly in the brain. Tolerating spike in the body is always a mistake unless the things I have read about spike on its own are in error.
So two questions:
1 Does free spike have the destructive potential to we have heard it does?
2 What is the 'half life' of spike without the rest of the virus? Or of free floating virus in the body, if it can't find a target for whatever reason?
I think free spike might not be as toxic / inflammatory once you already have circulating antibodies. Otherwise I don't know how to explain why boosters haven't made everyone drop dead. It's also always worth noting that most of what is bad about spike might be true for any foreign protein or molecule, we just haven't looked into it; the example I use here is always Pretorius et al.'s findings on LPS, which is a component of common household dust https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5046953/
2 I'm sure spike is always being broken down by random proteases which are everywhere in the body. That doesn't answer the question obviously. So, apart from situations when it's being actively produced so it's like spike is "playing on the molecular radio," I dunno how long it lasts.
With the acknowledgement that I know very little about virology or immunology, my thinking is this.
If we assume that spike is the BAMF killer that it is portrayed as(herein referenced as SAS'-Silent Assassin Spike'), it is still concentration dependant and the damage that it does is probabilistic not targeted. So, a very small amount of SAS may randomly damage something crucial and cause myocarditis or sudden death, presumably thru cerebral damage, but probably not. Whereas a continual supply of SAS being produced in your shoulder(HAHA or nuts more likely), can be expected to break something important if it goes on long enough. There are too many unknowns with the shots to say anything for sure about why the boosters act the way they do.
Being an ignorant virus denier person I have 33% of my brain circuitry overwhelmed by this post, but I am doing a sincere effort to understand as much of this as possible.
In the spirit of the old "Remember, there are no stupid questions, only stupid people" I bring you two questions:
First. I don't know if I understand the metaphor at the end, the one about deputizing the raccoons. I understand it to mean a grim future where the body never stops attacking itself. That's his new programming: destroy yourself slowly, with the help of these well trained police raccoons. Did I understand that correctly, or is it the other way around, that is, deputizing the raccoons is a good situation?
Second question: I understood somehow that the cytokines act as a drug that sends the adaptive immune response to sleep, and the lack of adaptve immune response fosters more viral damage in more healthy cells. (I doubt I got that right.) But this happens only in that stage of "severe covid." But severe covid is rare. Most people never got there. What piece fails so that mild covid finally expands into in that severe covid which causes that adaptive response suppression? I'm guessing that there is a "race condition" here, as in electronics: if T cells mature before the lymph nodes freeze, there is no severe disease, and if they fail to mature in time, their maturation process will be shut down even harder.
So ::dons the conspiracy hat:: it seems there is a physical exploit built in into the pseudovaccines. They learned how the immune system fails sometimes, and designed a drug to make that effect more likely to happen in some people. Maybe it was a fluke that they are so bad?
I'm sorry to complicate this even more by summoning here the one of the most esoteric parts of electronics design. Immunology is already difficult as it is, no one needs more metaphors.
1 The raccoons are the virus. IgG4 sticks to the spike protein and tells the immune system to ignore it; so whereas IgG1 or IgG3 would stick to the raccoon and say "kill this raccoon, police officer" IgG4 says "leave this alone." Same with spike sticking out of infected cells. Again it's a question of balance though, because the raccoon has a harder time getting into cells with the police hat stuck onto its face. So maybe the result (as long as you didn't get to tolerance via a huge out of control acute infection) is total homeostasis, no problem.
2 The "more viral damage" that results from suppressed adaptive response might be marginal. As Wherry says, the immune system is containing the virus, so maybe it's like a slow smoldering. But yes, I think "race condition" basically describes the problem. If you get adaptive response moving (making future memory B Cells and T Cells in germinal centers) in time then you avoid the huge amount of tissue destruction that results in suppressing adaptive response (which occurs because now having T Cell "scent-trained-dogs" around would make the raccoon-infested kitchen even more of a mess; and you might also accidentally train T Cells to hunt self-peptides from cellular debris). So this goes back to the "early immune response protects" example in pt 2 https://unglossed.substack.com/i/101728352/early-seroconversion-protects
I get the IGG4 elevation. Question I have is how strong is the igG4 and how much of the iGg1 does it suppress? Does it suppress enough to truly depress immune reactions?
There isn't much I can add to these questions from my original post on the subject. ie, that IgG4 is usually considered to be highly affinity-maturated (because the corresponding B-Cells have been through multiple rounds of stimulation and SHM), so it will be competitive if not superior for binding; and Irrgang et al. demonstrated suppressed phagocytosis in post-booster serum in vitro https://unglossed.substack.com/p/boosting-tolerance-igg4
I'm on board with everything you are saying. Makes sense.
About a week ago, a commenter (Massimaux) called attention to a study from the European Journal of Internal Medicine: "Serum IgG4 level predicts COVID-19 related mortality" (https://doi.org/10.1016/j.ejim.2021.09.012)
Have you seen this study?
From said study: "[A] concentration of serum IgG4 > 700 mg/dl and an IgG4/IgG1 ratio > 0.05 were associated with a significantly increased mortality at 30-days . . . . Of note, a significantly positive correlation was found between serum IgG4 and IL-6 level, an established predictor of COVID-19 related mortality . . . . In this prospective study we found that serum IgG4 level predicts a poor COVID-19 outcome. Based on the available literature, IgG4 antibodies may contribute to COVID-19 progression . . . ."
Their findings seem to support what you are saying. However, the head-scratcher here is that the patients in this study had Covid between June and December 2020, prior to the rollout of the mRNA vaccines. Thoughts?
As for Della-Torre, et al. - it wouldn't be surprising if high overall IgG4 predicts worse outcomes, as IgG4 might be like the "wrinkles" of the immune system - a general marker for age-related wear and tear. So it is important to emphasize that this study is just measuring overall IgG4, not IgG4 for spike. Just as with "IgG4-Related-Disease," my inclination is to regard IgG4 as a bystander to autoimmunity, not an instigator. In fact, Pillai offers the same take in his opinion piece last week.
Having said all that, the IgG4 distribution in Fig 1 is not impressive - subtract a handful of outliers from the severe outcomes group and IgG4 distribution is equal. So, it doesn't seem like most severe outcomes are being driven by (baseline overall) IgG4.
This doesn't mean that spike-specific IgG4 might some day cause much stronger disease enhancement. Just that generic IgG4 doesn't seem required for severe disease in natural infection.
I'm starting to really appreciate Brian Mowrey's contribution to this whole Covid-19 topic. His explanation as to the myth of the cytokine storm (as opposed to DAD) was welcomed. Now, I wish I have more of a serviceable grip on "all-things virology and vaccinology" but...
I have been re-reading this series of postings and have derived a lot of benefit from them.
However, I watched the Pillai video (because you insisted I do so) and one thing struck me.
He tells us that the wiruses go through a Darvinian process and damage to our innate immune system can prevent the ewolution of our development of the appropriate antibodies.
However, you have made a strong case, and I find it persuasive for a number of reasons, that the virus cannot mutate much and remain functional. Sure, it can change its Spike protein (possibly the S1 most) but it will not be able to do much to the N protein, and if you have ever been exposed to a Corona Wirus in the past then you likely have memory T cells that recognize it and can cleanup cells infected with SARS-CoV-2 as well.
So, is that a good explanation or is it simply that, as you seem to point out, it just shuts down the adaptive immune system for a period of time?
(/cease-indian-accent-now)
One thing I was confused about was the use of ADE in this post as it seemed atypical to its normal use.
I took ADE to refer to effector function as a method of mediating the enhancement, and strangely ADE appears to be found mostly with infection of effector cells. So would the case of IgG4 be appropriately termed as ADE or more like kooky "I don't see anything" immune tolerance.
Right, but ADE can't exclude novel ways that antibodies enhance disease, because, well, someone went and named it "antibodies enhancing disease." *edit: wait a minute the D is for dependent, anyway imagine I used that in the sentence and it still works. I added a footnote on Sunday acknowledging that this wouldn't be one of the traditional applications. But if IgG4 eventually results in severe disease / pneumonia there's no way to not call it ADE.
Great series of posts Brian! It's probably tough catching flak from both sides, but ultimately I think this process is producing the strongest arguments.
Regarding testing, especially in the US, almost all testing is nasal swabs which is of the mucus membranes. My understanding is IgM dominates the response there. It seems that response will be identical in both Vaccinated and Unvaccinated. If the immune tolerancing theory is correct and the Vaccinated start having persistent infections, would it continue to show up in the nasal swab tests or would anal swab tests or blood serum tests be more accurate?
Anecdotally, I have seen a case where a "vaccinated"19 year old healthy BMI female has had a persistent cough for 1.5 months. Tests "negative" for Covid with a nasal swab and has no other symptoms. I also see plenty of anecdotes about persistent viral infections "but it's not covid". Is it possible that we are already seeing persistent infections but our testing regime is failing us? Keeping in mind of course that there really are other viruses out there that we routinely do not test for.
Thank you!
In general, at least a trace amount of persistent infections seem to be reflected by PCR (for example .5% or 1 in 200 of all sequenced infections when using near-same-sequence on multiple days to define persistent infection vs reinfections in https://www.medrxiv.org/content/10.1101/2023.01.29.23285160v1 )
But there is a larger "iceberg" of persistent infections that are still almost hypothetical, because PCR / swab testing doesn't reveal anything. Plasma/stool/urine testing maybe reveals some of this iceberg (https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-022-07153-4 - but that is only four weeks after infection, when even nasal PCR will still often be positive for "residual" virus) but there still seems to be more that we can only see indirectly (i.e. spike S1 lingering in monocytes in Long Covid, and tissue histology and PCR in autopsies https://onlinelibrary.wiley.com/doi/10.1002/path.6035). We would have to be able to chop people up and test every tissue and put them back together again to get a full look.
So even without the question of antibody masking in the nasal cavity, I think it safe to presume that persistent infections won't show on nasal PCR , plasma/stool/urine might give a better look, might not (I'll see if there are any studies with longer time-points). If it's coughing all the time, I don't think antibody masking should mess up PCR, maybe antigen assay - my guess would be generic immune suppression from the shots leading to an opportunistic infection, i.e. some degree of "VAIDS" at work.
It's very weird to me that current events have made amateur immunologists out of every thinking person in the world. Very weird.
But what I took away from that, is that when the virus and the immune system reach their stalemate, this is worse than is obvious. Even if the virus is not rapidly infecting and destroying cells there is a baseline load of spike that is still proinflammatory and still doing random vascular damage possibly in the brain. Tolerating spike in the body is always a mistake unless the things I have read about spike on its own are in error.
So two questions:
1 Does free spike have the destructive potential to we have heard it does?
2 What is the 'half life' of spike without the rest of the virus? Or of free floating virus in the body, if it can't find a target for whatever reason?
I think free spike might not be as toxic / inflammatory once you already have circulating antibodies. Otherwise I don't know how to explain why boosters haven't made everyone drop dead. It's also always worth noting that most of what is bad about spike might be true for any foreign protein or molecule, we just haven't looked into it; the example I use here is always Pretorius et al.'s findings on LPS, which is a component of common household dust https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5046953/
2 I'm sure spike is always being broken down by random proteases which are everywhere in the body. That doesn't answer the question obviously. So, apart from situations when it's being actively produced so it's like spike is "playing on the molecular radio," I dunno how long it lasts.
With the acknowledgement that I know very little about virology or immunology, my thinking is this.
If we assume that spike is the BAMF killer that it is portrayed as(herein referenced as SAS'-Silent Assassin Spike'), it is still concentration dependant and the damage that it does is probabilistic not targeted. So, a very small amount of SAS may randomly damage something crucial and cause myocarditis or sudden death, presumably thru cerebral damage, but probably not. Whereas a continual supply of SAS being produced in your shoulder(HAHA or nuts more likely), can be expected to break something important if it goes on long enough. There are too many unknowns with the shots to say anything for sure about why the boosters act the way they do.
Right, and that kind of stochastic risk probably applies to this virus and a lot of other viruses. It's a constellation of lotteries.
Being an ignorant virus denier person I have 33% of my brain circuitry overwhelmed by this post, but I am doing a sincere effort to understand as much of this as possible.
In the spirit of the old "Remember, there are no stupid questions, only stupid people" I bring you two questions:
First. I don't know if I understand the metaphor at the end, the one about deputizing the raccoons. I understand it to mean a grim future where the body never stops attacking itself. That's his new programming: destroy yourself slowly, with the help of these well trained police raccoons. Did I understand that correctly, or is it the other way around, that is, deputizing the raccoons is a good situation?
Second question: I understood somehow that the cytokines act as a drug that sends the adaptive immune response to sleep, and the lack of adaptve immune response fosters more viral damage in more healthy cells. (I doubt I got that right.) But this happens only in that stage of "severe covid." But severe covid is rare. Most people never got there. What piece fails so that mild covid finally expands into in that severe covid which causes that adaptive response suppression? I'm guessing that there is a "race condition" here, as in electronics: if T cells mature before the lymph nodes freeze, there is no severe disease, and if they fail to mature in time, their maturation process will be shut down even harder.
So ::dons the conspiracy hat:: it seems there is a physical exploit built in into the pseudovaccines. They learned how the immune system fails sometimes, and designed a drug to make that effect more likely to happen in some people. Maybe it was a fluke that they are so bad?
I'm sorry to complicate this even more by summoning here the one of the most esoteric parts of electronics design. Immunology is already difficult as it is, no one needs more metaphors.
Thank you for the post!
1 The raccoons are the virus. IgG4 sticks to the spike protein and tells the immune system to ignore it; so whereas IgG1 or IgG3 would stick to the raccoon and say "kill this raccoon, police officer" IgG4 says "leave this alone." Same with spike sticking out of infected cells. Again it's a question of balance though, because the raccoon has a harder time getting into cells with the police hat stuck onto its face. So maybe the result (as long as you didn't get to tolerance via a huge out of control acute infection) is total homeostasis, no problem.
2 The "more viral damage" that results from suppressed adaptive response might be marginal. As Wherry says, the immune system is containing the virus, so maybe it's like a slow smoldering. But yes, I think "race condition" basically describes the problem. If you get adaptive response moving (making future memory B Cells and T Cells in germinal centers) in time then you avoid the huge amount of tissue destruction that results in suppressing adaptive response (which occurs because now having T Cell "scent-trained-dogs" around would make the raccoon-infested kitchen even more of a mess; and you might also accidentally train T Cells to hunt self-peptides from cellular debris). So this goes back to the "early immune response protects" example in pt 2 https://unglossed.substack.com/i/101728352/early-seroconversion-protects
Thank you very much, Brian.
I get the IGG4 elevation. Question I have is how strong is the igG4 and how much of the iGg1 does it suppress? Does it suppress enough to truly depress immune reactions?
There isn't much I can add to these questions from my original post on the subject. ie, that IgG4 is usually considered to be highly affinity-maturated (because the corresponding B-Cells have been through multiple rounds of stimulation and SHM), so it will be competitive if not superior for binding; and Irrgang et al. demonstrated suppressed phagocytosis in post-booster serum in vitro https://unglossed.substack.com/p/boosting-tolerance-igg4
Pardon the digression, Brian, but did you ever get around to having a Zoom chat with Nick? If so, can the public access it?
Yes, and it went well. But it was not broadcast nor, I believe, recorded (Nick was on phone app)
I'm on board with everything you are saying. Makes sense.
About a week ago, a commenter (Massimaux) called attention to a study from the European Journal of Internal Medicine: "Serum IgG4 level predicts COVID-19 related mortality" (https://doi.org/10.1016/j.ejim.2021.09.012)
Have you seen this study?
From said study: "[A] concentration of serum IgG4 > 700 mg/dl and an IgG4/IgG1 ratio > 0.05 were associated with a significantly increased mortality at 30-days . . . . Of note, a significantly positive correlation was found between serum IgG4 and IL-6 level, an established predictor of COVID-19 related mortality . . . . In this prospective study we found that serum IgG4 level predicts a poor COVID-19 outcome. Based on the available literature, IgG4 antibodies may contribute to COVID-19 progression . . . ."
Their findings seem to support what you are saying. However, the head-scratcher here is that the patients in this study had Covid between June and December 2020, prior to the rollout of the mRNA vaccines. Thoughts?
As for Della-Torre, et al. - it wouldn't be surprising if high overall IgG4 predicts worse outcomes, as IgG4 might be like the "wrinkles" of the immune system - a general marker for age-related wear and tear. So it is important to emphasize that this study is just measuring overall IgG4, not IgG4 for spike. Just as with "IgG4-Related-Disease," my inclination is to regard IgG4 as a bystander to autoimmunity, not an instigator. In fact, Pillai offers the same take in his opinion piece last week.
Having said all that, the IgG4 distribution in Fig 1 is not impressive - subtract a handful of outliers from the severe outcomes group and IgG4 distribution is equal. So, it doesn't seem like most severe outcomes are being driven by (baseline overall) IgG4.
This doesn't mean that spike-specific IgG4 might some day cause much stronger disease enhancement. Just that generic IgG4 doesn't seem required for severe disease in natural infection.
Ahhhhh...I missed the spike-specific part. Thanks. Appreciate you taking the time and effort to research and explain all of this.
I'm starting to really appreciate Brian Mowrey's contribution to this whole Covid-19 topic. His explanation as to the myth of the cytokine storm (as opposed to DAD) was welcomed. Now, I wish I have more of a serviceable grip on "all-things virology and vaccinology" but...
Thanks!