Thanks for sharing this Boccaccio. I'm no longer keeping up with the science.
Some thoughts on this paper:
1. The authors are from universities, research institutes, and hospitals in Florida, Saudi Arabia, Egypt, Canada, and Mexico. I'd be curious to learn how they found each other and decided to collaborate on this.
2. It's a hypothesis paper, presenting a possible mechanism that could explain published findings rather than presenting the findings themselves. It is in some ways a more academic and informed presentation of my tolerance hypothesis, but with added nuance and new pathways to harm.
3. Some key quotes (and thoughts):
"In this paper, we provide the scientific rationale showing that repeated vaccination with mRNA vaccines generates an immune tolerance mechanism, thereby favoring unopposed SARS-CoV-2 replication. The immediate consequence of this tolerance is the establishment of a permissive state of the host leading to chronic infection and other unintended consequences induced by mRNA vaccination."
"IgG4 antibodies do, however, function as tissue-damaging autoantibodies in some disor- ders, as seen in myasthenia gravis [47], idiopathic membranous glomerulonephritis [48], and pemphigus vulgaris (PV) [49]."
(The idea that "tolerance" IgG4 antibodies might directly contribute to pathogenicity and autoimmunity is new to me. I do personally know of two people who have been debilitated by myasthenia gravis since the vaccine rollout.)
"More IgG4 seems to be linked to more aggressive cancer growth, and both were strongly associated with higher cancer malignancy and poor prognosis. It was dis- covered that IgG4 can contend with IgG1 (as shown in Figure 3) in binding to Fc receptors present on some immune cells in vitro. This competition results in the inhibition of typical immune responses against cancer cells, such as cell and complement cytotoxicity, and cell phagocytosis, which are mediated by IgG1 antibodies."
(So now we have another possible explanation for turbo-cancer, and it appears that IgG4 effects are not necessarily specific to the target antigen.)
"However, they were unable to detect this rise after two doses of the AZD1222 vaccine in uninfected individuals up to day 270, showing that only mRNA vaccines induce produce detectable and prolonged IgG4 responses until day 270. Importantly, in patients who had a previous COVID-19 infection (before vaccination), IgG4 did not rise, even after mRNA injections, implying that those with higher IgG4 levels are uninfected people who were immunized with mRNA vaccines before having their COVID-19 infection [94]."
(Summarizing previous findings, IgG4 tolerance appears to be only induced by the mRNA injections, and only in the absence of prior infection.)
"T cells can undergo a process known as "terminal differentiation" when vaccines are given in high concentrations, T cells undergo this process and become highly special- ized, losing the capacity to divide and procreate. The immune system becomes ex- hausted as a result and is unable to mount a successful defense against subsequent ill- nesses. This is a problem since it might undermine the protective advantages of vaccina- tions. To balance the advantages of immunological protection and the potential disad- vantages of immune exhaustion, it is crucial to carefully determine the ideal dose of vac- cines."
(Separately from IgG4 antibody effects, T cell tolerance can also be induced by repeated exposure to high antigen concentrations. The authors go on to note that a more typical vaccination strategy would be a high antigen dose for initial vaccination followed by much lower doses for boosting, which would mimic the natural pattern of immunity being developed during acute illness and then strengthened during subsequent exposures in which the pathogen is destroyed before replicating to high levels.)
"It is important to note that the probability of contracting malaria increased by around three times when non-neutralizing IgG4 levels doubled. Up to the age of 24 months, IgG1 and IgG3 demonstrated 51% and 56% protective effects respectively, however, IgG4 was linked to a higher risk of malaria infection throughout this age range [105]. It's interesting to note that a separate study also found a link between high IgG4 levels and a higher risk of infection and malaria exacerbations [111]."
(The authors summarize findings from failed HIV and malaria vaccine trials [not using mRNA technology, but using repeated injection of high antigen doses] in which IgG4 antibodies were produced in some subjects and correlated with loss of efficacy or negative efficacy.)
4. I'm still surprised that none of the tolerance treatises cite this paper - https://www.science.org/doi/10.1126/science.aay3638 (summaraized here: https://www.nature.com/articles/s41587-021-00880-0) - which proved that mRNA vaccination technology can specifically induce tolerance when that is the goal. I'm also surprised they don't more broadly explore the unique mechanism of mRNA vaccination - i.e. otherwise-healthy cells induced to become antigen factories in the absence of any other markers of infection - and why that might logically be expected to induce tolerance responses.
5. The authors are positing both *specific* tolerance - increased susceptibility to SARS-CoV2 - and *broad* tolerance (increased susceptibility to other pathogens and cancer). They appear to be suggesting three mechanisms for the broad tolerance: A) direct (but transient) suppression of immune function following vaccination, B) suppression of immune function due to chronic/persistent SARS-CoV2 infection, and C) direct nonspecific effects of high IgG4 levels on regulatory T cells and tumor-fighting pathways. Mechanism C is new to me, but not entirely surprising.
6. The authors are also positing "tolerance-induced autoimmunity", which seems counterintuitive given that the states are effectively opposites. However, one component of my tolerance hypothesis was that disruption of the immune system's delicate "self/non-self" discrimination system would lead to errors in both directions - toward tolerance and autoimmunity - and indeed this seems to be documented in the case of IgG4 imbalances.
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branchandroot
Re: Tolerance
Date: 2023-03-30 06:42 pm (UTC)Some thoughts on this paper:
1. The authors are from universities, research institutes, and hospitals in Florida, Saudi Arabia, Egypt, Canada, and Mexico. I'd be curious to learn how they found each other and decided to collaborate on this.
2. It's a hypothesis paper, presenting a possible mechanism that could explain published findings rather than presenting the findings themselves. It is in some ways a more academic and informed presentation of my tolerance hypothesis, but with added nuance and new pathways to harm.
3. Some key quotes (and thoughts):
"In this paper, we provide the scientific rationale showing that repeated vaccination with mRNA vaccines generates an immune tolerance mechanism, thereby favoring unopposed SARS-CoV-2 replication. The immediate consequence of this tolerance is the establishment of a permissive state of the host leading to chronic infection and other unintended consequences induced by mRNA vaccination."
"IgG4 antibodies do, however, function as tissue-damaging autoantibodies in some disor-
ders, as seen in myasthenia gravis [47], idiopathic membranous glomerulonephritis [48],
and pemphigus vulgaris (PV) [49]."
(The idea that "tolerance" IgG4 antibodies might directly contribute to pathogenicity and autoimmunity is new to me. I do personally know of two people who have been debilitated by myasthenia gravis since the vaccine rollout.)
"More IgG4 seems to be linked to more aggressive cancer growth, and both
were strongly associated with higher cancer malignancy and poor prognosis. It was dis-
covered that IgG4 can contend with IgG1 (as shown in Figure 3) in binding to Fc receptors
present on some immune cells in vitro. This competition results in the inhibition of typical
immune responses against cancer cells, such as cell and complement cytotoxicity, and cell
phagocytosis, which are mediated by IgG1 antibodies."
(So now we have another possible explanation for turbo-cancer, and it appears that IgG4 effects are not necessarily specific to the target antigen.)
"However, they were unable to detect this rise after two
doses of the AZD1222 vaccine in uninfected individuals up to day 270, showing that only
mRNA vaccines induce produce detectable and prolonged IgG4 responses until day 270.
Importantly, in patients who had a previous COVID-19 infection (before vaccination),
IgG4 did not rise, even after mRNA injections, implying that those with higher IgG4 levels
are uninfected people who were immunized with mRNA vaccines before having their
COVID-19 infection [94]."
(Summarizing previous findings, IgG4 tolerance appears to be only induced by the mRNA injections, and only in the absence of prior infection.)
"T cells can undergo a process known as "terminal differentiation" when vaccines
are given in high concentrations, T cells undergo this process and become highly special-
ized, losing the capacity to divide and procreate. The immune system becomes ex-
hausted as a result and is unable to mount a successful defense against subsequent ill-
nesses. This is a problem since it might undermine the protective advantages of vaccina-
tions. To balance the advantages of immunological protection and the potential disad-
vantages of immune exhaustion, it is crucial to carefully determine the ideal dose of vac-
cines."
(Separately from IgG4 antibody effects, T cell tolerance can also be induced by repeated exposure to high antigen concentrations. The authors go on to note that a more typical vaccination strategy would be a high antigen dose for initial vaccination followed by much lower doses for boosting, which would mimic the natural pattern of immunity being developed during acute illness and then strengthened during subsequent exposures in which the pathogen is destroyed before replicating to high levels.)
"It is important to note that the probability of contracting malaria increased by around
three times when non-neutralizing IgG4 levels doubled. Up to the age of 24 months, IgG1
and IgG3 demonstrated 51% and 56% protective effects respectively, however, IgG4 was
linked to a higher risk of malaria infection throughout this age range [105]. It's interesting
to note that a separate study also found a link between high IgG4 levels and a higher risk
of infection and malaria exacerbations [111]."
(The authors summarize findings from failed HIV and malaria vaccine trials [not using mRNA technology, but using repeated injection of high antigen doses] in which IgG4 antibodies were produced in some subjects and correlated with loss of efficacy or negative efficacy.)
4. I'm still surprised that none of the tolerance treatises cite this paper - https://www.science.org/doi/10.1126/science.aay3638 (summaraized here: https://www.nature.com/articles/s41587-021-00880-0) - which proved that mRNA vaccination technology can specifically induce tolerance when that is the goal. I'm also surprised they don't more broadly explore the unique mechanism of mRNA vaccination - i.e. otherwise-healthy cells induced to become antigen factories in the absence of any other markers of infection - and why that might logically be expected to induce tolerance responses.
5. The authors are positing both *specific* tolerance - increased susceptibility to SARS-CoV2 - and *broad* tolerance (increased susceptibility to other pathogens and cancer). They appear to be suggesting three mechanisms for the broad tolerance: A) direct (but transient) suppression of immune function following vaccination, B) suppression of immune function due to chronic/persistent SARS-CoV2 infection, and C) direct nonspecific effects of high IgG4 levels on regulatory T cells and tumor-fighting pathways. Mechanism C is new to me, but not entirely surprising.
6. The authors are also positing "tolerance-induced autoimmunity", which seems counterintuitive given that the states are effectively opposites. However, one component of my tolerance hypothesis was that disruption of the immune system's delicate "self/non-self" discrimination system would lead to errors in both directions - toward tolerance and autoimmunity - and indeed this seems to be documented in the case of IgG4 imbalances.