Immune System tolerance is inversely related to the number of COVID vaccinations (PubMed analysis) - Oct 2023

Trial SiteNews   Dr. Ronald N. Kostoff

OVERVIEW AND INTRODUCTION

Turbo-cancers, which are very aggressive cancers characterized by 1) rapid progression and 2) diagnosis at a late stage, have been increasing significantly in the last couple of years.  One of the major factors that may be contributing to this increase is the COVID-19 vaccine, especially those vaccines operating on the mRNA platform.  In particular, one of the major mechanisms associated with the modus operandi of these mRNA vaccines is the class-switch from IgG3 to IgG4, and the subsequent reversal in the phenomenon known as Immune Tolerance.

Immune Tolerance can be defined as

• 1) “the process by which immune cells are made unresponsive to self-antigens to prevent damage to healthy tissues. It prevents an immune response to antigens produced by the body itself or recognized from a prior encounter.”, or
• 2) “the state of an active, highly regulated unresponsiveness of the immune system to self-antigens or against a particular antigen that can induce an immune response in the body.”, or
• 3) “prevention of an immune response against a particular antigen. For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body's own cells, tissues, and organs. However, when tolerance is reduced substantially, disorders like autoimmune disease or food allergy may occur.”

Immune tolerance is analogous to a military operation defending one’s homeland against invasion from without and within, where it is desired to do maximum damage to the invaders and minimum damage to the homeland and its residents (also see the following references for more comprehensive analyses of Immune Tolerance (link#1; link#2; link#3; link#4; link#5; link#6). 

Immune Tolerance is important for analyzing biological mechanisms, and for examining the onset and progression of many diseases.  A more comprehensive view of Immune Tolerance would be useful for understanding its mechanisms and impacts.  This Op-ed provides an overview of Immune Tolerance, based on the contents of the premier biomedical literature (Medline).  The main output of this study is a hierarchical taxonomy of the Immune Tolerance biomedical literature, where the taxonomy is generated using a text-clustering approach.  This Op-ed will show how the immune system uses Immune Tolerance to destroy foreign invaders or endogenous dysfunctional processes like rapid cancer cell multiplication without destroying the host in the process, or, conversely, how the immune system allows mild foreign invaders, such as allergens, to co-exist within the host with minimal damage to the host.  It will also show how factors that adversely impact the immune system can distort the function of Immune Tolerance, and allow foreign invaders or endogenous dysfunctional processes to exert massive damage on the host.

METHODOLOGY

A query was developed to retrieve articles from Pubmed that focused on Immune Tolerance, and was entered into the Pubmed search engine on 25 September 2023.  It retrieved 23,049 articles (with Abstracts only) for the period 1 January 1993-31 December 2023.  The records retrieved were imported into the CLUTO text-clustering software, 64 leaf clusters were selected, and a hierarchical taxonomy was generated by the algorithm.  Each leaf cluster was analyzed by visual inspection, and aggregate categories consisting of related leaf clusters were constructed. 

The Immune Tolerance phenomena related to COVID-19 vaccine effects were identified from the records retrieved by the Pubmed query (as well as records related to the records retrieved by the query). and discussed.

The Pubmed query used is: "Immune Tolerance" [Majr] OR "immune tolerance" [tiab] OR “immune system tolerance" [tiab] OR “immunological tolerance" [tiab], where Majr is major MeSH theme and tiab is title and abstract.

RESULTS

The 64 leaf clusters, including the cluster number, the cluster theme, and the number of records in each cluster, are shown in Appendix 1, Table 1A-1.  These individual clusters are grouped by similar themes into larger aggregated clusters in Table 1A-1.  Sample titles of records from each of the 64 leaf clusters are shown in Appendix 2, Tables 2A-1 to 2A-64, where the clusters are arranged in order of cluster number.  The first row of each of the 64 leaf clusters consists of cluster number, theme, and number of records.  All other rows shown in each leaf cluster contain the sample title only.

DISCUSSION

This Discussion section addresses three topics:

• 1) structure and content of the hierarchical taxonomy shown in the Results section;
• 2) role of contributing factors (CFs) in immune system/immune tolerance dysfunction;
• 3) role of immune dysfunction/immune tolerance in COVID-19 pandemic.

Structure and Content of Immune Tolerance Hierarchical Taxonomy
This discussion will center around the contents of the hierarchical taxonomy of the Immune Tolerance biomedical literature shown in Table A1-1.  The structure of the table was determined by the computer algorithm, and the themes of each leaf (lowest-level) cluster and fourth-level cluster were generated by the author after visual inspection of the data. 

The first level of the taxonomy consisted of one cluster (not shown) containing the 23,049 records retrieved from Pubmed.  All eight of the fourth-level clusters shown in Table A1-1 are contained within the one first-level cluster.

The computer algorithm divided the first-level cluster into two second-level clusters (not shown).  The first of these second-level clusters contains about fifteen percent of the total records retrieved from Pubmed, and focuses on methods to increase host Immune Tolerance (e.g., for transplantation, allografts, allergies, autoimmune disease treatments, etc.).  The first four fourth-level clusters shown in Table A1-1 fall within this category.  The second of these second-level clusters contains about 85 percent of the total records retrieved from Pubmed, and focuses on methods to decrease Immune Tolerance (e.g., for cancer cell/tumor destruction, pathogenic micro-organism destruction/neutralization, etc.).  The last four fourth-level clusters shown in Table A1-1 fall within this category.

Each of the fourth-level clusters will now be described in the order they are presented in Table A1-1.  Cluster 101 contains about six percent of the total records, and concentrates on Immune Tolerance Enhancement for Improved Organ Transplantation.  Its three component leaf clusters center strongly around this theme.  Ordinarily, the host’s immune system will attack and destroy foreign substances, so methods must be developed to mute this strong immune response.  These immunosuppressive techniques are associated with side effects of their own. 

Cluster 104 contains about eight percent of the total records, and concentrates on Immune Tolerance Enhancement for Improved Tissue Allografts.  Its four component leaf clusters center strongly around this theme.  There is obviously much mechanistic overlap between Clusters 101 and 104, including the concern that the immunosuppressive techniques employed to increase Immune Tolerance for these foreign transplanted bodies have their own side-effects to consider.

Cluster 86 contains about two percent of the total records, and focuses strongly on Immune Tolerance Augmentation in the Treatment of Autoimmune Diabetes.  This small fourth-level cluster contains only two leaf clusters, both strongly related to each other and to the central theme of the fourth-level cluster.  Autoimmune diabetes is characterized by insufficient insulin production stemming from immune system attack and destruction of insulin-producing cells that make insulin.  Therapies for autoimmune diabetes described in Cluster 86 aim to attenuate these autoreactive T cells.

Cluster 91 contains about three percent of the total records, and focuses strongly on Immune Tolerance Augmentation Through Transplantation of Donor Stem Cells.  As in Cluster 86, this small fourth-level cluster contains only two leaf clusters, both strongly related to each other and to the central theme of the fourth-level cluster.  The main difference between the two leaf clusters is that the hematopoietic stem cells differentiate into blood cells and blood components, while the mesenchymal stem cells can differentiate into other type of cells such as neurons and cartilage.  Some of the main applications are immunosuppression for organ and tissue transplants, and countering autoimmune disease.

Cluster 103 contains about seven percent of the total records, and is the smallest fourth-level cluster in the Immune Yolerance reduction group.  It focuses on the Role of Regulatory T Cells in Immune Response.  It is a transition cluster, overlapping between the group of fourth level clusters aimed at increasing Immune Tolerance and the group of fourth-level clusters aimed at decreasing Immune Tolerance.  It focuses on regulatory T cell (Tregs) mechanisms, and can use the insights gained to modify the Tregs performance for applications of interest. 

Cluster 118 contains about eighteen percent of the total records, and focuses on the Role of Dendritic Cells in T Cell Response.  “Dendritic cells (DC) are antigen-presenting cells that can communicate with T cells both directly and indirectly, regulating our adaptive immune responses against environmental and self-antigens. Under some microenvironmental conditions DC develop into anti-inflammatory cells which can induce immunologic tolerance. A substantial body of literature has confirmed that in such settings regulatory DC (DCreg) induce T cell tolerance by suppression of effector T cells as well as by induction of regulatory T cells”. While the leaf clusters reflect both increasing and decreasing Immune Tolerance, there appears to be more weight on enhancing the T cell effector function to attack and destroy pathogenic micro-organisms and cancer cells/tumors.

Cluster 121 contains about nine percent of total records.  It has two main themes: 1) Immune Tolerance Induction to Induce FVIII Antigen-Specific Tolerance in Patients with Hemophilia A and Inhibitors (which is spread among four closely-related leaf clusters), and 2) Role of B Cells in Immunological Tolerance and Autoimmunity (which is contained in one large leaf cluster). 

“Hemophilia A (coagulation factor VIII deficiency) is a debilitating genetic disorder that is primarily treated with intravenous replacement therapy”.  “the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered factor VIII (FVIII), which occurs in approximately 30% of all patients with severe hemophilia A. This antibody response renders FVIII replacement therapy ineffective, thereby increasing the risk for uncontrollable bleeding and morbidity…..The only proven effective therapy to eradicate these inhibitors is immune-based. Using a protocol called “immune tolerance induction” (ITI), the repeated and frequent administration of FVIII under non-inflammatory conditions downregulates the established antibody response and induces immune tolerance.”.  The articles in the first four leaf clusters listed under Cluster 121 present myriad approaches and mechanisms to address theme 1) above. 

Cluster 123 is the last of the eight fourth-level clusters.  It is the largest by far, containing about 47 percent of total records.  There are 35 leaf clusters, and they contain myriad diverse themes.  The umbrella theme is Mechanisms of Immune Response Regulation.  It includes sub-themes of Immune Tolerance mechanisms related to transplantation of tissues and organs, pregnancy (especially loss and complications), allergies (especially food), cancer, autoimmune diseases, infections, immune privilege, and a minor emphasis on epigenetic/stress influences on Immune Tolerance.

Contributing Factors to Immune System Dysfunctionality
Many of the records in the above taxonomy reflect an immune system gone awry, and the dysfunctional Immune Tolerance response is one marker of a dysfunctional immune system.  Some/much of the immune system dysfunction can be attributed to genetic deficiencies and to CFs (mainly toxic exposures and toxic behaviors).  Very few of the above records address the adverse effects of the CFs on immune system dysfunctionality and, more specifically, on Immune Tolerance dysfunctionality.  In my view, to make real progress in eliminating Immune Tolerance dysfunctionality, the CFs mainly responsible for the dysfunctional immune system must be identified and eliminated.

In mid-2020, our research group published a monograph titled “COVID-19: Preventing Future Pandemics”. The analytical portion of this monograph was focused on identifying modifiable factors that contributed to a dysfunctional immune system, since we believed at the time (and still believe) that COVID-19 resulted in part (perhaps in large part) from a dysfunctional immune system that was not capable of blocking viral infection at the earliest stages.  A brief summary of the key findings of this 2020 study is reproduced in Appendix 3.  For a full list of the CFs to immune system dysfunctionality we identified, the reader is directed to the heavily-referenced 2020 monograph.

1. Role of Immune Dysfunction/Immune Tolerance in COVID-19 Pandemic

Both the SARS-CoV-2 virus and the vaccines (mainly mRNA) used for COVID-19 infection are toxic, and trigger immune system dysfunction, leading to many other diseases.  A good summary of these issues can be found in the paper Spikeopathy. 

SARS-CoV-2 spike protein
The issues pertaining to the spike protein in Spikeopathy are:

-SARS-CoV-2 spike protein is pathogenic, whether from the virus or created from genetic code in mRNA and adenovector DNA vaccines

-The spike protein exerts its pathophysiological effects (‘spikeopathy’) via several mechanisms that lead to inflammation, thrombogenesis, and endotheliitis-related tissue damage and prion-related dysregulation.

mRNA vaccines
The issues pertaining to the mRNA vaccines in Spikeopathy are:

-Production of foreign proteins such as spike protein on cell surfaces can induce autoimmune responses and tissue damage. This has profoundly negative implications for any future mRNA-based drug or vaccine.

-Interaction of the vaccine-encoded spike protein with ACE-2, P53 and BRCA1 suggests a wide range of possible biological interference with oncological potential.

-Repeated COVID-19 vaccine booster doses appear to induce tolerance and may contribute to recurrent COVID-19 infection and ‘long COVID’.

-Biodistribution rodent study data show lipid nanoparticles carry mRNA to all organs and cross blood-brain and blood-placenta barriers. Some of these tissues are likely to be impervious to viral infection; therefore, the biohazard is particularly from vaccination.

-Lipid-nanoparticles have inflammatory properties.

-The modification of mRNA with N1-methylpseudouridine for increased stability leads to the production of spike proteins for months. It is uncertain how many cells and from which organs mRNA spike proteins are produced, and therefore, the exact effective dose delivered per vaccine vial is unknown.

-The mRNA and adenovector DNA vaccines act as ‘synthetic viruses’.

-In the young and healthy, and even in many older individuals with vulnerable comorbidities, the encoding-based COVID-19 vaccines will likely transfect a far more diverse set of tissues than infection by the virus itself.

-Evidence suggests reverse transcription of mRNA into a DNA copy is possible. This further suggests the possibility of intergenerational transmission if germline cells incorporate the DNA copy into the host genome.

The remaining part of this discussion will address 1) the specific impacts of the SARS-CoV-2 virus on Immune Tolerance and 2) the specific impacts of the COVID-19 (mainly) mRNA vaccines on Immune Tolerance.

3A. Immune Tolerance related to COVID-19 infection/SARS-CoV-2 virus
This section starts with two overview papers that place the Immune Tolerance issue in perspective.  The first overview paper on SARS-CoV-2 and immune responses states the following objectives: “it is essential to actively identify the mechanisms by which SARS-CoV-2 evades the host immune system, study the long-lasting effects of COVID-19 and develop therapeutics targeting SARS-CoV-2 infections in humans and preclinical models. In this review, we describe the pathogenic mechanisms of SARS-CoV-2 infection as well as the innate and adaptive host immune responses to infection.”  Some of their findings relative to Immune Tolerance include: ”It was observed that the three mutations in the RBD region of the Beta strain K417N, E484K and N501Y substitutions, did not increase infectivity but may have led to immune invasion from neutralising antibodies…..Another study which examined interactions between the Delta strain RBD mutations with the ACE2 receptor and neutralizing antibodies showed reduced interactions between RBD and neutralizing antibodies leading to immune evasion…..The substantial number of mutations in the spike protein has also been associated with reduced vaccine-induced neutralizing antibody responses…..While interferon responses are pertinent to restricting viral activity, coronaviruses, including SARS-CoV-2, have been implicated in antagonizing the antiviral responses to evade clearance…..The non-structural proteins, accessory proteins and structural proteins of SARS-CoV-2 can suppress various components of the interferon response…..The ability of SARS-CoV-2 to suppress interferon responses allows for delayed clearance and uncontested replication”.

The second recent paper on SARS-CoV-2 and the host-immune response provides more detailed insight to the specific mechanisms underlying immune tolerance induced by the SARS-CoV-2 virus: “IFN antiviral pathway is one of the most important innate mechanisms against viral infections…..the suppressed IFN response is a major determinant of COVID-19 clinical severity…..In the case of the M protein, it antagonizes innate immunity by inhibiting the TRAF complex, which is involved in the promoter activation of NF-κB and subsequent IFN transcription…..Additionally, the M protein interacts with MAVS, impairing the IFN downstream response, and further, blocks phosphorylation of STAT1, an element responsible for inducing ISG…..the M protein triggers cell apoptosis with the N protein as a cofactor…..Switching to the N protein, it targets the initiation of RIG-1 pathway via blocking TRIM25, and additionally prevents phosphorylation of STAT1, STAT2, and IRF3, blocking the entry of all three into the nucleus and inhibiting the IFN and ISG responses…..The N protein is also shown to prevent the aggregation of MAVS, as well as promote the activation and assembly of the inflammasome…..Nsp1 blocks the phosphorylation of IRF3, IRF7, STAT1, and cJun. Nsp1 additionally directly inhibits the IFN and NF-κB promoters and interacts with host 40S ribosomal subunits via 18S rRNA to inhibit host protein translation…..Nsp3, like N protein, also block the phosphorylation of IRF3, preventing nuclear translocation, and antagonize type I IFN activity…..Transitioning to nsp5, it proteolytically cleaves RIG-I and induces the degradation of MAVS, thus preventing detection of viral dsRNA and inhibiting the IFN pathway…..In the case of nsp8 and nsp9, they bind to the SRP and disrupt protein trafficking, suppressing the type I IFN response…..As for nsp10, it impairs the activity of IRF3 and NF-κB binding sites…..Exploring nsp6 and nsp13, they bind to an intermediary between MAVS and IRF3 signaling; thus limiting IRF3 activation…..Nsp6 and nsp13 also inhibit phosphorylation of STAT1 and STAT2…..nsp13 limits nuclear translocation of NF-κB…..Nsp13, nsp14, nsp15, and ORF6 prevent nuclear translocation of IRF3…..nsp14, nsp15, and nsp16…..modify the viral RNA and prevent recognition by RIG-1 and MDA-5…..Nsp14 additionally targets the IFNAR receptor for lysosomal degradation…..nsp16 additionally binds to the spliceosome and interrupts mRNA splicing, further suppressing the IFN response…..ORF3a blocks the phosphorylation of STAT1, activates the NLRP3 inflammasome, prevents phagosome and lysosome fusion, and induces cell death via the extrinsic apoptosis pathway…..ORF3b antagonizes type I IFN activity…..ORF6…..blocks the translocation of IRF3 and the STAT1 complex into the nucleus and inhibits the MHC class I pathway…..ORF6 also binds to the interferon-inducible nuclear export complex of Nup98 and Rae1, preventing the nuclear release of mRNA…..ORF6, ORF3b and ORF8 inhibit the ISRE to type I IFN production…..ORF7a…..inhibits the translocation of STAT2 to the nucleus, reduces phagolysosome acidity, and binds to monocytes, decreasing their ability to present antigens…..ORF7b…..suppresses STAT1 and STAT2 phosphorylation…..ORF8…..directly interacts with MHC class I proteins on the ER membrane and facilitates their degradation via autophagosome degradation…..ORF8 is a secreted protein that mimics IL17A and interacts with IL17 receptors on monocytes. This interaction of monocytes upregulates gene expression in fibrosis signaling, coagulation dysregulation, and inflammation…..ORF9b…..interacts with Tom70, thereby interfering with MAVS and type I IFN expression…..ORF9c…..upregulates IL-6 signaling while impairing IFN signaling…..ORF10 induces mitophagy and thereby causes the degradation of MAVS”

As these two overview papers show, the ability of the SARS-CoV-2 virus to impair Type I and Type III Interferon response is an important contributor to its induced Immune Tolerance.  Further insights into the mechanisms behind the virus’ ability to impair the Interferon response can be found in the following references: (Link#1; Link#2; Link#3; Link#4; Link#5).

Another contributor to Immune Tolerance from SARS-CoV-2 infection is increased IgG4 antibodies.  The following reference makes this point explicitly, as follows: “Research has shown that severe SARS-CoV-2 infection promotes the synthesis of IgG4 antibodies…..IgG4 antibodies produced by B cells in response to infection by SARS-CoV-2 generate immunological tolerance, which prevents its elimination and leads to persistent and chronic infection. In summary, we believe that this constitutes another immune evasion mechanism that bears striking similarities to that developed by cancer cells to evade immune surveillance.” Increased IgG4 can have myriad adverse impacts, as the following articles on IgG4-related diseases show: Link#1; Link#2; Link#3; Link#4; Link#5; Link#6; Link#7; Link#8; Link#9

3B. Immune Tolerance related to COVID-19 mRNA vaccines
Some of the mechanisms through which the vaccines can induce Immune Tolerance will be listed below, and the relevant papers will be referenced.

3B1.  Class switching to increased IgG4
Deliberately increasing Immune Tolerance by increasing levels of IgG4 has been used in e.g. vaccinology for treatment of allergies, for minimizing rejection of transplants, for treating autoimmune diseases, etc.  However, increasing Immune Tolerance by increasing levels of IgG4 is the opposite of what is needed when the antigen is pathogenic, such as a pathogenic micro-organism (virus, bacteria, parasite) or a cancer cell/tumor.  Unfortunately, COVID-19 mRNA vaccination is associated with increased levels of IgG4, which results in reactivation of dormant viral infections and cancers under remission.  COVID-19 mRNA vaccination also results in increased susceptibility to new micro-organisms and associated diseases, increased susceptibility to highly aggressive cancers (aka turbo-cancers), and increased susceptibility to autoimmune diseases, among many other adverse effects.  The following references provide copious evidence of the adverse effects from increasing IgG4 levels by the mRNA vaccines: (Link#1; Link#2; Link#3). The copious references to IgG4 shown in the previous section also apply here.

3B2.  Incorporation of pseudouridine into mRNA
The impact of this mechanism on Immune Tolerance is summarized in the following: “therapeutic mRNA had at least two additional big challenges: 1) the in vitro transcribed (IVT) mRNA would be prone to nuclease degradation when injected into animals, and 2) the IVT mRNA would also lead to innate immunogenicity similar to what would happen when infected by a pathogen…..pseudouridine…..can enhance RNA stability and, in the meantime, decrease anti-RNA immune response”.  Also see here.

3B3.  Multiple mRNA injections
There appears to be increased Immune Tolerance with multiple injections of COVID-19 mRNA vaccines (Link#1;Link#2).

3B4.  Degradation and suppression of the immune system potentially leading to cancer
A recent Op-ed in Trial Site News examined many post-mRNA vaccination mechanisms that had the potential to induce and accelerate the turbo-cancers that are exploding globally. The mechanisms in that Op-ed not addressed above will be listed here.  The interested reader should examine the referenced Op-ed for the copious references that support each mechanism.

3B4a.  Suppression of Toll-Like Receptors
3B4b.  Impact on Tumor Suppressor Protein p53 and Genomic Transposable Element LINE-1
3B4c.  Spike Protein Interference with DNA Repair Mechanisms
3B4d.  Vaccines contaminated with Plasmid DNA containing SARS-CoV-2 spike protein
3B4e.  Simian virus 40 (SV40) in DNA discovered in Pfizer mRNA vaccine vials
3B4f.  Enhanced expression of PD-L1
3B4g.  Induction of pseudo-autoimmunity (more focused on autoimmunity rather than cancer)
3B5.  Other examples of immunosuppression and Immune Tolerance post-COVID-19 vaccination

Other papers that address different aspects of unwanted Immune Tolerance post-COVID-19 vaccines include:

3B5a.  “Immunogenicity mechanism of mRNA vaccines and their limitations in promoting adaptive protection against SARS-CoV-2…..Incorporation of naturally modified nucleosides, such as m5C, m6A, m5U, s2U or pseudouridine and 1-methylpseudouridine into mRNA prevents activation of the endosomal sensors Toll-like receptor 3 (TLR-3), TLR-7 and TLR-8…..RNA recognition by these endosomal sensors induces type I interferon (IFN) production and thus incorporating modified nucleosides could potentially reduce type I IFN signaling, hence decreasing the host innate immune response towards the RNA…..nAbs against the SARS-CoV-2 S glycoprotein have been shown to cross-react with structurally similar human proteins such as α-myosin and transglutaminases, possibly leading to an increase in autoimmune diseases…..the Omicron variant is more likely to evade neutralization by antibodies from individuals vaccinated with the Pfizer/BioNTech vaccine, compared to the wild-type and Delta variant”;

3B5b.  “Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs…..many alterations in the vaccine mRNA hide the mRNA from cellular defenses and promote a longer biological half-life and high production of spike protein….. vaccination induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health…..We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances potentially have a causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell's palsy, liver disease, impaired adaptive immunity, impaired DNA damage response and tumorigenesis…..the inadequacy of phase I, II, and III trials to evaluate mid-term and long-term side effects from mRNA genetic vaccines may have been misleading on their suppressive impact on the innate immunity of the vaccinees…..subversion of innate immunity, primarily via suppression of IFN-α and its associated signaling cascade. This suppression will have a wide range of consequences, not the least of which include the reactivation of latent viral infections and the reduced ability to effectively combat future infections…..dysregulation of the system for both preventing and detecting genetically driven malignant transformation within cells and the consequent potential for vaccination to promote those transformations…..mRNA vaccination potentially disrupts intracellular communication carried out by exosomes, and induces cells taking up spike glycoprotein mRNA to produce high levels of spike-glycoprotein-carrying exosomes, with potentially serious inflammatory consequences.”

3B5c.  “Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice…..Multiple vaccine boosters after the conventional vaccination course significantly decreased RBD-specific antibody titers and serum neutralizing efficacy against the Delta and Omicron variants, and profoundly impaired CD4+ and CD8+T cell activation and increased PD-1 and LAG-3 expressions in these T cells. Mechanistically, we confirmed that extended vaccination with RBD boosters overturned the protective immune memories by promoting adaptive immune tolerance. Our findings demonstrate potential risks with the continuous use of SARS-CoV-2 vaccine boosters, providing immediate implications for the global COVID-19 vaccination enhancement strategies…..extended vaccination not only fully impaired the amount and the neutralizing efficacy of serum RBD-specific antibodies, but also shortened the long-term humoral memory. This is associated with immune tolerance in germinal center response, along with decreased numbers of spleen germinal center B and Tfh cells. Moreover, we demonstrated that extended immunization reduced the functional responses of CD4+ and CD8+T cells, restrained the population of memory T cells, and up-regulated the expression of PD-1 and LAG-3 in Te sub-type cells. An increased percentile of Treg cells was also observed, accompanied by significant elevation of IL-10 production. Together, we provided crucial evidence that repetitive administration of RBD booster vaccines may negatively impact the immune response established by a conventional vaccination course and promote adaptive immune tolerance…..over-vaccination may generate an immunosuppression micro-environment that is also an important facilitator of immune tolerance. We demonstrated that both the percentage of CD25+Foxp3+CD4+ Treg cells and the levels of immunosuppression cytokines IL-10 were up-regulated after extended RBD vaccine booster vaccination. This may result in reduced activation and differentiation of B cells on antigen stimulation, as well as functional inhibition of antigen-presenting cells (APCs) and consequential decrease in CD8+T cell activation…..we observed both humoral and cellular immune tolerance with the doses of extended booster administrations, which made it safe to speculate that over-vaccination might severely impact the immune protective efficacy established by conventional SARS-CoV-2 immunization, and probably enhance disease severity for new COVID-19 patients or re-infectants.”

3B5d.  “Herpesviruses reactivation following COVID-19 vaccination: a systematic review and meta-analysis…..administration of COVID-19 vaccine, especially mRNA-based ones, could be associated with VZV reactivation…..Vaccine administration can provide some of these triggers, such as hyperthermia and tissue injury as other side effects and also immunodeficiency state…..it may theoretically result in the reactivation of herpes viruses. DNA repair and the immune system are known as the two essential systems for defending against threats; loss of function of DNA repair may lead to disability of production of B and T cells resulting in immunodeficiency…..A recent study…..involved the pathophysiological alterations after the COVID-19 vaccine in which CD8+ T cells reduction, increase in classic monocyte contents, increased NF-κB signaling, and reduced type I interferon responses were reported; they have admitted that in the first 28 days after a vaccine injection, the immune system is in the vulnerable state…..Type I IFN receptor signaling in CD8+ T cells has an essential role in regulating memory cell response to viral infection and blockage of reactivation…..These examples suffice to show that after COVID-19 vaccine administration, reactivation of the herpes virus family may occur.”

3B5e.  “Potential health risks of mRNA-based vaccine therapy: A hypothesis…..The modifications made to nms-mRNA vaccines confer intracellular mRNA stability…..and increase translation efficiency…..but could also be a significant determinant of autoinflammatory and autoimmune responses if, as hypothesized, they activate TEs and other nucleic acid sensors, lead to type-1 interferon and pro-inflammatory cytokine expression, and affect the cell’s innate ability to discriminate non-self vs self cytosolic motifs…..by disrupting host innate immune tolerance to cytosolic self-DNA….. The induction of a sustained anti-viral cellular status via up-regulation of relevant genes, including those that encode IFN-α and IFN-β, following nms-mRNA vaccination, would likely lead to the chronic upregulation of a pro-inflammatory gene network that could predispose to autoinflammatory and autoimmune conditions. In addition, the pro-inflammatory status and the activation of intracellular RNA and DNA sensors would unsilence endogenous retroelements. These molecular events would increase the risk of genomic, chromosomal, and cellular instability, and carcinogenesis…..phenotypic and transcriptional profiling of immune cells revealed striking up-regulation of type-I and type-II IFNs in COVID-19 patients, but not in vaccinated individuals…..anti-COVID-19 mRNA vaccines actively suppress type-I IFN signalling while eliciting a robust adaptive immune response…..SARS-CoV-2 mRNA vaccination impairs type-I IFN signalling, and can affect the regulatory control of protein synthesis and onco-surveillance, paving the way to an increased risk of neurodegeneration, immune thrombocytopenia, myocarditis, Bell's palsy, hepatic disease, suppression of adaptive immune responses, diminished DNA damage repair, and tumorigenesis…..the active suppression of Type-I IFN production that has been observed in vaccinated individuals…..reflects dysregulation of Type-I IFN-signalling triggered by the NLRP3, AIM2, or MxA inflammasome activation by host-derived molecules recruited upon detection of endogenous indicators of cellular danger or stress…..as the cytosolic accumulation of either synthetic mRNA, cleavage products of RNAs generated by the antiviral RNAse L pathway or retrotranscribed DNAs. Activation of the inflammasome occurs in response to self and foreign activators”

3B5f.  “Immune Response and Molecular Mechanisms of Cardiovascular Adverse Effects of Spike Proteins from SARS-CoV-2 and mRNA Vaccines…..Viral RNA is recognized by the human cells as foreign, and this triggers defence reactions that impair its translation into proteins, while directing its degradation…..Replacing uridines with pseudouridines or (even better) with methyl-pseudouridine, overcomes the recognition as a foreign mRNA by the Toll-Like Receptors (TLR) and the subsequent activation of IFN type I…..To stabilize the mRNA and thus improve its translation, anti-COVID-19 mRNA vaccines have this characteristic…..immune response to the virus and to the mRNA vaccines differ in that the former is characterized by strong induction of interferon and circulating effector B and T lymphocytes, whereas the latter is essentially restricted to circulating memory cells….. the mRNA vaccine “theory” neglects the possibility that any cell producing the Spike protein and displaying it on its membrane (associated or not with MHC-I) will be attacked and destroyed by CD8+T cells. The severity of the consequences for the host following the vaccination will depend on the type and number of cells affected and the tissue where the reaction occurs. For example, myocarditis is considered an adverse reaction to mRNA vaccination…..The facts that this event is more frequent after the second dose and it occurs a few days after the inoculation…..suggest an immune-mediated mechanism analogous to an auto-immune reaction…..An important concern is whether the mRNA vaccination for producing the Spike protein could determine a break in the tolerance and development of an autoimmune disease because of the molecular mimicry. The risk increases with frequent and close together administrations of the vaccine, that challenge the immunogenic versus tolerogenic state of the immune system. In this condition, proinflammatory cytokines may alter the control of immunoregulatory circuitry so that self-reactive T cells could become effective and trigger autoimmunity…..In addition, the “homologies” between the Spike protein and human proteins are much greater than for other viruses and bacteria, increasing the risk of developing autoimmune diseases.”

3B5g.  “Adverse effects of COVID-19 vaccines and measures to prevent them…..immune function among vaccinated individuals 8 months after the administration of two doses of COVID-19 vaccine was lower than that among unvaccinated individuals. These findings were more pronounced in older adults and individuals with pre-existing conditions. According to the European Medicines Agency’s recommendations, frequent COVID-19 booster shots could adversely affect the immune response and may not be feasible…..The decrease in immunity is caused by several factors. First, N1-methylpseudouridine is used as a substitute for uracil in the genetic code. The modified protein may induce the activation of regulatory T cells, resulting in decreased cellular immunity…..Newly generated antibodies of the spike protein damage the cells and tissues that are primed to produce spike proteins…..vascular endothelial cells are damaged by spike proteins in the bloodstream…..this may damage the immune system organs such as the adrenal gland……antibody-dependent enhancement may occur, wherein infection-enhancing antibodies attenuate the effect of neutralizing antibodies in preventing infection…..the residual immune memory of the Wuhan-type vaccine may prevent the vaccine from being sufficiently effective against variant strains…..Some studies suggest a link between COVID-19 vaccines and reactivation of the virus that causes shingles…..This condition is sometimes referred to as vaccine-acquired immunodeficiency syndrome…..Department of Cardiovascular Surgery, Okamura Memorial Hospital, Shizuoka, Japan…..has encountered cases of infections that are difficult to control. For example, there were several cases of suspected infections due to inflammation after open-heart surgery, which could not be controlled even after several weeks of use of multiple antibiotics. The patients showed signs of being immunocompromised…..Besides the risk of infections owing to lowered immune functions, there is a possible risk of unknown organ damage caused by the vaccine that has remained hidden without apparent clinical presentations, mainly in the circulatory system…..COVID-19 vaccination is a major risk factor for infections in critically ill patients”.

3B5h.  “Biological and Immune Responses to Current Anti-SARS-CoV-2 mRNA Vaccines beyond Anti-Spike Antibody Production…..mRNA-dependent anti-SARS-CoV-2 vaccination seems unable to induce levels of oral immunity adequate to protect vaccines from replicating and transmitting infecting viruses. The obvious consequence, as also supported by real-world evidences, is that also vaccinees can be infected by SARS-CoV-2. Furthermore, the very recent demonstrations that the levels of viral replication in the mucosa of vaccinated and unvaccinated subjects are similar…..support the idea that vaccine-induced immunity is not able to block virus transmission…..antibody waning, unsatisfactory mucosal immunity, and the “antigenic original sin” mechanisms should be adequately evaluated at the time of decision to proceed towards additional cycles of vaccination. In fact, challenging an emerging VoC (as in the case of the widespread Omicron variants) with repeated injections of vaccines designed for a virtually disappeared virus quasispecies may be not the best strategy, as also suggested by the strong decrease of vaccine effectiveness calculated after the fourth dose,,,,,the likelihood of side effect occurrence increases with the number of injections.”

CONCLUSIONS

A functional and healthy immune system uses Immune Tolerance to destroy foreign invaders or endogenous dysfunctional processes like rapid cancer cell multiplication without destroying the host in the process. This functional and healthy immune system also allows mild foreign invaders, such as allergens, to co-exist within the host with minimal damage.  Factors that adversely impact the health of the immune system can distort the function of Immune Tolerance, and allow foreign invaders or endogenous dysfunctional processes to exert massive damage on the host.

The hierarchical taxonomy of the Immune Tolerance biomedical literature (as reflected by Medline publications) has two main categories:

• 1) methods to increase host Immune Tolerance (e.g., for transplantation, allografts, allergies, autoimmune disease treatments, etc.), which constituted about fifteen percent of the retrieved records, and
• 2) methods to decrease Immune Tolerance (e.g., for cancer cell/tumor destruction, pathogenic micro-organism destruction/neutralization, etc.), which constituted about 85 percent of the retrieved records. 

The sub-categories under Category 1 are:

• 1a) Immune Tolerance Enhancement for Improved Organ Transplantation,
• 1b) Immune Tolerance Enhancement for Improved Tissue Allografts,
• 1c) Immune Tolerance Augmentation in the Treatment of Autoimmune Diabetes, and
• 1d) Immune Tolerance Augmentation Through Transplantation of Donor Stem Cells. 

The sub-categories under Category 2 are:

• 2a) Role of Regulatory T Cells in Immune Response,
• 2b) Role of Dendritic Cells in T Cell Response.
• 2c) Immune Tolerance Induction to Induce FVIII Antigen-Specific Tolerance in Patients with Hemophilia A and Inhibitors and Role of B Cells in Immunological Tolerance and Autoimmunity. and
• 2d) Mechanisms of Immune Response Regulation. 

Many of the records in the above taxonomy reflect an immune system gone awry, and the dysfunctional Immune Tolerance response is one marker of a dysfunctional immune system.  Some/much of the immune system dysfunction can be attributed to genetic deficiencies and to CFs (mainly toxic exposures and toxic behaviors).  Very few of the above records address the adverse effects of the CFs on immune system dysfunctionality and, more specifically, on Immune Tolerance dysfunctionality.  To make real progress in eliminating Immune Tolerance dysfunctionality, the CFs mainly responsible for the dysfunctional immune system must be identified and eliminated.  Some CFs identified in a previous study on immune system dysfunction are presented in summary form in the Appendices.

Some of the more egregious contributors to immune system dysfunction and, in some sense, promoters of unwanted Immune Tolerance to both micro-organisms and cancer cells are the present bioweapon injections masquerading as COVID-19 vaccines.  The immune system consequences of these injections are highlighted here because of the large number of people who received them.  Our studies have shown that the fundamental modus operandi of these injections is destruction of the immune system, where the level of immune system destruction increases with each injection. This immune system destruction can potentially lead to

• i) increased numbers of, and more aggressive, cancers,
• ii) reactivation of dormant viruses, and
• iii) increases in autoimmune diseases. 

The Immune Tolerance that accompanies this immune system destruction plays a strong role in each of the three adverse effects mentioned above.

Specific mechanisms of both the SARS-CoV-2 virus and the COVID-19 (mainly) mRNA vaccines that could induce unwanted Immune Tolerance were presented in the text, but only those arising from the COVID-19 vaccines will be presented here.  They include:

• Class switching to increased IgG4;
• Incorporation of pseudouridine into mRNA;
• Multiple mRNA injections;
• Degradation and suppression of the immune system potentially leading to cancer (Suppression of Toll-Like Receptors,
• Impact on Tumor Suppressor Protein p53 and Genomic Transposable Element LINE-1,
• Spike Protein Interference with DNA Repair Mechanisms,
• Vaccines contaminated with Plasmid DNA containing SARS-CoV-2 spike protein,
• Simian virus 40 (SV40) in DNA discovered in Pfizer mRNA vaccine vials,
• Enhanced expression of PD-L1,
• Induction of pseudo-autoimmunity (more focused on autoimmunity rather than cancer)). 

Additionally, excerpts from critical papers show some of the synergies among these mechanisms acting in concert.

While many adverse effects (including substantial numbers of deaths) have resulted from administration of these injections so far, we may only be seeing the tip of the iceberg.  Some of the serious diseases resulting from dysfunctional Immune Tolerance shown in this Op-ed, such as cancer and autoimmune diseases, could take years or decades to emerge.  The fact that many cancers and autoimmune diseases have emerged over this relatively short period since the injections were administered is an ominous sign.  Autopsies of post-vaccination deaths have shown that the spike protein, and the lymphocytes that attack cells expressing the spike protein on their surface, have penetrated and damaged tissues and organs in almost all recipients of the injections, and this damage cannot but lead to reduced lifespans. 

References/ Appendex

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Vitamin D Life - 47 studies in both categories Immunity and Virus

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Searched Pubmed for ("Immune Tolerance" OR "immune system tolerance") (Vaccine OR Vaccination) COVID

41 items as of Oct 2023, which include

• IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein - May 2023 10.3390/vaccines11050991 FREE PDF
• Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination - Mar 2022 doi: 10.1016/j.cell.2022.01.018 FREE PDF
• Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19.- July 2020 doi: 10.1111/all.14364 FREE PDF