Spike/LNP > NK cell/CTL activation > CCR2/5 engagement > CCL4 callouts > cardiac tissue damage > 'repair'/remodeling = fibrosis

Induction of a cascade of cytokine-mediated events following mRNA injection that leads to cardiac damage and fibrotic scarring -> cardiac amyloidosis?

A new paper just got published entitled: “Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis”. It was published in Science Immunology in May 2023 and it lends some insight into why we are seeing myocarditis post COVID-19 modified mRNA injection. I propose that what we are seeing is cardiac amyloidosis.

They provide evidence that modified mRNA injection-induced ‘myocarditis’ is not due to hypersensitivity or antibody-mediated processes (ie: not autoimmune-mediated), but rather due to a cytokine-mediated process that leads to cardiac tissue remodeling and fibrosis.

Update: Just to be clear, I believe that autoimmunity/molecular mimicry is driving much of what we are seeing in terms of immunologically-based damages with regard to the COVID modified mRNA injections. The size of the cohorts used to draw the conclusions in this study are very small, and there are quite a few self-admitted limitations. You should know that this study was funded by ghates, soros and NIAID/NIH. And yes, that really matters. That’s how this article ended up in ‘Science’ in the first place.

But I’m listening…

Before I dig into the dirt of this article, let’s define some cell types and immune mediators.

Interleukin-15 (IL-15) and Natural Killer cells (NK cells)

IL-15 is an inflammatory cytokine secreted by mononuclear phagocytes (one nucleus consumers) to induce proliferation (expansion) of NK cells.

NK cells are the front-line killer cells (cytotoxic lymphocytes) as part of the innate immune system. They kill damaged or infected cells using proteins called granzyme and perforin. It’s kind of like carpet bombing - the granzyme and perforin team poke holes in the membranes of the cells via perforin and granzyme gets in there and induces programmed cell death, aka: apoptosis.

These cells are amazing and act quickly in the absence of antibodies or specific-receptor-mediated activation - especially in the context of viral infections - to recognize and kill stressed cells. This allows for a much faster immune reaction than the adaptive system permits, and also gives the adaptive branch the leeway it needs to do its thing.

NK cells can also kill other cells by antibody-dependent cellular cytotoxicity, which is when they synergistically act with antibodies that tag infected cells, to kill stressed cells, for example.

Cytokines play critical roles in activating NK cells, and inducing them to proliferate. NK cells can also clear senescent cells. They are really important little guys.

Non-classical versus classical monocytes

Monocytes are white blood cells that can become macrophages or dendritic cells depending on the signaling milieu. They traffic around, sampling environmental merchandise until they get a signal to differentiate which again, will depend on the body’s need. There are different monocyte subpopulations, and they can exert specific functions. CD14^dim CD16⁺ non-classical monocytes, are commonly anti-inflammatory, while CD14⁺ CD16⁻ classical monocytes are inflammatory. High numbers of the CD14⁺⁺CD16⁺ intermediate monocytes have been shown to be predictive of cardiovascular events.¹

As mentioned, the cytokine and immune system/danger signal milieu will dictate the requirements for anti or pro-inflammatory phenotypes.

Macrophages (CCR2⁺)

Macrophages are big white cells that eat other cells as part of innate immune defenses. They are very important players in immune response mediation and scavenge all sorts of stuff, including the stuff that results from cellular damage or injury.

CCR2 is a chemokine that mediates monocyte movement. A CCR2⁺ macrophage is one that is expressing the CCR2 receptor. What’s really interesting about this CCR2 expression is that it is associated with cognitive decline.² “Higher CCR2 expression was associated with worse performance on the mini-mental state examination (MMSE) assessment of cognitive function.”³

The difference in observations between mice (CCR2 depletion causes cognitive decline) and humans (higher CCR2 associated with lower cognitive function) could be due to increased demand for macrophage activation during cognitive decline, associated with increased β-amyloid deposition (a core feature of Alzheimer's disease progression).⁴

This is very interesting, as there is an association between this phenotype and increased amyloid deposition. What if this is happening in the cardiac tissue? In addition, the authors note that a CCR2⁺ macrophage is associated with cardiac remodeling and fibrosis.⁵⁶

CD4+ and CD8+ T cells

These are white blood cells that play major roles in the functioning of the adaptive immune system. As part of their phenotypes, they can be helper T cells (CD4+) or cytotoxic T cells (CTL - CD8+), that are activated and proliferate in response to new and specific pathogens as part of a mighty anti-bad-guy force. CD4+ T cells coordinate other immune cells involved in adaptive responses and without them, this branch is pretty much dead in the water. They are vital players in proper immune system functioning. That’s why HIV is so detrimental - it preferentially infects CD4+ T cells using the CD4 and CCR5 receptors and decimates these populations.

CD8+ T cells can become CTLs and kill using granzyme and perforin (lytic granules) as well. NK cells and CD8+ T cells have a lot in common. In the gorgeous image below, the red color represents the lytic granules in 3 CTLs about to kill a cancer cell shown in the middle.

https://en.wikipedia.org/wiki/Cytotoxic_T_cell#/media/File:Killer_T_cells_surround_a_cancer_cell.png

CTLs also kill by receptor-mediated methods.

Matrix metalloproteinases (MMPs)

MMPs are also thought to play a major role in cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host defense.⁷ For the most part, their roles include degrading extracellular matrix proteins. This is important with regard to tissue remodeling.

The MMPs play an important role in tissue remodeling associated with various physiological or pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis, and metastasis.

An idea I have had with regard to cardiac amyloidosis

I have been harping, for quite some time now, about how COVID-19 injection-induced myocarditis - so prevalently reported since 2021 - is actually not myocarditis but instead, cardiac amyloidosis. You can read about that here and here. The findings in this paper give credence to this idea.

Myocarditis and cardiac amyloidosis are very similar pathologically, but there are ways to discern between them in order to make a correct diagnosis, without having to do a full-scale bench-work/in silico studies like these authors have done. For example, following a tissue biopsy, hematoxylin–eosin (H&E) stain can be used for visualizing eosinophylic amyloid in biopsied tissue. In addition, in the case of cardiac amyloidosis, electrocardiograms (ECG) and imaging may yield findings that resemble myocardial fibrosis (low voltage, hypertrophy and signs of fibrosis).

Various biomarkers can help to discern between the two as well, but perhaps the most useful diagnostic tool is a cardiac MRI. When this is done in the context of acute chest pain, it can more easily enable a correct diagnosis of cardiac amyloidosis. “Chest pain secondary to myocardial ischaemia is a presentation of cardiac amyloidosis and is attributed to the deposition of protein molecules in the coronary microvasculature which can spare the epicardial coronaries.”⁸ A biopsy staining for amyloid would be definitive.

The case study I wrote about in one of the referenced articles above involves a change from a diagnosis of myocarditis to cardiac amyloidosis in a 21-year old male. The authors write:

Diagnostic pathway of cardiac amyloidosis includes: echocardiography cardiovascular magnetic resonance (CMR) which also gives a prognostic value, 99m Technetium pyrophosphate (Tc99m-PYP) and 99m Technetium 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), laboratory work-up and biopsy.

The reason this new paper supports the cardiac amyloidosis diagnosis is due to the cardiac tissue damage that leads to scarring (remodeling/building of damaged tissue). This is likely due to NK cell cytotoxic engagement. It is also due to excessive - and likely continued - activation of CD4+ and CD8+ T cells (CTLs) expressing the CXCR3 and CCR5 co-receptors. The ligands of these receptors: chemokines CXCL10 and CCL4, were found to be significantly elevated according to serum analysis.

Wound healing is necessary when continued damage to tissue ensues, but in the context of the heart, this can be catastrophic. Scar tissue is not flexible like healthy cardiac tissue, and thus the heart cannot beat properly when too much scar tissue replaces healthy cardiac tissue.

CXCL10 and CCL4 recruit T cells to heart tissue and can lead to cardiac infiltration of pro-inflammatory cytotoxic T lymphocytes (CTLs).⁹¹⁰¹¹¹²¹³¹⁴¹⁵¹⁶¹⁷ CTLs secrete granzyme as part of their defense mechanisms, and this basically causes other cells to kill themselves. So as part of their mechanism of action, they kill damaged or infected cells thus also damaging tissue in cases where many cells are involved. These cells appear to be activated via a cytokine-dependent activation pathway, according to the authors’ findings.

So, recruit CTLs to the heart via chemokines and whammo, heart damage. No antibody-induced damage required. Interesting.

The necessary next step for the body is to heal the damaged tissue - ie: wound healing via structural immunity.¹⁸ This is where fibrosis can become a problem, however. Excessive deposition of fibrous tissue is the wrong place can be a very bad thing, such as is the case with cardiac fibrosis. What if this fibrotic tissue also has amyloids as a constituent in addition to collagen and fibers, for example? It is very interesting to me that they found ‘an abundance of CCR2⁺ macrophages’. As previously stated, this indicates fibrosis and furthermore, since higher CCR2 levels are associated with increased β-amyloid deposition. This also lends credence to the cardiac amyloidosis hypothesis.

Recently, another paper was published entitled: “SARS-CoV-2 uses CD4 to infect T helper lymphocytes”. The authors demonstrate infection of CD4+ T cells by SARS-CoV-2, whereby the CD4 receptor acts as a stabilizer of SARS-CoV-2 until it finds ACE-2 for subsequent binding and entry. I will review this paper in a subsequent article. Safe to say, this is a confirmation of the engagement of the CD4 receptor and the activation of the cells. The authors also find that there is no infection of CD8+ T cells, but they do not mention CD8 activation status. Clearly, CD8s are engaged and activated according to the findings in the cytokinopathy paper.

All in all, the authors found NK cell dysregulation and activation, elevations in circulating interleukins (IL-1β, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1), and expansion of what looked to be cytokine-driven activated CXCR3⁺ cytotoxic T cells and NK cells and signatures of inflammatory and profibrotic CCR2⁺ CD163⁺ monocytes (coupled with elevated serum-soluble CD163). As a point of interest, those matrix metalloproteases are really important players in wound healing.¹⁹ It has been shown that they can be post-transcriptionally controlled by cytokines, nitric oxide (think ACE-2 binding) and micro-RNA (miRNA).²⁰

Although I still think there is likely molecular mimicry and autoimmune antibody-mediated damage ensuing in some individuals (the numbers are small in this study), ultimately, this paper confirms a cytokine-mediated pathway to fibrosis. Therefore, in my opinion, because of the combined high levels of CCR2⁺ macrophages and elevations of MMPs, there is a good reason to think about examining the possibility that these are cases of cardiac amyloidosis.

I think it would be very interesting if the authors did some heart biopsies and stained for amyloid. If these diagnoses can be confirmed, then solutions can be implemented.

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