A New Paradigm for Severe COVID

Arginine depletion and T cell suppression in severe COVID may be the rapid onset of a somewhat cancer-reminiscent state where vitamins A and D and other myeloid differentiation factors run out.

This is not medical advice. Please see the full disclaimer at the bottom.

I am working intensively on finishing my vitamin C report for you (see the preliminary report here) but in the process may have stumbled into a major paradigm shift in how to view what is happening in severe COVID.

It has been known since early February, 2020 that severe COVID is characterized by depletion of lymphocytes, mainly CD4 (helper) and CD8 (killer) T cells and since late March, 2020 that low lymphocyte levels are a strong predictor of the risk of death.

I covered this on April 6, 2020 (in two articles, one on elderberry and the other on using lymphocytes as a risk marker), but at the time I was not familiar with the research on myeloid-derived suppressor cells (MDSCs), so it had not occurred to me that there was an extremely simple explanation for the low lymphocytes based on decades of research on these cells.

As it turns out, “massive expansion” of MDSCs had been identified as a hallmark of severe COVID as early as June, 2020. These cells specialize in suppressing helper and killer T cells, and thus clearly lie at the root of what is driving one of the main risk factors for death.

Unfortunately, I only first encountered this research when the arginine trial came out, in late 2021. Moreover, I only started looking into it in depth this week when I realized that if vitamin C and glutathione are concerns for nitric oxide toxicity, I need to better understand when and where nitric oxide levels are likely to be high or low over the course of a COVID infection or after COVID vaccines.

Now that I am somewhat immersed in the research on MDSCs, I believe that better understanding why they arise and why they hang out too long leads to a paradigm-shifting breakthrough in our understanding of severe COVID, with a central role for depletion of myeloid differentiation factors such as vitamins A and D.

What Is an MDSC?

Let’s take a brief step back to look at the big picture of how these cells fit into our immune repertoire.

All background information throughout this entire article that is not directly cited with a specific link is built on several reviews linked in footnote 1.¹

The Blood Cells

Blood cells are all derived from hematopoietic stem cells, which during fetal development colonize the thymus, spleen, and bone marrow. Blood cells are broadly classified into three groups: erythroid, lymphoid, and myeloid cells.

• Erythroid cells are red blood cells, which carry oxygen. Closely related to this lineage but not quite fitting into any of the three categories are platelets, involved in clotting, and mast cells, involved in the release of histamine and other inflammatory compounds.

• Lymphoid cells include B cells and T cells.

• Myeloid cells include monocytes, macrophages, dendritic cells, neutrophils, basophils, and eosinophils.

Lymphoid and myeloid cells together make up the leukocytes, or white blood cells.

The lymphoid cells, or lymphocytes, contain the major portions of the adaptive immune system. This is part of the immune system that uses a precision approach to target identifiable features known as antigens of whatever they are tasked to dispose of. This system is adaptive because it spends a little time learning how to respond to new targets as they arise. B cells make antigen-specific antibodies. Killer T (CD8) cells kill cells that express specific antigens. Helper T (CD4) cells help antigen-specific B cells and killer T cells proliferate. Helper Ts also have an inverse, suppressor Ts, that do the exact opposite.

Natural killer cells are a type of T cell, and thus a lymphocyte, but part of the innate immune system. This system is “innate” because the capacity is always with us, without any learning required. Natural killers kill cells that demonstrate signs of stress rather than those that express specific antigens.

Mast cells, sharing their lineage with the red blood cells and platelets, are also part of the innate immune system.

Beyond natural killer cells and mast cells, however, the innate immune system mostly lines up with the myeloid cells.

The myeloid cells can be subdivided into the granulocytes (neutrophils, basophils, and eosinophils) and to the separate lineage giving rise to the monocytes, macrophages, and dendritic cells. Granulocytes are so named because they store granules containing many different proteins (histamine, and various toxins, cytokines, and growth factors) that can be released in response to stimuli. They are also known as polymorphonuclear (PMN) cells because their nuclei have two or three distinct lobes. Briefly, these are the main functions of myeloid cells:

• Monocytes usually circulate through the blood, while macrophages take up residence in tissues. Monocytes can often develop into macrophages. Both are involved in surveillance and removal of things that don’t belong.

• Dendritic cells capture, digest, and present antigens to the adaptive immune system.

• Neutrophils are first responders to infections or traumatic damage, and specialize in gobbling up and destroying pathogens or debris in an emergency.

• Basophils and eosinophils are associated with more intense inflammatory reactions and, like mast cells, are elevated the most in allergies.

The MDSCs

Myeloid-derived suppressor cells (MDSCs) are immature versions of either monocytes or neutrophils. They have only partly differentiated from precursor stem cells. When these cells multiply without differentiating all the way to monocytes or neutrophils, they can be activated by certain stimuli. Once activated, their main characteristic is T cell suppression. That is, they stop CD4 (helper) and CD8 (killer) T cells from multiplying and render them dysfunctional. By suppressing helper T cells, they also indirectly suppress antibody-producing B cells.

MDSCs are divided into two classes depending on the lineage from which they are derived. Those otherwise destined to be monocytes are called monocytic MDSCs (M-MDSCs). Those otherwise destined to become neutrophils are called granulocytic or polymorphonuclear MDSCs (G-MDSCs or PMN-MDSCs), which are interchangeable terms.

Compared to M-MDSCs, PMN-MDSCs are more likely to suppress T cells that respond to specific antigens rather than all T cells that happen to be nearby.

MDSCs are absent or nearly absent under most normal, healthful, physiological conditions.

However, they rise in pregnancy and prevent the mother’s immune system from attacking her baby. Lactoferrin in mother’s milk stimulates their development in the newborn gut, which stops the infant’s immune system from creating an inflammatory reaction to the newly seeding gut microbiome.

MDSCs are found in autoimmune disorders, where they appear to restrain the degree of autoimmunity and serve a protective function.

Similarly, in sepsis or traumatic injury, where unrestrained immune activity can itself make the clinical outcome worse, MDSCs play a protective role in restraining the full onslaught of inflammation.

In cancer, the tumor recruits myeloid cells to its local environment to become an army of highly antigen-specific MDSCs whose primary purpose is to serve the tumor, their master. They suppress any T cells that would attack the tumor, and they even help restructure the local environment to hijack the circulation and route the bloodstream and all its nutrients directly into the tumor’s coffers. From the perspective of the tumor, MDSCs are beneficial. From the perspective of the human the tumor is invading, however, MDSCs are harmful.

In an acute infection, MDSCs naturally rise in the first day, first few days, or first week, and then start falling. If they stay high, they can worsen the clinical outcome, leading to death or to chronic infection by preventing the immune system from clearing the pathogen.

This principle was well demonstrated in a very small study of acute liver failure associated with hepatitis B infection. As a proportion of non-granulocytic white blood cells, M-MDSCs were 4-10% for all patients at the start of treatment. Within a week, they had declined to 3-7%. In those who recovered, they continued to decline further and further each week over four weeks of observation. In those who deteriorated, they went back up to their highest levels and remained high through week four. The mean percentage of MDSCs in the fourth week was 32% higher in those who died than in those who survived.

While we cannot prove cause and effect in an observational study, these results are consistent with the idea that MDSCs staying high rather than falling early in the infection prevented the immune system from doing its job in clearing the infection, leading to deterioration and, in the worse case, death.

Chronic, low-grade inflammation — caused by such things as obesity and poor gut health — generates chronic, low-grade elevation of MDSCs. This increases immunosuppressive tone, and probably plays a role in why obesity and poor gut health predispose to worse outcomes in infectious diseases, such as COVID.

Vaccinations, like infections, cause a transient rise and fall in MDSCs. In humans, they have been shown to be elevated two days after vaccination. In monkeys, they are markedly increased on day 1 of vaccination. The authors in that study claimed they returned to baseline by day 7 but did not show the data. Presumably, MDSCs have fallen by the time a robust antibody response emerges.

My Personal Suspicion on the Rise and Fall in Acute Infection

I have some suspicions, reading between the lines a little, on why the MDSCs rise and fall in acute infection. Here is my model:

The natural rise in MDSCs in the early part of an acute infection plays an important role in restraining the adaptive immune system until it can spend some time learning to make its antigen-responsiveness more specific.

It does this by suppressing antigen-specific CD8 (killer) T cells and CD4 (helper) T cells. Indirectly, the suppression of helper Ts also suppresses the antibody-producing B cells.

This, perhaps, prevents excessive tissue damage or even auto-immunity by preventing careless assaults of killer T cells and B cell-created antibodies on antigens that have too much cross-reactivity with natural proteins in our own tissues.

Once the adaptive immune system has had some time to perfect its attack plan, MDSCs fall and the T and B cells go in for the kill. The early rise and fall of MDSCs thus turns what would have been a carpet bombing approach into a special ops deployment.

If MDSCs fail to fall, the adaptive attack falters, and chronic infections or deterioration and death become far more likely.

Given that MDSCs restrain autoimmunity, however, this would seem to suggest that severe infections with high MDSCs should have lower risk of autoimmunity. This is contradicted by the broad-based autoimmunity that rises in severe COVID.

However, I think this might be reconciled as follows: if the precision special ops deployment falters, the body has no choice but to fall back on carpet bombing. This creates a storm of tissue damage. Tissue damage provides “damage associated molecular patterns” (DAMPs). DAMPs train the adaptive immune system to attack whatever is found nearby, on the assumption that things nearby must be the cause of the tissue damage. Falling back on the carpet bombing approach creates a huge array of DAMPs that confuse the adaptive immune system to target far too many things. This, then, results in autoimmunity.

I would go another step and say that immune-driven tissue damage might not even be necessary. As I will cover below, since the spike protein alone can recreate the full spectrum of tissue damage that occurs in COVID pneumonia, extended suppression of the adaptive response may simply allow more replication of spike protein and more spike-induced tissue damage, with the same result: damaged tissues release a broad array of DAMPs that confuse the adaptive immune system to start responding to everything.

Thus, it isn’t so much that more MDSCs makes for less autoimmunity. It’s that the natural, orderly, rhythmic rise and fall of MDSCs makes for less severe disease and less chance of autoimmunity, whereas the deviation from that natural rhythm leads to more severe disease and more autoimmunity.

What Causes MDSCs to Develop and Activate?

If we look through the various conditions associated with MDSCs, most of them are easily explainable by an adaptive purpose. For example, the restraining of autoimmunity or inflammatory damage, the mother’s tolerance of her fetus, and the newborn’s tolerance of the newly seeding gut microbiota. Even cancer, where MDSCs are pathological, are easily explainable by their benefits to the tumor.

In chronic, low-grade inflammation, MDSCs are undesirable yet this is unsurprising because the chronic low-grade inflammation itself is undesirable.

The real puzzle to solve is why some people with acute infections do not experience the natural fall of MDSCs early in the infection. Since, among a population infected with the same pathogen, this phenomenon separates those who have a good outcome from those who have a poor outcome, this seems to have something to do with the person who is infected, rather than any kind of immunosuppressive advantage of the infection itself.

With our aim to solve this puzzle, let us now cover what is known about why MDSCs arise and what keeps them from falling.

The rise and activation of MDSCs in any context requires three things to happen:

• They begin differentiating from their stem cell precursors, and multiplying.

• Something stops them from fully differentiating into monocytes or neutrophils.

• Something activates their T cell-suppressive properties.

“Emergency myelopoiesis” broadly expands myeloid cells from their precursors and is a normal reaction to infection or injury. This takes care of step 1.

There are many biochemical signals that stop MDSCs from differentiating further, but chief among them are IL-6 and STAT3.

Both of these are increased in obesity. IL-6 activates STAT3, and STAT3 has long been known to play a central role in leptin resistance, which is arguably the the central hormonal dysfunction of obesity.

A wide variety of inflammatory cytokines, most of which converge on signaling through nuclear factor kappa-B (NFκB), activate MDSCs to become immunosuppressive.

While avoiding obesity, poor gut function, and any other causes of chronic low-grade inflammation will likely restrain the rise in inflammatory cytokines that multiply and activate MDSCs, directly blocking these inflammatory signals with drugs or herbs is not the best approach to lower MDSCs for two reasons:

• First, we want these cells to follow their natural rise-and-fall rhythm. We don’t want to knock them out completely.

• Second, these cytokines have many functions beyond raising or activating MDSCs. We do not want to slow down the entire immune system. We just want to lift the adaptive immune system from under the thumb of the MDSCs at the right time.

This brings us to the chief promoter of the further differentiation of MDSCs to mature immune cells: all-trans retinoic acid, the activated form of vitamin A.

All-trans retinoic acid has shown promising results in human trials of cancers of the lungs, kidney and skin, where it has been used to reduce MDSCs and improve clinical outcomes. In mice, it has shown some promise in models of infectious diseases, including hepatitis B, and pneumocystitis pneumonia.

The fact that all-trans retinoic acid stimulates differentiation of MDSCs to more mature cells is so well established that it is found ubiquitously in any review on the topic. Only rarely, by contrast, has it been suggested that vitamin D, also known to stimulate myeloid differentiation, might also play a role.

As we will see below, the emphasis should be on synergy and balance between vitamins A and D.

This leads me to a central part of the model I will propose below: MDSCs fail to fall in dysfunctional responses to infection because myeloid differentiation factors such as vitamins A and D run into short supply.

How Do MDSCs Suppress T Cells?

MDSCs suppress T cells through several means:

• They make the enzyme arginase, which breaks down the amino acid arginine into ornithine and urea. They also make the enzyme inducible nitric oxide synthase (iNOS), which breaks down arginine into citrulline and nitric oxide. This leads to arginine depletion. T cells need arginine to replicate, so arginine depletion prevents them from replicating.

• They make the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades the amino acid tryptophan to N-formyl-kynurenine. This leads to tryptophan depletion. Like arginine, T cells need tryptophan to replicate, so tryptophan depletion prevents them from replicating.

• T cells need cysteine to make glutathione to protect themselves from oxidative stress. However, they lack enzymes needed to digest the forms of cysteine that circulate in the blood (as glutathione and as cystine, which is two cysteine molecules bound together) and rely on nearby cells to do that for them. MDSCs digest circulating forms of cysteine and import them without exporting any free cysteine to nearby T cells. This leads to cysteine sequestration, which hurts the ability of T cells to protect themselves.

• They produce superoxide and nitric oxide, which combine to form peroxynitrite, which directly damages T cell receptors.

• They produce methylglyoxal, which forms advanced glycation endproducts (AGEs) with arginine, exacerbating arginine depletion, and damaging the role of arginine in any proteins that contain it. They direct this methylglyoxal straight at nearby T cells.

Together, these suggest that repletion of arginine, tryptophan, and cysteine, along with nutrients to defend against oxidative stress and glycation, would be the best ways to reverse the T cell suppression under conditions of high MDSCs.

This, in fact, is the first time I have come across a possibly strong rationale for supplementing with N-acetyl-cysteine (NAC) instead of glutathione: if NAC can get into T cells, it has a much better chance of reversing the cysteine sequestration, since T cells cannot break down glutathione or cystine.

However, these interventions do not get to the root of the problem, which is why the MDSCs remain elevated in the first place.

Let us now turn to the research on MDSCs in COVID and come back to how we solve the root of the problem.

MDSCs in COVID

There are numerous papers showing a role for MDSCs in COVID. Here are the key findings:

• Among 18 hospitalized COVID patients, PMN-MDSCs were 5-fold higher in severe patients than in mild patients.

• In 24 severe, 5 asymptomatic, and 26 recovered patients compared to 15 healthy controls, severe patients had 10-fold higher PMN-MDSCs, 3.4-fold higher M-MDSCs, and 60% less arginine in their blood than the controls. Recovered patients seemed to have 27% less arginine, and asymptomatics 45% less, but they showed no signs of increased MDSCs and the arginine differences were not statistically significant. The lungs of ten patients who died of COVID showed infiltration of PMN-MDSCs and “virtually no T cells.”

• Among 147 COVID patients, PMN-MDSCs were 61% higher in moderate patients than mild patients, 3.8-fold higher in severe patients, and 9.6-fold higher in those who died.

• In the same study, a smoothed model of M-MDSCs in the blood suggested that mild patients started with low levels that were in decline from the first day of symptoms; moderate patients peaked on day 16 at levels that were similar to the day 1 levels in mild patients; severe patients had these cells keep increasing until day 28, at which point they were 3.2 times higher than any amount reached in the mild patients; those who died had the highest levels and they peaked a little earlier than the severe patients due to many of them dying and being taken out of the time course. Thus, severe COVID is associated with MDSCs that peak late and reach high levels, while mild COVID is associated with MDSCs that start low and decline early.

• In 32 adults hospitalized with COVID compared to 28 healthy controls, mean arginine levels were 37% lower in COVID patients, and mean tryptophan levels were 47% lower. This is very consistent with MDSCs suppressing T cells by depleting arginine and tryptophan.

Nitric Oxide in COVID

One open question is whether the arginine depletion that occurs in COVID leads to lower nitric oxide levels. This would be expected if nitric oxide synthase enzymes stay the same, since they use arginine to make nitric oxide.

However, many immune cells, especially M-MDSCs, have high expression of iNOS, which would increase nitric oxide production, at the expense of further depleting the store of arginine.

When the arginine trial showed a 7-fold increase in the number of severe COVID patients who had respiratory improvement in ten days but found no effect on blood lymphocyte levels, I speculated that the arginine must have been enhancing nitric oxide formation. This would dilate the blood vessels and airways.

Nitric oxide cannot be measured on its own because it has a half life of five seconds. It degrades mainly into nitrate, which can be converted to nitrite by bacteria. Thus, the sum of nitrites and nitrates represents a signature of nitric oxide exposure. Blood levels of this sum are not different between COVID patients of any severity and controls.

However, it is notable that PMN-MDSCs make superoxide as their main free radical, while M-MDSCs mainly make nitric oxide as their main free radical. While both PMN- and M-MDSCs are found in the blood, it appears that PMN-MDSCs are found in the lungs while M-MDSCs are not. This is based on findings in the lungs of ten people who died of COVID and lower respiratory samples of twenty intubated patients.

Thus, it is entirely possible that M-MDSCs are compensating for the arginine shortage by making extra nitric oxide in the blood, while PMN-MDSCs are not doing that in the lungs. Worse, superoxide made by PMN-MDSCs in the lungs would scavenge nitric oxide, turn it into peroxynitrite, and thereby damage the lungs while depleting nitric oxide available for opening the airways.

Thus, it is entirely possible that the arginine trial improved otherwise low levels of nitric oxide in the lungs.

Similarly, we must keep in mind that the lack of an effect on lymphocytes was also found in the blood. In ten patients who died of COVID, their lungs were characterized by an abundance of PMN-MDSCs and “virtually no T cells.” So it is entirely possible that the arginine trial improved T cell levels in the lungs.

Thus, it is an entirely open question whether nitric oxide levels are depleted in the lungs of COVID patients, and whether arginine supplementation works by improving nitric oxide levels, improving T cell proliferation and activity, or both.

Is the Immune System Really Overactive in Severe COVID?

For most of 2020 and 2021, I assumed that the “cytokine storm” represented an overactivity of certain parts of the immune system that was better characterized by “dysregulation” than “overactivity,” but that still represented the immune reaction doing most of the damage.

I began to question this when when it was demonstrated that, in mice, direct injection of the spike protein’s S1 subunit into the trachea, blown with air into the lungs, causes COVID-like illness, COVID-like lung damage, and a COVID-like cytokine storm across the span of three days.

I began to seriously question it when I discovered that almost the same thing is true for Streptococcus pneumoniae, the main cause of community-acquired pneumonia. It makes a toxin known as pneumolysin with very similar properties to the COVID virus’s spike protein. Direct application of pneumolysin to the lungs of mice causes the major features of lung injury that occur in bacterial pneumonia, including edema (swelling) in the lungs, leakage of the blood vessels, and pulmonary hypertension. What’s more: all this damage gets started before the immune system arrives.

While I do not doubt at all that high amounts of free radicals and other oxidants produced by immune cells can cause their own damage, and that if the immune system begins attacking human cells expressing the spike protein this too can cause damage, the following remains the case:

• The spike protein itself, especially after being cleaved into subunits, is sufficient on its own to replicate the full spectrum of the disease.

• If pneumolysin is a guide, the full spectrum of damage may start before the immune system even arrives.

• IL-6 was identified as early as April 4, 2020 as the primary predictor of whether a COVID patient needs mechanical ventilation. Blocking IL-6 quickly became a chief objective in moderating the so-called “cytokine storm,” with moderately beneficial results. IL-6 is net immunosuppressive by eliciting a sustained rise in MDSCs that suppress the adaptive immune system.

• In mouse models of sepsis, where it is known that the immune system is contributing to mortality, blocking IL-6 makes things worse; in COVID, it makes things mildly better. COVID is thus inconsistent with models where immune damage is equally or more important than pathogen toxicity.

• The sustained rise in MDSCs is by far and away the easiest way to explain the low levels of CD4 and CD8 T cells that were known to be the main predictors of death since the beginning of the pandemic.

• The immunosuppressive MDSCs are radically higher and sustained for radically longer in severe patients than in mild patients.

• That lungs from those who died of COVID patients are rich in MDSCs with “virtually no T cells” supports the concept that they died from net immunosuppression in their lungs.

To the extent there is immunological damage, it is probably a reaction to spike protein toxicity. That is, the suppression of the adaptive immune system by MDSCs allows much greater replication of spike protein, and thus far more spike protein toxicity. The damage done to cells releases damage-associated molecular patterns (DAMPs) that elicit even further damage from an immune system that gets confused by the widespread damage done by the spike protein.

But what kills a person? It doesn’t seem to be the adaptive immune system attacking the lungs, since these lungs are full of MDSCs and “virtually no T cells.”

Granted, there is almost certainly damage being done by accumulation of innate immune cells such as neutrophils. And the same studies that identified low CD4 and CD8 T cells as predictors of death also identified high neutrophils as predictors.

I do not deny this is present.

It just seems to me that MDSCs tell a much more coherent story of suppressing the adaptive response to the spike toxicity. This seems to be the central story.

The immune system is definitely dysregulated. But it is far more underactive than overactive.

The Importance of Nutrients

It seems shocking to me that MDSC researchers identified the importance of these cells as early as June, 2020 and that the broader immunology field didn’t immediately make an effort to study everything known about MDSCs in cancer to try to repurpose it for COVID.

Had that happened, all-trans retinoic acid — the activated form of vitamin A — would have been looked at first.

This emerging model has two nutritional components: the first and most root cause of these is promoting the differentiation of MDSCs to more mature myeloid cells using myeloid differentiation factors; the second is doing damage control by supplying T cells with arginine, tryptophan, and cysteine, and protecting them from oxidative stress and glycation.

Vitamins A and D as Differentiation Factors

The effects of the activated forms of vitamins A (retinoic acid) and D (calcitriol) on the differentiation of blood cells have been studied a lot, mainly in the context of myeloid leukemia, but also in normal cells. The gist of these studies² is that calcitriol differentiates myeloid cells into monocytes and macrophages, whereas retinoic acid differentiates them into granulocytes.

Assuming these effects would apply to MDSCs, we would expect the following:

• More total MDSCs will be differentiated with the two vitamins together, because they are providing the differentiation of two different cell types, and the need for either cell type is not infinite.

• Retinoic acid would be more important for differentiating PMN-MDSCs, since they differentiate into granulocytes.

• Calcitriol would be more important for differentiating M-MDSCs, since they differentiate into monocytes.

Notably, these last two points seem to suggest vitamin A would be more important than vitamin D in getting rid of MDSCs in the lungs, since those seem to be overwhelmingly the PMN type.

The MDSC literature tends to treat all-trans retinoic acid as if it’s a drug. I believe this misses the point, and that results may often be superior with vitamins.

Vitamins A and D are not signals themselves. Not even their active metabolites are signals.

Rather, they are the raw materials from which cells make signals.

In the olden days, they would be analogous to pens and paper. In the modern day, perhaps to internet connectivity and server space.

If you had a team in the 1800s whose managers communicated with workers by pen and paper, the managers would not be able to send out any messages if you suddenly ran out of pens and paper.

If you were managing a team of workers today and you communicated by email, you would not be able to send out any messages if your ability to connect to the internet failed, or if your email service provider ran out of server space.

The result is a breakdown of communication.

Restocking the pen and paper allows you to communicate, but does not send out any particular signal. Fixing the internet issues allows you to communicate, but does not send out any particular signal.

Thus, all-trans retinoic acid causes the differentiation of MDSCs in tumor-bearing mice, but does nothing to them in sepsis. Why? We don’t know the exact mechanisms, but MDSCs are pathological in cancer and protective in sepsis. So even with the activated form, it behaves more like a raw material with which the body makes the signal it decides to make, rather than a drug that achieves the objective of the pharmacologist.

Still, providing all-trans retinoic acid rather than vitamin A bypasses several nodes of control the body has over how much vitamin A is activated at any given time. It is a bit like providing managers with quill pens that have already been dipped in wet ink, or fixing the internet but launching 100 blank emails addressed to each employee on restart. It doesn’t achieve a specific message, but it is more likely to cause a mess.

Along these lines, one might worry that vitamins A and D would suppress needed MDSCs in autoimmune conditions. I doubt it. Vitamins A and D synergistically suppress pro-autoimmune Th17 cells and protect against contact sensitivity in mice.

They are the raw material the body uses for communication. Supplying them in proper amounts allows the body to achieve normal rhythms of regulation.

Calcitriol and retinoic acid require zinc and magnesium to carry out their functions, so these minerals are also likely to be needed for their effects on MDSC differentiation.

Damage Control With Amino Acids, Antioxidants, and Anti-Glycation Nutrients

While the fat-soluble vitamins, zinc, and magnesium are the first line of defense to promote MDSC differentiation, assuming MDSCs are high, damage control becomes important.

Arginine and tryptophan are important to directly replete. N-acetyl-cysteine (NAC) is probably the best way to get cysteine into T cells and bypass their inability to break down glutathione and cystine.

The antioxidant nutrients include protein (especially the sulfur amino acids), vitamins E and C, selenium, zinc, copper, iron, and manganese.

Antioxidant defense is completely dependent on the system of energy metabolism, where sufficient calories; blood glucose that is neither too high nor too low; health of the thyroid, adrenal, and sex hormone axes; diabetes prevention; all of the B vitamins; and magnesium, iron, copper, and sulfur stand out as the most important nutrients.

Glycation defense is dependent on all the foregoing antioxidant and energy nutrients, but puts special emphasis on zinc, protein (especially the sulfur amino acids), and the points about diabetes and blood glucose above.

Insulin stimulates many aspects of antioxidant and glycation defense, so as long as one stays within the constraints of healthy blood glucose levels, dietary carbohydrate will generally be beneficial.

Severe COVID: The New Paradigm

Here is my current working model.

In the healthy response to COVID, assuming mucosal secretory IgA hasn’t already stopped it, the innate immune system kicks into gear first. MDSCs immediately rise on the first day and moderate the activity of the adaptive immune system so it can spend some time increasing its precision before it launches its attack. By the end of day 1, MDSCs are already starting to decline. As they gradually decline over the first week, the adaptive immune system begins to rise. When ready, it launches a precision attack and cleans house.

In the dysfunctional response to COVID, all of this starts to happen.

Two things go wrong.

First, comorbidities and risk factors contributing to chronic low-grade inflammation have primed the system to respond with too many MDSCs.

Second, myeloid differentiation factors — chief among them vitamins A and D — run in short supply. As they run out, the MDSCs start to accumulate and rise to higher and higher levels over the course of 20-30 days rather than receding.

The body wants to signal them to differentiate along the path to fully mature immune cells, but it is just running out of what it needs. It’s running out of pen and paper. The wifi doesn’t connect. The servers shut down. The communication doesn’t happen.

In fact, we know these differentiating factors are indeed depleted in COVID. Vitamin D status is nearly cut in half from pre-COVID levels by the time someone is admitted to the hospital. Three days in the ICU rapidly depletes it further. We know from several studies (here, here, and here) that COVID patients have lower vitamin A levels than healthy people and that severe COVID patients have lower vitamin A levels than mild patients.

As MDSCs continue to rise through the first three weeks, this leads to greater and greater suppression of the adaptive immune system through depletion of arginine and tryptophan, sequestration of cysteine, and oxidative and glycative damage directed straight at killer and helper T cells.

This leads to a less effective immune response overall, with greater viral replication, higher loads of the toxic spike protein, and greater risk of chronic infection, severe outcome, or death.

Most of the damage is done by the spike protein.

However, the special ops deployment that should have come from the adaptive immune system is replaced by a more carpet bombing approach from the innate immune system. The MDSCs themselves contribute to this, since they make superoxide, nitric oxide, peroxynitrite, and antimicrobial tryptophan derivatives. This lays on a secondary level of damage, but it is not clear whether it is more important or even as important as the havoc wreaked by the spike protein itself.

Eventually the adaptive immune system is reduced to confusion, emerging from a haze of MDSC repression, mounting a half-assed response to the mess where now everything looks like a target. This adds another layer of destruction and induces autoimmunity.

The key turning point from the healthy reaction to the dysfunctional reaction is the depletion of myeloid differentiation factors.

It is not just COVID that depletes them. Every immune event taxes the myeloid differentiation factors:

• The tolerance the newborn infant needs for its newly seeded gut microbiota.

• Every single vaccination received.

• Every single illness one catches.

• Every single injury by which one is befallen.

• The tolerance one needs for the fetus during pregnancy.

• Every source of chronic inflammation.

And this is to say nothing of all the other stresses of daily life that increase the demand for nutrients.

Implementing Nutritional Strategies

Vitamins A and D should be properly balanced with each other, and with vitamins E and K. My COVID-specific recommendations for this balance are in the COVID Guide, and recommendations for balancing them in various different contexts are included in the Vitamins and Minerals 101 Cliff Notes, both of which are freely available to paid Substack subscribers.

These also contain general (Cliff Notes) or COVID-specific (COVID Guide) information for managing all the other nutrients mentioned. I will be updating the COVID guide next time to include tryptophan and N-acetylcysteine whenever arginine is used, but other than that this new paradigm does not alter the protocol. It does, however, move much more emphasis to A and D, and bring A onto much more equal footing with D.

Notably, one of the major findings of this research is that there is no evidence that arginine depletion lessons the concerns for nitric oxide toxicity. Therefore, my upcoming vitamin C report (see the preliminary report here) will be very important for balancing vitamin C with glutathione with applicability not only to COVID vaccine side effects but to any stage of the COVID illness.

Disclaimer

I am not a medical doctor and this is not medical advice. My goal is to empower you with information. Please make all health decisions yourself, consulting sources you trust, including a caring health care professional.

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1. Ontogeny of Myeloid Cells, Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity, Myeloid-Derived Suppressor Cells: A Propitious Road to Clinic, Myeloid-Derived Suppressor Cells, Myeloid-derived-suppressor cells as regulators of the immune system, Deciphering myeloid-derived suppressor cells: isolation and markers in humans, mice and non-human primates, MDSCs in infectious diseases: regulation, roles, and readjustment, Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection, A Paradoxical Role for Myeloid-Derived Suppressor Cells in Sepsis and Trauma

2. As examples, see here, here, here, and here.