Innately Trained

The above illustration¹ represents one of the most important recent developments in immunology. It has radically changed the way we think about the innate immune system, and immunity in general.

It turns out that the innate immune system has a memory². This is not like the memory of the adaptive immune system, which can be life-long; the bulk of innate immune memory lasts for only a few days, although certain aspects of it may remain for a few years³. But it is critically important, and it can be trained.

Positive innate immune training enhances health, and dietary tools can be used to achieve this. Negative training leads to disease, and dietary components play a role here too. 

For non-scientists, a very basic intro. 

The innate immune system is the body’s first line of defence against potential pathogens. It consists of physical barriers, antimicrobial peptides, antimicrobial enzymes including lactoperoxidase (subject of a future post), and innate immune cells. These include neutrophils, natural killer cells, mast cells, macrophages and a half dozen others, each of which contain sub-populations with different but coordinating roles.

The adaptive immune system is generally not activated unless pathogens manage to bypass the first line of defence and enter the blood and deeper tissues in significant numbers. At this point adaptive immune cells, informed by the innate cells, start to mount a slower but more specific response. They have the ability to form a longer-term memory of that pathogen so that it can be more effectively countered at a subsequent meeting, decades later. This is the basis of immunisation.

Partly because immunisation has become such an important source of revenue to Big Pharma, and partly because it was believed that the innate immune system was a constant, innate immunity has been rather ignored. Until very recently.

In the last 15 years evidence has emerged that Pathogen-Associated Molecular Patterns (PAMPs), found on the surface of different types of pathogens, induce epigenetic changes in innate immune cells^4-6 which up-regulate their ability to respond to future pathogens. They do this partly by increasing innate immune cells’ ability to generate energy, via up-regulated glycolysis^7-9. 

The cells are then able to migrate more quickly (chemotaxis) to the site of an infection, and behave more aggressively towards the pathogens (phagocytosis) when they arise at the site of infection. Accelerated chemotaxis and enhanced phagocytosis mean a more effective acute inflammatory response, and improved resistance to many different pathogens. There are knock-on improvements in adaptive immune function also^{ie 10}.

This innate enhancement is thought to last as long as the epigenetically re-engineered immune cells last. Macrophages live up to several years¹¹ but monocytes live only for a day or so¹¹ and neutrophils, the most numerous innate immune cells, have a half-life in the blood of 6-8 hours¹². It is probably best therefore to prime the innate immune system on a daily basis. In an earlier and less sanitised age, this is exactly what happened; see below.

The 1-3, 1-6 beta glucans are arguably among the most important PAMPs.

Their importance is revealed by the fact that they are recognised by at least 6 different classes of receptors¹³ present on all innate immune cells (and some T-cells), and enhance key aspects of innate immune function in every animal species tested so far¹⁴.

The fact that 1-3, 1-6 beta glucan supplements improve resistance to infection^15-18, reduce allergy^19-21 and exert significant anti-cancer effects²² indicates that we are not consuming optimal amounts of them. If we were, beta glucan supplements would have no effect. And given that diets low in beta glucans are negatively impacting our personal and public health, it seems fair to classify 1-3, 1-6 beta glucans as essential if atypical nutrients. 

Lipopolysaccharides, which are structural elements in the cell walls of gram-negative bacteria, are another well-characterised PAMP. They trigger intense inflammation which, unlike the immune training induced by the beta glucans, becomes destructive if exposure is high and sustained. This occurs in endotoxaemia, and is one of the mechanisms whereby a low-fibre (ie Western) diet increases the risk of many degenerative diseases. 

It is not just PAMPs that train the innate immune system. There are also DAMPs, which exert similarly positive effects; and LAMPs, which appear to be entirely negative. 

Damaged tissue produces specific Danger-or Damage-Associated Molecular Patterns (DAMPs), some of which are termed ’alarmins’. These behave rather like PAMPs and generally lead, as PAMPs do, to a more effective subsequent immune response^22, and to various sickness behaviours²³. This is quite logical, as tissue damage would generally allow the ingress of pathogens into deeper tissues; and the perception of danger might well portend the same thing. 

Don’t confuse PAMPs and DAMPs with AMPs, anti-microbial proteins which kill pathogens and are essential components in the innate immune system. These are produced by our immune cells when supplied with vitamin D²⁵, and by probiotic species in our intestines when these are fed with prebiotic fiber^{26, 75}. 

iDAMPs and cDAMPs, which relate to cell stress and death pathways, are fascinating but outside the scope of this post.

In marked contrast the LAMPs, Lifestyle-Associated Molecular Patterns²⁸, induce innate mal-training. These include such familiar toxins as oxidised LDL cholesterol and monosodium urate (ie gout crystals). Levels of the former are increased by a diet low in antioxidants such as the amphiphile polyphenols²⁹, levels of the latter are increased by a high purine intake; raised levels of both are linked to an increased risk of disease and early death^{30, 31}.

Other candidate LAMPs include proteins damaged by carbamylation, proteins damaged by glycation (AGEs) and advanced lipoxidation end-products (ALEs). 

Immune cells are not very effective at clearing LAMPS^{ie 28}, so if you persist with an unhealthy lifestyle, they accumulate in the body³¹. This triggers the inflammasome, causing persistent leucocyte hyperactivation and (sterile) chronic inflammation, which drives progressive damage to the extra-cellular matrix^{1, 28, 32, 33}. This, as blog readers may recall, contributes to ageing and to illness³⁴.

Carbamylated proteins are increased by smoking, and by under-hydration³⁵. AGEs and ALEs, which are produced when foods are cooked at high temperatures, occur at high levels in many ultra-processed foods^36-38. 

The negative effects of LAMPs seem to be quite long-lasting. One pre-clinical study stands out. In atherosclerosis-prone Ldlr-/- mice, 4 weeks of a Western-style diet epigenetically re-programmed various innate immune cells so that the mice developed exaggerated inflammatory responses, which persisted even after a further 4 weeks of healthy eating³⁹. 

To recap: exposure to LAMPS is increased by ultra-processed foods and by the Western-type diet in general, which is rich in fats and sugars and low in prebiotic fibres and the 1-3, 1-6 beta glucans. Such a diet is also depleted in antioxidants and anti-inflammatory nutrients. This toxic combination inevitably leads to chronic inflammation, progressive tissue damage, downgraded immunity and increased rates of chronic degenerative diseases such as cancer. 

This situation is made worse by our substantially reduced dietary intakes of the key dietary PAMP, the 1-3, 1-6 beta glucans.

The idea that the removal of these beta glucans has made us more vulnerable to cancer derives from studies documenting these compounds’ distinct cancer-fighting properties, many of which are related to innate immune training. 

In ‘successful’ cancers, host immune cells are recruited by the tumor cells to alter the immune cell phenotype/function and tricked into immune suppression or tolerance^{40, 41}. The beta glucans are thought to be able to switch the suppressed immune cells back on via innate training, thus restoring local cancer-hostile immunity^42-44. 

This is why the beta glucans’ ability to induce positively trained innate immunity is now being suggested as a potentially important anti-cancer strategy⁴²; and why there are so many recent and on-going pre-clinical and clinical cancer trials⁴³.

Unfortunately, the 1-3, 1-6 beta glucans have largely disappeared from our diet.

These structural carbohydrate compounds occur only in the cell walls of fungi, and the most common fungal food sources are yeast and mushrooms. Due to the different cell wall requirements of unicellular yeast and multicellular mushrooms, beta glucans from these two sources have different forms. These include lengths of the 1-3 side chains, 1-6 chain lengths and tertiary helical and annular structures^44-48.

Yeast beta glucans are more potent innate immune primers in some assays and mushroom-derived glucans do better in others, but I generally favour yeast derivates. My simplistic thinking is that our innate immune systems were designed to fight off yeasts and other single cell fungi, rather than truffles.

Yeasts, some of the most pervasive members of the fungal kingdom^{ie 49}, were formally omnipresent in our diet. They were present in large amounts in fermented foods such as beer, wine and breads, and at lower levels as a background contaminant in almost all other foods⁵⁰.

Prior to the 1950’s the natural fungicides used in agriculture were not particularly effective, so that fungal residues were present in practically everything we ate. The more potent synthetic compounds which started to became common usage in the 50’s reduced fungal spoilage considerably, reducing yeast contamination on fruits, grains and vegetables⁵¹. 

Food production chains have been tightened to minimize contamination and spoilage, and improve quality. Today crops are collected and, in some cases, flash-frozen within minutes of harvesting⁵². The effective abolition of storage time reduces background levels of yeast even further.

Processing changes have also impacted the yeast-fermented beverages. Filtration of beer was introduced by the German engineer Lorenz Enzinger at a brewing trade show in 1880, designed to produce beer that was abiotic and had better storage qualities. The technology graduated from paper and cotton filters to kieselguhr and finally, in the 1960’s, to ultra-filtration using cross-flow membranes.

These produce a sterile beer that keeps for months but contains only homeopathic amounts of beta glucan. The same filtration process removes the sediments from wines (decanters have become an affectation) and so the lees, and the beta glucans, have been removed from these too.

Breads and other baked goods still contain beta glucans but we eat far less of these foods than did our ancestors, due to our reduced calorific requirements⁵³.

While it is hard to quantify the effects on our health of the reduction in our intake of 1-3, 1-6 beta glucans, there is some evidence that we may have become more vulnerable to developing sepsis⁵⁴, although this apparent increase may also reflect better diagnosis⁵⁵. The fact that cancers are emerging in progressively younger groups of patients⁵⁶ could be another sign of impaired immunosurveillance^42-44.

It certainly looks as if paediatric health is impacted. Yest-derived beta glucans are routinely added to infant formula, because they have been shown to reduce rotavirus infection⁵⁷. In other words, beta glucan-depleted toddlers are immunologically weaker and more prone to infection.

It is time to put these valuable natural compounds back in all our foods, where they used to be. It makes sense also to use them to train the innate immune systems of elective surgery patients, because the hospital environments where they will be operated on are hotbeds of antibiotic-resistant bacteria^{58, 59}.

Beta glucans are not the only PAMPs but they are safe, inexpensive and widely available.

And, they have a feel-good effect. Among the many innate immune cells they train are the microglia, the primary innate immune cells in the brain⁶⁰. The resulting changes in microglial function which include physiological (ie low level) neuroinflammation^60-62 may explain the improvement in mood that has been consistently linked to beta glucan use^63-66.

Equally important, there is emerging evidence that the ability of the beta glucans to induce physiological levels of neuroinflammation facilitates neuronal repair^{67, 68}, enhances various aspects of intelligence⁶⁹, and likely reduces the risk of neurodegenerative disease⁷⁰.

Taking a 1-3, 1-6 beta glucan supplement seems like an innately smart thing to do. While you’re at it, take a 1-3, 1-4 beta glucan supplement to transform your dysbiotic gut into another functional part of your innate immune system.

Next week: Middle C, and the music of meat.

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