Manipulating the way the immune system functions will come with benefits and threats to our health and well-being, and trained immunity is no exception.
What is trained immunity?
Once upon a time – about 100 years ago, actually – Sweden introduced BCG (Bacillus Calmette-Guérin) vaccination. BCG is the anti-tuberculosis vaccination. It very modestly reduced tuberculosis deaths which usually occur later in life. However, infants vaccinated with BCG had a much lower mortality than those not vaccinated. The assumption at the time was that BCG might result in a ‘non-specific immunity’, thus protection from all-cause mortality.
Fast forward to this day, we have found out that certain encounters with perceived threats will act like priming agents on our innate immunity. We used to think it was the adaptive or acquired immunity that was based on memory, whilst the innate immunity would be the primitive and unrefined branch of the immune system. Interestingly, that’s no longer the case.
Some infections or vaccinations (the latter also being, in fact, exposures to different infectious agents) will lead to a reprogramming of how innate immune cells work. This is called trained immunity. It doesn’t involve the cells that produce antibodies or that specifically recognise an infectious agent.
Age is not an issue when we aim to train the immunity. A recent study showed that the same BCG vaccine mentioned above in relation to infants, was a safe way of reducing all infections and especially respiratory ones, in elderly people (1). Indeed, this was associated with immune markers suggestive of trained immunity.
How exactly do we achieve trained immunity?
Innate immunity cells continuously scan our internal environment for threats. They are the guardians. If danger is identified, innate immune cells become activated and conduct an immediate attack to ensure our safety. Activation means that certain genes that were silent, are expressed and the cells can produce their specific chemical warfare and signalling to other cells. Once the threat is eliminated, innate immune cells return to a resting mode where the above genes are once again silenced.
The old paradigm states that this is a cycle whereby the innate immunity would predictably do its job, but lacking the refinement of recognising previously encountered pathogens. However, it exists a memory-like response of innate immunity. The innate immune cells can become ‘trained’ following their encounter with some microbes. This means that their reaction will be quicker and stronger upon a subsequent contact with the same or other infectious agents. The cells still have the same genes, but they have an enhanced capacity to activate them when re-stimulated. This is what trained immunity is all about.
Furthermore, it’s not just the cells that actually fought an infection or that were there during vaccine administration. The precursor cells in the bone marrow – the ones which will generate new innate immune cells in the long-term, will undergo the same changes in how their genes function. Thus, the renewed peripheral immune cells will maintain this characteristic when they replace the initial cells (2).
Which are the inducers of trained immunity?
Other than BCG, we have evidence that beta-glucan from the fungus Candida Albicans and from other sources can train innate immunity, as well as a range of bacterial and viral infections, and some vaccines.
Interestingly, some internal factors can induce trained immunity, such as oxidised LDL-cholesterol (3). This is the kind of fat we don’t want in our bodies and which we already knew it was a trigger of immune activation.
Our health is a complex matrix and various reciprocal influences contribute to the final result. For immune health, this is especially relevant, because immune system’s components are present throughout the body.
The importance of trained immunity
We know that innate immunity is our first line of defence. The better it protects us, the safer we are. We may eliminate infections more effectively if this early mechanism is strong enough. If we can achieve a broad-spectrum anti-infectious protection, this will probably make a difference in overall disease and death burden, potentially in all age groups.
Additionally, even elimination of cancer cells could be more efficient.
As a consequence of eliminating or mitigating infections early, the immune system’s excessive activation is more likely to be avoided. Thus, pathogen-associated and immune-associated damage (as in sepsis or cytokine storm) could be reduced.
Are things ever that simple? Not necessarily. With people whose immune system is already in an alert state, such as in autoimmunity, or with people predisposed to autoimmunity, we certainly need a nuanced approach.
What are the risks of trained immunity?
Why mention autoimmunity? In autoimmunity, the immune system conducts an attack against the structures of self, the person’s own tissues. It is, however, an acquired or adaptive immune response, involving auto-reactive cells or antibodies. These can specifically recognise their target, unlike the innate immune cells. How can innate immunity function be a relevant risk factor for autoimmunity?
We now know that there is a continuum between autoimmunity and inflammation, and reciprocal influence. This means that the non-specific innate immune response can alter autoimmunity risk. It can, in turn, contribute to immune tolerance as well. This has profound implications, because stimuli from the internal and external environment can trigger innate immune responses. These stimuli can be vaccines, microbial encounters (either with disease-causing agents or with colonising commensal microbes), tissue destruction debris, chemical products from reactions in the body, or, indeed, foods.
For example, we know that there are gender differences in autoimmune diseases prevalence. This may be a direct consequence of hormonal influence on immune function, but also of hormones’ influence on colonising microbes (4). These microbes interact with the immune system, and primarily with its innate branch. And because we know that lifestyle factors influence the composition of microbial and fungal populations in and on us, and microorganisms modulate immune function, we again come to the conclusion that we can probably influence autoimmunity risk with our everyday choices in terms of diet and other habits.
Furthermore, some of the fungal components that can induce trained immunity, are also present in certain foods. Other dietary habits will promote the production of innate immunity-stimulating chemicals in the internal environment.
These are all reasons why complex approaches, that account for multiple potential influences and for individual risk, stand the best chance to promote optimal health.
So, is trained immunity a relevant player in the induction and perpetuation of autoimmune and autoinflammatory reactions? We don’t have direct causal evidence, but data supports his hypothesis (5). Does it matter if trained immunity contributes to autoimmunity? Yes, if we want to design both preventative and therapeutic strategies with optimal efficiency.
Other clinical implications of trained immunity
Trained immune cells produce chemical signals which define the type of inflammatory environment where adaptive immunity will be shaped. This may promote autoimmunity in some cases, as discussed.
Moreover, research is still ongoing to elucidate whether trained immunity could play a role in development of allergies or if in some cases it may be protective (6). Indeed, studies have shown that enhanced innate immune responses were present from birth in allergic children, unlike in healthy controls. On the other hand, innate immune cells known to promote immune tolerance were better represented in healthy patients (7).
We can expect promising results from assessing parallels between the natural course of allergic disease and the innate immune function. Whether or not pro-inflammatory activity of innate immune cells persists in individuals who managed to overcome their allergies, should offer important clues that may improve understanding and management of allergy, including preventative strategies.
Interesting insights may also be possible from the analysis of different allergies, as patterns may differ, and from discriminating between cases of allergic disease, allergic sensitisation (without clinical manifestations), normal controls and individuals who have outgrown their allergies.
Clinical applications of trained immunity
Ideally, we would design health programmes that account for the potential role of trained immunity in autoimmunity and other pathologies.
The first thing to consider is exposure to trained immunity inducers. We have covered this in the article thus far.
Further considerations may be the role of methylation and acetylation (chemical alterations of DNA) in influencing gene expression, and how the cells’ metabolism, or chemical reactions (i.e., energy production), play a crucial role in allowing the establishment of trained immunity.
If these levers seem too complicated to even begin to imagine, much less influence, then rest assured that diet and lifestyle interventions have been shown to exert epigenetic (gene expression) and metabolic (cell function) influences. However, we need more research to test such interventions in relation to trained immunity, and in the end a personalised programme will probably achieve the best results.
Interventions targeting trained immunity
Firstly, we already know that therapeutic strategies for autoimmune diseases consider certain anti-inflammatory supplements (8).
Moreover, health interventions targeting other aspects of health may influence the development of trained immunity via factors such as blood lipid profile, uric acid or hormones involved in stress response and in mineral balance and blood pressure regulation, as well as via vitamin levels, exposure to bacterial fragments and overall inflammatory environment in the body.
For now, pharmaceutical interventions may also be considered in research settings, with the caveat that they tend to act in a strong, sometimes non-specific and irreversible way, lacking the modulating quality of lifestyle measures, thus are more prone to adverse reactions (9). On the other hand, nanotechnologies developed for targeted drug delivery might prove to be a successful strategy.
In terms of diet and lifestyle interventions, there is evidence that a Western-type diet will not only create a transitory inflammatory state, but will train immune progenitor cells for long-term enhanced responses to innate immune triggers. Studies have shown that immune signalling pathways are essential in sensing the Western diet as a trigger and in achieving the trained immunity effect (10). In order to avoid unwanted inflammation, sustained dietary interventions are a first-line intervention.
So, is trained immunity in the ‘no, thanks’ category for patients with autoimmunity propensity?
Not necessarily. Or, it depends! Animal studies have shown that stimuli produced by certain parasites can actually train innate immune cells to be anti-inflammatory. Thus, they may contribute to reduced susceptibility to autoimmune disease. Furthermore, this training is imprinted in stem cells responsible for regenerating immune cells populations long-term (at least 8 months in this study) (11). Transplantation of these stem cells, confers the same autoimmunity resistance advantage to naïve animals.
Moreover, context is once again important. The same BCG vaccine that induces enhanced immune responses, was shown to prevent and even reverse initial stages of autoimmunity development, and to contribute to lower disease activity in some cases (12). Similarly, beta-glucan can either aggravate or ameliorate autoimmunity depending on its source and quantity.
Could we use this information in humans? It’s early days, and there may be risks. Firstly, nobody would want to host the above parasite (and probably any other similar organism), and we will need adequate evidence to assess safety and efficacy of parasite extracts or other interventions for therapeutic or preventative use.
What is relevant, though, is that there is evidence that immune modulation is achieved by epigenetic changes (13), which means a change in how genes are expressed, induced by environmental factors. And we can always manipulate at least some of the environmental factors.
Data available so far suggests that trained immunity is not a permanent state, and this makes sense considering that there are no genetic mutations in immune cells, like when adaptive immunity develops, but rather a different way of expressing existing genes (14).
However, we know that offspring can inherit some epigenetic/expression changes.
It is not yet certain whether trained immunity-specific gene expression alterations can be passed on to future generations, but this is certainly a possibility. These would be some of the epigenetic marks potentially associated with autoimmunity risk.
What we do know is that lifestyle measures to address gene expression will always be relevant. So, whether or not somebody has the genes associated with autoimmunity, or has a propensity to express genes that will favour autoimmunity development, either inherited or acquired during their lifetime, lifestyle interventions have the ability to modulate gene expression and thus reduce disease risk. The earlier the interventions, the more likely a favourable outcome is.
In conclusion, the discovery of trained immunity is very empowering.
Acting on this knowledge, we may improve immune responses where they are deficient, we can improve vaccine efficacy, but also we can develop strategies for autoimmunity and even allergy management.
Knowledge solves problems.
Ideally, your doctor’s knowledge will solve your problems.
At The Allergy-Immunology Doctor, we look at all aspects that may be relevant to patients’ health goals, and we use our knowledge and skills, as well as the comprehensive Functional Medicine toolkit, to design the best interventions in order to optimise the immune function, the main orchestrator of health.
You may want to book a free discovery call to find out how suitable is our approach for your current goals.
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13. Quinn SM, Cunningham K, Raverdeau M, Walsh RJ, Curham L, Malara A, et al. Anti-inflammatory Trained Immunity Mediated by Helminth Products Attenuates the Induction of T Cell-Mediated Autoimmune Disease. Front Immunol. 2019;10:1109.
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