Review Defining trained immunity and its role in health and disease, 2020, Netea et al.

[SNT Gatchaman]

Defining trained immunity and its role in health and disease
Netea, Mihai G.; Domínguez-Andrés, Jorge; Barreiro, Luis B.; Chavakis, Triantafyllos; Divangahi, Maziar; Fuchs, Elaine; Joosten, Leo A. B.; van der Meer, Jos W. M.; Mhlanga, Musa M.; Mulder, Willem J. M.; Riksen, Niels P.; Schlitzer, Andreas; Schultze, Joachim L.; Stabell Benn, Christine; Sun, Joseph C.; Xavier, Ramnik J.; Latz, Eicke

Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed ‘trained immunity’, a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases.

Here we define ‘trained immunity’ as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.

Link | PDF (Nature Reviews Immunology)

 

[SNT Gatchaman]

Summary quotes —

Defining trained immunity
The concept of trained immunity describes the long-term functional reprogramming of innate immune cells, which is evoked by exogenous or endogenous insults and which leads to an altered response towards a second challenge after the return to a non-activated state.

It is important to underline that trained immunity represents the concept of long-term adaptation of innate immune cells rather than a particular transcriptional or functional programme

In contrast to adaptive immune responses, epigenetic reprogramming of transcriptional pathways — rather than gene recombination — mediates trained immunity.

Trained immunity in humans
An increasing body of evidence suggests that trained immunity plays a critical role in humans. First, an extensive collection of epidemiological data argues that live vaccines such as the BCG vaccine, measles vaccine, smallpox vaccine and oral polio vaccine have beneficial, non-specific protective effects against infections other than the target diseases

Trained immunity in stromal and epidermal stem cells
Intriguingly, the induction of innate immune memory is not exclusively confined to immune cells but can also occur in stromal and epithelial cells. The discovery of inflammatory memory behaviour in epidermal stem cells is of particular relevance, as tissue stem cells are the cornerstone of regeneration in homeostasis and they reside in distinct microenvironments or niches and exchange signals that define their tasks and their molecular behaviours.

Similarly, inflammation and infections perturb the niche microenvironment, which can override the normal homeostatic cues and prompt changes in stem cell behaviours. Thus, through their ability to sense and respond to niche signals, stem cells can adjust to and survive stressful situations. Remarkably, stem cells form an enduring epigenetic memory from such encounters, which equips them with the ability to mobilize more rapidly during subsequent assaults.

Although it is still unfolding, the molecular communication avenue between stem cells and immune cells appears to be bidirectional. Stem cells do not merely take instructions but rather they also actively instruct the immune system.

 

[SNT Gatchaman]

Cont'd —

Central versus peripheral trained immunity
Trained immunity was initially shown to act through mature myeloid cells. Until recently this hypothesis resulted in a conundrum as mature myeloid cells, such as monocytes and DCs, in both mice and humans are short-lived, with an average half-life of 5–7 days. Therefore, how trained immunity can be maintained in myeloid cells for several months, years and even decades remained unknown. More recent work has helped to resolve this issue by showing that trained immunity can occur in bone marrow progenitor cells (central trained immunity), as well as in blood monocytes and tissue macrophages (peripheral trained immunity).

The discovery that HSCs, similarly to epithelial stem cells, display a memory function could explain the long- standing mystery as to why short- lived immune cells such as monocytes can acquire memory.

Epigenetic reprogramming
Induction of a trained immune phenotype in innate immune cells enables them to react with stronger, more rapid or qualitatively different transcriptional responses when challenged with subsequent triggers. The molecular basis of this altered responsiveness of a defined subset of inflammatory genes is only partially understood, but evidence supports the convergence of multiple regulatory layers, including changes in chromatin organization at the level of the topologically associated domains (TADs), transcription of long non- coding RNAs (lncRNAs), DNA methylation and reprogramming of cellular metabolism.

In quiescent myeloid cells, most of the proinflammatory gene loci are in a repressed configuration, hindering access of the transcriptional machinery to the regulatory regions driving expression of inflammatory factors. Many studies have demonstrated that stimulation of innate immune cells can leave an ‘epigenetic scar’ at the level of stimulated genes, changing the long-term responsiveness of the cells that manifests itself as functional trained immunity programmes.

A recent study demonstrated how TAD structure enables a class of lncRNAs called ‘immune gene-priming lncRNAs’ (IPLs) to be brought into close proximity with transcriptionally poised innate immune genes, before their transcriptional activation.

 

[SNT Gatchaman]

Cont'd —

Immunometabolic circuits
Cellular metabolism is a critical mediator of the trained immunity-dependent epigenetic reprogramming of innate immune cells and their progenitors. It is well established that metabolites can modulate the activity of chromatin-modifying enzymes; hence, metabolic rewiring of innate immune cells or their progenitors will regulate their plasticity and epigenomic reprogramming in the context of trained immunity. Increased aerobic glycolysis is a hallmark of β-glucan-trained monocytes; this is mediated by a pathway that involves the activity of AKT, [mTOR and HIF1α].

Of note, itaconate-induced tolerance in human monocytes is counteracted by β-glucan-induced trained immunity as β-glucan inhibits the expression of immune-responsive gene 1 (IRG1) protein, the enzyme responsible for itaconate generation. Consistent with fumarate accumulation in β-glucan-trained monocytes, β-glucan-mediated inhibition of IRG1 results in elevated expression of succinate dehydrogenase. Thus, β-glucan-induced trained immunity is associated with enhanced succinate dehydrogenase activity and accumulation of fumarate as well as with reversing the endotoxin tolerance-inducing effects of itaconate, which acts as an antagonist of succinate dehydrogenase.

Enhanced cholesterol synthesis is also an important hallmark of β-glucan-trained monocytes. The [HMG-CoA] reductase inhibitor fluvastatin blocks trained immunity in primary human monocytes. Interestingly, this is accomplished not by cholesterol biosynthesis but rather by an accumulation of the upstream metabolite mevalonate.

Pathological outcomes of trained immunity
Infections were the most common causes of death throughout the world 150 years ago, and they continue to represent the most significant threats to health in low-income countries. Therefore, strong evolutionary pressure has shaped antimicrobial immune functions, including trained immunity. Although trained immunity evolved as a beneficial immune process to protect against infection, one may envisage situations in which reprogramming of innate immunity and increased inflammatory responses to exogenous or endogenous stimuli may also have harmful effects.

It is becoming increasingly evident that sterile inflammation in response to lifestyle changes in Western societies forms the basis on which chronic inflammatory diseases develop.

Trained immunity could, in part, explain the epidemiological link between infections and atherosclerotic cardiovascular disease.

Conclusions and future challenges
The impact of trained immunity, and more generally of epigenetic rewiring in various processes of priming, adaptation or tolerance during disease, warrants further studies.

 

[duncan]

Although trained immunity evolved as a beneficial immune process to protect against infection, one may envisage situations in which reprogramming of innate immunity and increased inflammatory responses to exogenous or endogenous stimuli may also have harmful effects.

I'm wondering how trained immunity might tie into immune tolerance (as in the exact opposite) where a damaged immune system lets in pathogens or toxins it otherwise would not, or allows for the reactivation of latent viruses, while, in theory at least, simultaneously muting antibody response (so that typical diagnostics are unremarkable). Could that somehow be related to ME/CFS?

I can't get my brain around it any way. If antibody responses are blunted, what causes symptoms?

Sorry, not meant to derail this thread. It just struck me as a doppleganger topic that I just happen to be reading about lately.

 

[SNT Gatchaman]

Yes it can go in either direction: up- or down-regulated.

The secondary response to the subsequent non-specific stimulus can be altered in such a way that the cells respond more or less strongly than to the primary response, conferring context-adjusted and time-adjusted responses.

Fig. 1 | Trained immunity and tolerance: two opposite functional programmes of innate immunity. Infections or sterile tissue triggers induce inflammation and the activation of immune effector mechanisms. Concomitant to a proinflammatory response, anti-inflammatory mechanisms are provoked to prevent overshooting inflammation and tissue damage and to limit the inflammatory response in time. Trained immunity involves epigenetic and metabolic reprogramming of the innate immune cells, allowing qualitatively and quantitatively adjusted responses of innate immune cells to subsequent time-delayed heterologous stimulation. Misguided trained immunity responses can contribute to disease progression, resulting in either a chronic hyperinflammatory state or a persistent state of immunological tolerance, a mechanism that dampens the inflammatory response of the host to maintain homeostasis and prevent tissue damage and organ failure, with the subsequent risk of secondary infections and other diseases related to decreased activity of the immune system.

 

[Jonathan Edwards]

Packaging immunological processes into pigeon holes like this has always been a bad idea. I cannot see merit in this one. It muddles together all sorts of different factors.

 

[arnoble]

Packaging immunological processes into pigeon holes like this has always been a bad idea. I cannot see merit in this one. It muddles together all sorts of different factors.

Do you think "trained immunity" is unlikely to be relevant to ME, and if so can you highlight the main issues? Are there other studies that do a better job of characterising the relationship, if any, between ME and "trained immunity"?

Many thanks - I am keen to travel up this learning curve.