Trained immunity is a newly emerging concept that defines the ability of the innate immune system to form immune memory and provide long-lasting protection against foreign invaders.
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What is immunity?
The human immune system broadly works through two branches – innate and adaptive. Innate immunity is characterized by rapid, non-specific responses of the immune system against pathogens and tissue damage.
The innate immune system cells, such as monocytes and macrophages, recognize foreign invaders through pattern recognition receptors and trigger a series of cellular phenomena, including phagocytosis, cell motility, killing and elimination of pathogens, and production of proinflammatory cytokines.
The activity of the adaptive immune system, also called the acquired immune system, is mediated by specialized white blood cells (lymphocytes) namely B cells and T cells. There are mainly two types of responses: antibody-mediated immune response (B cells) and cell-mediated immune response (T cells).
Upon pathogen invasion, both innate and adaptive immune systems are activated simultaneously; however, unlike innate immunity, adaptive immunity develops slowly and provides highly specific, long-lasting protection against pathogens.
For the past many decades, it was believed that the formation of immune memory was exclusively associated with adaptive immunity. However, recent studies have revealed that innate immune cells, especially monocytes and macrophages, can develop adaptive features after adequate priming.
What is trained immunity?
The ability of the innate immune system to develop adaptive features and provide long-term protection against pathogenic reinfection is termed as trained immunity. Epigenetic modification of various transcriptional pathways, as well as metabolic reprogramming of innate immune cells by both endogenous and exogenous stimuli, is the main driving force for trained immunity.
Alike adaptive immune response, trained immunity is associated with a heightened immune reaction in response to reinfections. In general, trained immunity is known to provide relatively short-term protection ranging from about 3 months to 1 year.
The immune cells primarily associated with trained immune response include circulating monocytes and tissue macrophages (peripheral trained immunity) as well as hematopoietic stem cells in the bone marrow (central trained immunity).
What are the triggers of trained immunity?
A wide range of stimuli, such as beta-glucan (fungal ligand) and BCG (bacillus Calmette–Guérin), are known to induce trained immunity. In humans, BCG vaccination-mediated non-specific protection against secondary infections is believed to be caused by trained immunity.
In addition, immune-modulatory effects of BCG vaccination against several cancer types, such as lymphoma, leukemia, bladder cancer, and melanoma, are associated with the induction of trained immunity in macrophages and monocytes.
Induction of trained immunity
When a pathogen enters the body, a series of metabolic alterations take place, such as induction of glycolysis, TCA cycle, and fatty acid metabolism. Certain metabolites (fumarate and acetyl-CoA) produced from these altered metabolic pathways subsequently modulate the activity of several enzymes associated with epigenetic remodeling processes, leading to an alteration in methylation and acetylation status of certain genes related to the innate immune response.
Mechanistically, studies have found that both BCG and beta-glycan trigger epigenetic modifications in histone trimethylation at H3K4 via NOD2 and dectin-1 signaling pathways, respectively. These changes in turn activate monocytes and macrophages, induce cytokine production, and alter cellular metabolic state from oxidative phosphorylation to aerobic glycolysis.
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What are the benefits of trained immunity?
Induction of trained immunity is considered to be a potential therapeutic strategy to manage various health conditions associated with immune system malfunctioning, such as cancer. Moreover, triggering trained immunity via live vaccines, such as BCG, measles, and oral polio vaccines, can be an effective approach in treating patients with severe infectious diseases, such as coronavirus disease 2019 (COVID-19).
Also, the induction of trained immunity can be a good approach to reduce the rate of morbidity and mortality in children with low birth weight.
Can trained immunity be detrimental?
Despite providing long-term benefits in fighting harmful pathogens, trained immunity can have detrimental effects in certain conditions. For example, hyperactivation of the innate immune system for a prolonged period as well as heightened immune reaction in response to secondary stimuli can link trained immunity with the risk of developing chronic inflammatory diseases, such as atherosclerosis.
In addition, specifically trained immunity phenotypes, such as increased cytokine production and histone trimethylation at H3K4 in the promoter region, have been observed in patients with hypercholesterolemia.
Trained immunity can be associated with the progression of neurodegenerative diseases. Studies conducted on mouse models of Alzheimer’s disease have revealed that chronic systemic inflammation can induce functional as well as epigenetic changes in microglia, which are similar to the peripheral trained immunity characteristics. These changes subsequently lead to abnormal accumulation of beta-amyloid, increased damage to the brain’s neuronal network, and cognitive decline.
Although robust activation of the immune system is one of the major criteria for cancer cell death, chronic inflammation associated with trained immunity can trigger neoplastic transformation and cancer progression.
Moreover, proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor (TNF), produced by trained innate immune cells are known to trigger tumorigenicity and metastasis in certain cancer types, including lung cancer, breast cancer, and oral squamous cell carcinoma.