Two 2021 papers on trained immunity, with the first a review:

“Effective memory immune responses rely on interaction between innate and adaptive immune cells. While activation of innate immunity provides the first line of defense against infections, it also primes the adaptive immune response.

Adaptive immunity can enhance antimicrobial machinery of innate cells, making them more effective at clearing pathogenic microorganisms. An additional layer of complexity adds to this network of interactions, with innate cells adopting a memory phenotype, which used to apply to only adaptive immunity. Furthermore, non-immune cells can develop some features of this memory-like phenotype.

Cell subsets in which trained immunity has been described. Different stimuli including Bacillus Calmette Guerin (BCG), β-glucan, cytokines, cytomegalovirus (CMV), and bacterial components can induce a trained immunity phenotype. A common hallmark of trained immunity in these cases is H3K4me3 in promoters of genes encoding for different cytokines.

• Mechanisms Underlying Establishment of Trained Immunity
• Trained Immunity in Neutrophils
• Trained Immunity in Monocytes and Macrophages: General Features
• Metabolic Pathways Involved in Training of Monocytes and Macrophages
• Hormonal Control of Trained Immunity Responses in Monocytes and Macrophages
• Trained Immunity on Alveolar Macrophages and Involvement of Resident Cells
• Trained Immunity in NK Cells
• Trained Immunity in Innate Lymphoid Cells
• Trained Immunity on Hematopoietic Stem Cells
• Trained Immunity in Bronchial Epithelial Cells
• Trained Immunity in Skin Stem Cells
• Trained Immunity in the Gastrointestinal Tract
• Immunity Training Against Protozoan-Mediated Pathologies
• Trained Immunity in Non-Infectious Pathologies

Many gaps of knowledge remain in this field. For example, how long changes associated to trained immunity last, and if, in addition to epigenetic modulation, there are other post-translational modifications on proteins relevant for induction of trained immunity.”

https://www.frontiersin.org/articles/10.3389/fimmu.2021.745332/full “Molecular and Cellular Mechanisms Modulating Trained Immunity by Various Cell Types in Response to Pathogen Encounter”

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This second paper was a human study cited for its glutathione findings as follows:

• “Plasma concentration of IL-1β from BCG-vaccinated individuals are positively associated with serum glutathione concentrations.
• Trained immunity up-regulates expression of genes involved in glutathione metabolism, suggesting an increase in glutathione synthesis and a higher glutathione recycling rate.
• Single nucleotide polymorphisms in these genes are associated with changes in pro-inflammatory cytokine production after in vitro training by β-glucan and BCG.

Enzymes whose activities are dependent on glutathione could be used as novel targets to modulate trained immunity.”

“We found a positive association between plasma glutathione concentration and ex vivo IL-1β production 90 days after BCG vaccination upon in vitro exposure to heterologous stimulus Staphylococcus aureus. Up-regulation of IL-1β production by BCG vaccination was also positively associated with circulating concentrations of other metabolites involved in glutathione metabolism, such as methionine, cysteine, glutamate, and glycine.

GSH metabolism was associated with trained immunity traits in 278 healthy individuals. Trained immunity mechanisms that are shaped by GSH metabolism remain to be further explored.”

https://www.mdpi.com/2073-4409/10/5/971/htm “Glutathione Metabolism Contributes to the Induction of Trained Immunity”

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