Abstract
Immune memory is a defining characteristic of adaptive immunity, but recent work has shown that the activation of innate immunity can also improve responsiveness in subsequent exposures. This has been coined “trained immunity” and diverges with the perception that the innate immune system is primitive, non-specific, and reacts to novel and recurrent antigen exposures similarly. The “exposome” is the cumulative exposures (diet, exercise, environmental exposure, vaccination, genetics, etc.) an individual has experienced and provides a mechanism for the establishment of immune training or immunotolerance. It is becoming increasingly clear that trained immunity constitutes a delicate balance between the dose, duration, and order of exposures. Upon innate stimuli, trained immunity or tolerance is shaped by epigenetic and metabolic changes that alter hematopoietic stem cell lineage commitment and responses to infection. Due to the immunomodulatory role of the exposome, understanding innate immune training is critical for understanding why some individuals exhibit protective phenotypes while closely related individuals may experience immunotolerant effects (e.g., the order of exposure can result in completely divergent immune responses). Research on the exposome and trained immunity may be leveraged to identify key factors for improving vaccination development, altering inflammatory disease development, and introducing potential new prophylactic treatments, especially for diseases such as COVID-19, which is currently a major health issue for the world. Furthermore, continued exposome research may prevent many deleterious effects caused by immunotolerance that frequently result in host morbidity or mortality.
Highlights
Innate immunity is the first line of host defense against external exposures
This review provides insight into cell lineage determination as well as epigenetic and metabolic mechanisms of trained immunity resulting from the exposome
They do play a supportive role in the development of trained immunity, as demonstrated by the loss of acquired resistance in mouse macrophages sensitized to the parasitic nematode Nippostrongylus brasiliensis in the absence of neutrophils
Summary
While traditionally viewed as primitive and nonspecific, a growing body of clinical and experimental evidence argues the innate immune system develops memory as a result of previous exposures, allowing the innate system to respond with enhanced and broad immunological protection upon exposure to a secondary stimulus [1,2]. This biological process of enhanced innate immunity response on secondary pathogen exposure has been termed “trained immunity” [2,3]. Understanding the combinations of exposures and their order is critical for implementing early health interventions, especially in low-birth-weight children, and is necessary to curb the rampant development of inflammatory diseases
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