Hormetic Dose-Response Relationships in Immunology: Occurrence, Quantitative Features of the Dose Response, Mechanistic Foundations, and Clinical Implications

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Abstract
This article provides an assessment of the occurrence of immune-system-related hormetic-like biphasic dose-response relationships. Such dose-response relationships are extensive, with over 90 different immune response-related endpoints reported, induced by over 70 endogenous agonists, over 100 drugs, and over 40 environmental contaminants. Such hormetic responses were reported in over 30 animal models, over a dozen mammalian and human cell lines. These findings demonstrate that immune-system-related hormetic-like biphasic dose-response relationships are common and highly generalizable according to model, endpoint, and chemical class. The quantitative features of the dose response are generally consistent with previously published examples of hormetic dose responses for other biological endpoints. These findings were generally recognized and explicitly discussed by the original authors, often with consideration given to possible mechanistic foundations as well as numerous clinical implications. Despite the recognition by individual authors of the hormetic nature of these observed responses, the overall widespread nature of immune-related hormetic responses has been only little appreciated, with a general lack of insight into the highly generalizable nature of this phenomenon as well as the complex regulatory networks affecting biological switching mechanisms that result in the hormetic responses.