Fragility of an aging immune system

Jones, Eric; Sheng, Jiming; Carlson, Jean; Wang, Shenshen

The adaptive and innate branches of the vertebrate immune system work in close collaboration to protect organisms from harmful pathogens. As an organism ages its immune system undergoes immunosenescence, characterized by declined performance or malfunction in either immune branch, which can lead to disease and death. In this study we develop a mathematical model of the immune system that incorporates both the innate and adaptive immune compartments, named the integrated immune branch (IIB) model, and investigate how immune behavior changes in response to a sequence of pathogen encounters. We find that repeated pathogen exposures induce a fragility, in which exposure to novel pathogens may cause the immune response to transition to a chronic inflammatory state. The chronic inflammatory state of the IIB model is qualitatively consistent with"inflammaging,"a clinically-observed condition in which aged individuals experience chronic low-grade inflammation even in the absence of pathogens. Thus, the IIB model quantitatively demonstrates how immunosenescence can manifest itself in the innate compartment as inflammaging. In particular, the onset of a persistent inflammatory response strongly depends on the history of encountered pathogens; the timing of its onset differs drastically when the same set of infections occurs in a different order. Lastly, the coupling between the two immune branches generates a trade-off between rapid pathogen clearance and a delayed onset of immunosenescence. By considering complex feedbacks between immune compartments, our work suggests potential mechanisms for immunosenescence and provides a theoretical framework to account for clinical observations.