Aging-induced fragility of the immune system

TL;DR

This paper presents a mathematical model of the immune system that explains how aging and repeated pathogen encounters lead to increased fragility and chronic inflammation, mirroring phenomena like inflammaging.

Contribution

The study introduces the integrated immune branch (IIB) model, a novel framework capturing immune dynamics, memory, and aging effects in a unified mathematical structure.

Findings

Repeated pathogen encounters can cause irreversible transition to chronic inflammation.

The onset of inflammaging depends on infection history and order.

Coupling immune branches balances pathogen clearance and immunosenescence delay.

Abstract

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 framework of coupled innate and adaptive immune responses, namely the integrated immune branch (IIB) model. This model describes dynamics of immune components in both branches, uses a shape-space representation to encode pathogen-specific immune memory, and exhibits three steady states -- health, septic death, and chronic inflammation -- qualitatively similar to clinically-observed immune outcomes. In this model, the immune system (initialized in the health state) is subjected to a sequence of pathogen encounters, and we use the number of prior pathogen encounters as a proxy for the "age" of the immune system. We find that repeated pathogen encounters may trigger a fragility in which any encounter with a novel pathogen will cause the system to irreversibly switch from health to chronic inflammation. This transition is consistent with the onset of "inflammaging", a condition observed in aged individuals who experience chronic low-grade inflammation even in the absence of pathogens. The IIB model predicts that the onset of chronic inflammation strongly depends on the history of encountered pathogens; the timing of onset differs drastically when the same set of infections occurs in a different order. Lastly, the coupling between the innate and adaptive immune branches generates a trade-off between rapid pathogen clearance and a delayed onset of immunosenescence.