Aging-induced fragility of the immune system (2005.12402v2)

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.

• The paper introduces the IIB model capturing immune system dynamics, showing that repeated pathogen encounters irreversibly shift health to chronic inflammation.
• The model uses coupled ODEs and a shape-space representation to simulate immunosenescence, detailing innate-adaptive interactions and memory inflation.
• Implications include exploring therapeutic trade-offs to balance pathogen clearance and immune suppression, paving the way for interventions against aging-related dysfunctions.

"Aging-induced fragility of the immune system" (2005.12402)

Introduction

The paper "Aging-induced fragility of the immune system" introduces a comprehensive mathematical framework called the integrated immune branch (IIB) model. This model analyzes the intricate dynamics of aging on the immune system by examining the interactions between innate and adaptive immune responses. Immunological senescence and the ensuing vulnerability to diseases are explored through the lens of repeated pathogen encounters over an organism's lifetime.

Model Description

The core of this study is the construction of the IIB model, incorporating both innate and adaptive immune system elements. It utilizes a shape-space representation to model pathogen-specific immune memory. The system is characterized by three steady states: health, septic death, and chronic inflammation - the latter akin to the inflammaging observed in elderly humans. The model employs coupled ordinary differential equations (ODEs) to simulate the interactions across multiple pathogen encounters, beginning with an initially healthy immune system.

Key Findings and Implications

The IIB model manifests that repeated pathogen encounters induce a fragility, such that any subsequent novel pathogen can shift the system from health to chronic inflammation irreversibly. Importantly, the history of pathogen exposure significantly impacts the onset of immunosenescence. The study reveals variability in immune outcomes, with the timing of such transitions being heavily contingent on past pathogen encounters' sequence.

Immunological memory is modeled by changes in naive and memory T cells over time, which highlights the critical role of memory inflation. This inflation, relying on past pathogen encounters, dictates the adaptive branch's ability to respond to new threats, ultimately guiding the immune system into a fragile state - a behavior consistent with clinical observations of aging immune profiles.

Model Applications and Trade-offs

The framework underlines a significant trade-off between pathogen clearance efficacy and the adaptive immune system's role in suppressing the innate branch's inflammatory responses. Adjustments in the parameters of the IIB model can simulate different scenarios of immune system aging, throwing light on potential therapeutic strategies that mitigate immunosenescence's adverse effects.

Moreover, the model provides quantitative insights into crosstalk between immune components and suggests potential interventions, including enhancing the innate-adaptive interplay to delay or preempt the onset of chronic inflammation.

Conclusion

The IIB model presented in this study is a significant theoretical advancement in modeling aging impacts on immunological functions. By establishing a predictive framework that captures immunosenescence dynamics, the paper sets the stage for future experimental and clinical research dedicated to unraveling the complex interactions fostering aging-induced immune fragility. The model's adaptability in simulating various immune strategies also opens pathways for developing interventions targeting aging-related immune dysfunctions.