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. Overall, by considering the complex feedback between immune compartments, our work suggests potential mechanisms for immunosenescence and provides a theoretical framework at the system level and on the scale of an organism’s lifetime to account for clinical observations.

脊椎动物免疫系统的适应性和先天性分支密切合作，以保护生物免受有害病原体的侵害。随着生物体的衰老，其免疫系统会经历免疫衰老，其特征是任一免疫分支的功能下降或功能障碍，这可能导致疾病和死亡。在这项研究中，我们建立了先天性和适应性免疫反应耦合的数学框架，即综合免疫分支（IIB）模型。该模型描述了两个分支中免疫成分的动态，使用形状空间表示来编码病原体特异性免疫记忆，并表现出三个稳态-健康，败血性死亡和慢性炎症-在质量上与临床观察到的免疫结果相似。在这个模型中 免疫系统（在健康状态下初始化）会经历一系列病原体遭遇，并且我们使用先前病原体遭遇的数量作为免疫系统“年龄”的代表。我们发现，反复接触病原体可能会触发脆弱性，其中与新病原体的任何接触都将导致系统不可逆转地从健康转变为慢性炎症。这种转变与“发炎”的发生是一致的，“发炎”是在即使没有病原体的情况下也经历慢性低度发炎的老年个体中观察到的状况。IIB模型预测，慢性炎症的发作在很大程度上取决于所遇病原体的历史。当同一组感染以不同顺序发生时，发作的时间会大大不同。最后，先天性和适应性免疫分支之间的耦合会在病原体快速清除和免疫衰老延迟发作之间产生一个折衷。总体而言，通过考虑免疫区室之间的复杂反馈，我们的工作提出了免疫衰老的潜在机制，并在系统水平和生物体生命周期的规模上提供了理论框架，以应对临床观察。