Willmann Katharina, Moita Luis F
J Clin Invest. 2025 Aug 1;135(15). doi: 10.1172/JCI191645.
The immune system must identify genuine threats and avoid reacting to harmless microbes because immune responses, while critical for organismal survival, can cause severe damage and use substantial energy resources. Models for immune response initiation have mostly focused on the direct sensing of microorganisms through pattern recognition receptors. Here, we summarize key features of the leading models of immune response initiation and identify issues they fail to solve individually, including how the immune system distinguishes between pathogens and commensals. We hypothesize and argue that surveillance of disruption to organismal homeostasis and core cellular activities is central to detecting and resolving relevant threats effectively, including infection. We propose that hosts use pattern recognition receptors to identify microorganisms and use sensing of homeostasis disruption to assess the level of threat they pose. We predict that both types of information can be integrated through molecular coincidence detectors (such as inflammasomes or others not yet discovered) and used to determine whether to initiate an immune response, its quality, and its magnitude. This conceptual framework may guide the identification of novel targets and therapeutic strategies to improve the progression and outcome of infection, cancer, autoimmunity, and chronic conditions in which inflammation plays a critical role.
免疫系统必须识别真正的威胁并避免对无害微生物产生反应，因为免疫反应虽然对机体生存至关重要，但可能会造成严重损害并消耗大量能量资源。免疫反应启动的模型大多集中在通过模式识别受体直接感知微生物。在这里，我们总结了免疫反应启动主要模型的关键特征，并指出它们各自未能解决的问题，包括免疫系统如何区分病原体和共生菌。我们假设并认为，监测机体稳态和核心细胞活动的破坏对于有效检测和解决相关威胁（包括感染）至关重要。我们提出，宿主利用模式识别受体识别微生物，并利用对稳态破坏的感知来评估它们所构成的威胁程度。我们预测，这两种类型的信息可以通过分子巧合探测器（如炎性小体或其他尚未发现的探测器）进行整合，并用于确定是否启动免疫反应、其质量和强度。这个概念框架可能会指导识别新的靶点和治疗策略，以改善感染、癌症、自身免疫性疾病以及炎症起关键作用的慢性疾病的进展和结局。
