Periodontitis is bidirectionally associated with systemic inflammatory disorders. The prevalence and severity of this oral disease and linked comorbidities increases with aging. Here, we review two newly emerged concepts, trained innate immunity (TII) and clonal hematopoiesis of indeterminate potential (CHIP), which together support a potential hypothesis on how periodontitis affects and is affected by comorbidities and why the susceptibility to periodontitis and comorbidities increases with aging. Given that chronic diseases are largely triggered by the action of inflammatory immune cells, modulation of their bone marrow precursors, the hematopoietic stem and progenitor cells (HSPCs), may affect multiple disorders that emerge as comorbidities. Such alterations in HSPCs can be mediated by TII and/or CHIP, two non-mutually exclusive processes sharing a bias for enhanced myelopoiesis and production of innate immune cells with heightened proinflammatory potential. TII is a state of elevated immune responsiveness based on innate immune (epigenetic) memory. Systemic inflammation can initiate TII in the bone marrow via sustained rewiring of HSPCs, which thereby display a skewing toward the myeloid lineage, resulting in generation of hyper-reactive or “trained” myeloid cells. CHIP arises from aging-related somatic mutations in HSPCs, which confer a survival and proliferation advantage to the mutant HSPCs and give rise to an outsized fraction of hyper-inflammatory mutant myeloid cells in the circulation and tissues. This review discusses emerging evidence that supports the notion that TII and CHIP may underlie a causal and age-related association between periodontitis and comorbidities. A holistic mechanistic understanding of the periodontitis-systemic disease connection may offer novel diagnostic and therapeutic targets for treating inflammatory comorbidities.

中文翻译：

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适应不良的训练免疫和克隆造血作为牙周炎和炎症合并症之间的潜在机制联系

牙周炎与全身炎症性疾病双向相关。这种口腔疾病和相关合并症的患病率和严重程度随着年龄的增长而增加。在这里，我们回顾了两个新出现的概念，训练有素的先天免疫 (TII) 和不确定潜能的克隆造血 (CHIP)，它们共同支持一个潜在的假设，即牙周炎如何影响并存病，以及为什么牙周炎和并存病的易感性随着老化。鉴于慢性疾病主要是由炎症免疫细胞的作用引发的，调节它们的骨髓前体细胞，即造血干细胞和祖细胞 (HSPC)，可能会影响作为合并症出现的多种疾病。HSPC 中的此类改变可由 TII 和/或 CHIP 介导，两个非相互排斥的过程都倾向于增强骨髓细胞生成和产生具有更高促炎潜力的先天免疫细胞。TII 是一种基于先天免疫（表观遗传）记忆的免疫反应性升高的状态。全身性炎症可以通过 HSPC 的持续重新布线在骨髓中启动 TII，从而显示出向骨髓谱系的倾斜，导致产生过度反应或“训练有素”的骨髓细胞。CHIP 源于 HSPC 中与衰老相关的体细胞突变，它赋予突变体 HSPC 生存和增殖优势，并在循环和组织中产生超大比例的超炎症突变髓细胞。这篇综述讨论了支持 TII 和 CHIP 可能是牙周炎和合并症之间因果和年龄相关关联这一概念的新证据。对牙周炎-全身性疾病联系的整体机制理解可能为治疗炎症性合并症提供新的诊断和治疗目标。