Martín-Cruz Leticia, Palomares Oscar
School of Chemistry, Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain.
School of Pharmacy, Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain.
Allergy. 2025 Mar;80(3):677-689. doi: 10.1111/all.16423. Epub 2024 Dec 6.
The high prevalence of allergic diseases reached over the last years is attributed to the complex interplay of genetic factors, lifestyle changes, and environmental exposome. Allergen-specific immunotherapy (AIT) is the single therapeutic strategy for allergic diseases with the potential capacity to modify the course of the disease. Our knowledge of the mechanisms involved in allergy and successful AIT has significantly improved. Recent findings indicate that long-term allergen tolerance upon AIT discontinuation not only relies on the generation of proper adaptive immune responses by the generation of allergen-specific regulatory T and B cells enabling the induction of different isotypes of blocking antibodies but also relies on the restoration of proper innate immune responses. Trained immunity (TRIM) is the process by which innate immune cells acquire memory by mechanisms depending on metabolic and epigenetic reprogramming, thus conferring the host with increased broad protection against infection. This concept was initially explored for infectious diseases, as well as for vaccination against infections, but compelling experimental evidence suggests that TRIM might also play a role in allergy and AIT. Hyperinflammatory innate immune responses in early life, likely due to TRIM maladaptations, lead to aberrant type 2 inflammation-enhancing allergy. However, exposure to farming environments and specific microbes prevents recurrent infections and allergy development, likely due to mechanisms partially depending on TRIM. TRIM-based vaccines and next-generation AIT vaccines inducing metabolic and epigenetic reprogramming in innate immune cells and their precursors have shown protective antiallergic effects. A better understanding of the factors involved in early-life TRIM mechanisms in the context of allergy and the identification and characterization of novel tolerance inducers might well enable the design of alternative TRIM-based allergen vaccines for allergic diseases.
在过去几年中，过敏性疾病的高患病率归因于遗传因素、生活方式改变和环境暴露组的复杂相互作用。变应原特异性免疫疗法（AIT）是过敏性疾病的单一治疗策略，具有改变疾病进程的潜在能力。我们对过敏和成功的AIT所涉及机制的认识有了显著提高。最近的研究结果表明，AIT停止后长期的变应原耐受性不仅依赖于通过产生变应原特异性调节性T细胞和B细胞来诱导不同亚型的阻断抗体，从而产生适当的适应性免疫反应，还依赖于恢复适当的固有免疫反应。训练免疫（TRIM）是固有免疫细胞通过依赖代谢和表观遗传重编程的机制获得记忆的过程，从而使宿主对感染具有更强的广泛保护作用。这一概念最初是针对传染病以及针对感染的疫苗接种进行探索的，但有力的实验证据表明，TRIM也可能在过敏和AIT中发挥作用。生命早期的高炎症性固有免疫反应，可能是由于TRIM适应不良，导致异常的2型炎症增强过敏。然而，接触农业环境和特定微生物可预防反复感染和过敏的发生，可能是由于部分依赖于TRIM的机制。基于TRIM的疫苗和下一代AIT疫苗可诱导固有免疫细胞及其前体发生代谢和表观遗传重编程，已显示出保护性抗过敏作用。更好地了解过敏背景下生命早期TRIM机制所涉及的因素，以及鉴定和表征新的耐受性诱导剂，很可能有助于设计针对过敏性疾病的基于TRIM的替代变应原疫苗。
