Giunta Sergio, Giuliani Angelica, Sabbatinelli Jacopo, Olivieri Fabiola
Casa di Cura Prof. Nobili (Gruppo Garofalo GHC), Castiglione dei Pepoli, Bologna, Italy.
Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy.
Cytokine Growth Factor Rev. 2025 Jul 5. doi: 10.1016/j.cytogfr.2025.07.001.
Long COVID is a chronic condition that arises after SARS-CoV-2 infection and is characterized by persistent and often debilitating symptoms, such as fatigue, cognitive dysfunction ("brain fog"), dyspnea, and autonomic disturbances. Increasing evidence suggests that Long COVID shares key immunopathological mechanisms with autoimmune diseases, primarily sustained immune dysregulation. In individuals with genetic or immunological susceptibility, SARS-CoV-2 infection can trigger the production of autoantibodies targeting cytokines, membrane receptors, and components of the autonomic nervous system (ANS), thereby disrupting neuroimmune homeostasis. This immune imbalance may impair anti-inflammatory regulatory pathways, such as the cholinergic anti-inflammatory pathway (CAP), and may contribute to a chronic state of inflammation and autoimmunity. One proposed contributor to this process is inflammaging - a chronic, low-grade inflammation associated with aging - which may not only predispose individuals to Long COVID but may also be amplified by the persistent immune activation seen in this condition. In this perspective, we propose a conceptual framework in which inflammaging, immune-tolerance breakdown, and autonomic dysfunctions interact to sustain the pathophysiology of Long COVID. We discuss emerging biomarkers across these axes, including inflammatory cytokines, circulating autoantibodies, immune cell phenotypes, epigenetic modifications, and heart rate variability. Advances in inflammaging-related biomarkers and biological clocks may support early identification of individuals at higher risk for persistent immune and autonomic dysregulation, ultimately informing more precise diagnostic and therapeutic strategies for Long COVID.
长期新冠是一种在感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）后出现的慢性疾病，其特征是出现持续且往往使人衰弱的症状，如疲劳、认知功能障碍（“脑雾”）、呼吸困难和自主神经紊乱。越来越多的证据表明，长期新冠与自身免疫性疾病具有关键的免疫病理机制，主要是持续的免疫失调。在具有遗传或免疫易感性的个体中，SARS-CoV-2感染可触发针对细胞因子、膜受体和自主神经系统（ANS）成分的自身抗体的产生，从而破坏神经免疫稳态。这种免疫失衡可能会损害抗炎调节途径，如胆碱能抗炎途径（CAP），并可能导致慢性炎症和自身免疫状态。这一过程的一个推测促成因素是炎症衰老——一种与衰老相关的慢性低度炎症——它不仅可能使个体易患长期新冠，还可能因这种情况下持续的免疫激活而加剧。从这个角度来看，我们提出了一个概念框架，其中炎症衰老、免疫耐受破坏和自主神经功能障碍相互作用，以维持长期新冠的病理生理学。我们讨论了这些方面新出现的生物标志物，包括炎性细胞因子、循环自身抗体、免疫细胞表型、表观遗传修饰和心率变异性。炎症衰老相关生物标志物和生物钟方面的进展可能有助于早期识别具有持续免疫和自主神经失调高风险的个体，最终为长期新冠提供更精确的诊断和治疗策略。
