Long COVID – also referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition – is a complex, multisystem disorder that develops in a subset of individuals following acute COVID-19. Unlike the acute phase, which typically resolves within four weeks, Long COVID involves persistent and often debilitating symptoms such as fatigue, cognitive impairment, and autonomic dysfunction, which can last for months after the resolution of the acute phase of illness [1]. Estimating the prevalence of Long COVID remains challenging due to inconsistent definitions, heterogeneous symptomatology, and methodological biases across studies [2]. Clinically, Long COVID is increasingly recognized as part of a broader category of conditions known as Post-Acute Infection Syndromes (PAISs), which are chronic disorders that arise following an infectious trigger. Despite differences in the causative pathogens, these syndromes are believed to emerge from overlapping mechanisms, including immune dysregulation, chronic inflammation, and multisystem involvement [3]. However, Long COVID is generally considered as a distinct condition, provisionally linked to COVID-19, and is notable for its complex clinical presentation, distinct immunopathogenic signature, and global epidemiological context [4].

Current evidence suggests that Long COVID arises through a multifactorial process involving persistent immune activation, possible viral antigen retention, and impaired homeostatic resolution.

Affected individuals may exhibit a breakdown in immune tolerance, endothelial imbalance, and signs of autonomic and autoimmune dysregulation [5], [6], [7], [8]. Of particular interest is the interaction between autonomic nervous system (ANS) dysfunction and autoimmunity, which appears to form a self-reinforcing pathogenic loop. Autonomic imbalance, characterized by sympathetic overactivation and impaired vagal tone, can disrupt neuroimmune regulation and attenuate key anti-inflammatory mechanisms, including the cholinergic anti-inflammatory reflex. This dysfunction not only promotes systemic inflammation but may also facilitate the emergence or amplification of autoimmune responses, especially the generation of autoantibodies targeting neural and autonomic membrane receptors [9], [10], [11]. In this context, autoimmunity does not act in isolation but amplifies ANS dysfunction, sustaining a cycle of immune dysregulation, vascular instability, and systemic symptomatology.

Crucially, these processes may be amplified by an age-associated proinflammatory shift in immune regulation, i.e. inflammaging. This immunological state, marked in particular by elevated IL-6 levels and impaired interferon signaling, creates a permissive environment for viral persistence, endothelial dysfunction, and failure to resolve inflammation effectively [12]. These alterations tend to be more pronounced in older adults, especially males, and may contribute not only to greater severity during the acute phase of infection but also to an increased risk of developing Long COVID, by predisposing the immune system to prolonged or dysregulated responses. These complex, interrelated processes make Long COVID not a singular disease, but a syndrome arising at the intersection of viral, immune, and host-specific factors.

In this perspective, we advance a framework that integrates neuroimmune dysregulation, innate immune activation, and autoantibody-mediated mechanisms to explain the persistence and heterogeneity of Long COVID. By highlighting the contribution of cells such as macrophages and neutrophils, and their interactions with the autonomic nervous system, we aim to inform future research efforts toward novel biomarkers and therapeutic targets relevant to Long COVID and related immune-mediated conditions.