Neuroinflammation: a critical bridge linking peripheral pathology and age-related degeneration in myasthenia gravis.

Myasthenia gravis (MG) has traditionally been conceptualized as a peripheral autoimmune disorder primarily mediated by autoantibodies targeting the neuromuscular junction. However, this classical paradigm fails to adequately explain the prevalent central nervous system (CNS) manifestations in patients, including profound fatigue and cognitive impairment. Emerging evidence indicates that neuroinflammation plays a pivotal role in bridging peripheral pathology and central symptoms. Systemic inflammatory mediators can breach the compromised blood-brain barrier (BBB) or activate CNS-resident microglia and astrocytes via neuroimmune pathways, thereby initiating neuroinflammatory cascades. Once activated, these glial cells release pro-inflammatory cytokines and reactive oxygen species (ROS), which impair neuronal energy metabolism, synaptic plasticity, and neurotransmitter homeostasis, directly contributing to central symptomatology. Critically, neuroinflammation serves as a key mechanistic bridge linking the peripheral autoimmune pathology of MG with age-related neurodegenerative changes. With advancing age, immunosenescence manifests as diminished T-cell repertoire diversity, impaired regulatory T-cell function, and chronic low-grade inflammation (inflammaging), which not only increases susceptibility to MG but also provides a permissive environment for the initiation and perpetuation of neuroinflammation. Concurrently, age-related degenerative alterations at the neuromuscular junction-including reduced acetylcholine receptor (AChR) density and mitochondrial dysfunction-decrease the safety margin of neuromuscular transmission, rendering elderly patients more vulnerable to autoantibody-mediated attack. A vicious cycle emerges among neuroinflammation, mitochondrial dysfunction, and oxidative stress, which synergistically accelerate neuronal damage and apoptosis. Consequently, the clinical phenotype, therapeutic response, and prognosis of MG demonstrate marked age-dependency. Late-onset MG patients typically experience more severe disease courses and poorer outcomes, attributable in part to the compounding effects of immunosenescence, underlying neurodegeneration, and neuroinflammation. Elucidating the central role of neuroinflammation and its intricate interactions with age-related pathological processes holds significant theoretical and clinical implications for developing novel neuroprotective strategies targeting CNS symptoms in MG and achieving personalized, precision medicine tailored to patients across different age groups.