Fusion of molecular mimicry, epigenetic predisposition, and new onset GBS: a narrative review of current understanding and future directions

Guillain-Barré syndrome (GBS) is a severe immune-driven polyneuropathy marked by the acute onset of flaccid paralysis, areflexia, and in severe cases, life-threatening autonomic or respiratory failure. Although the clinical presentation and diagnostic criteria are widely established, the precise mechanisms underlying GBS are complex and poorly understood. This review summarizes current literature on the interplay of post-infectious triggers, molecular mimicry, and host susceptibility as influenced by genetic and epigenetic variables. Infectious pathogens such as Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and, more recently, Zika and SARS-CoV-2 operate as initiators via molecular mimicry, in which pathogen antigens imitate peripheral nerve components, triggering the formation of autoreactive antibody and T-cell responses. Acute inflammatory demyelinating polyneuropathy (AIDP) is characterized by demyelination and inflammatory cytokine responses, whereas acute motor axonal neuropathy (AMAN) is associated with ganglioside-targeting antibodies and axonal loss. Genetic polymorphisms, such as those in HLA, TLR4, MMP9, and CD1A, influence vulnerability to the disease and its progression. Given that many patients experience persistent sensory, motor, and autonomic dysfunction despite treatment, the identification of long-term complications highlights the necessity of customized rehabilitation and long-term follow-up. Traditional therapeutic techniques, such as plasma exchange and intravenous immunoglobulin, remain in use, but current trials on complement inhibitors, antibody-degrading enzymes, and mesenchymal stem cell therapies indicate a move toward mechanism-driven approaches. Despite these advances, significant knowledge gaps remain regarding predictors of poor outcomes and underlying causes of persistent disabilities and complications, highlighting the need for continued translational and clinical research.