Gelsolin‐3: A Novel Myelin Autoantigen in Demyelinating Guillain‐Barré Syndrome

OBJECTIVE: Although immunoglobulin G (IgG) autoantibodies against gangliosides are well-established in axonal Guillain-Barré syndrome (GBS), specific autoantibodies in demyelinating GBS-including acute inflammatory demyelinating polyneuropathy (AIDP) and its variant, bifacial weakness with paresthesias (BFP)-remain unidentified. We aimed to identify novel autoantibodies and clarify the immunological link between AIDP and BFP. METHODS: Immunoprecipitation and mass spectrometry identified gelsolin from BFP serum IgG targeting non-compact, periaxonal myelin surrounding the nodes of Ranvier. Western blotting confirmed specific recognition of gelsolin-3, with no cross-reactivity to the other 2 isoforms. Anti-gelsolin-3 IgG prevalence was screened in 388 GBS patients and correlated with clinical and electrophysiological phenotypes. In vivo pathogenicity was assessed by intraneural IgG injection. RESULTS: Anti-gelsolin-3 IgG antibodies were detected in 24 GBS patients (6%, p < 0.001 vs both disease and healthy controls), with no positive controls. These autoantibodies were strongly associated with facial weakness (63% vs 18%, p < 0.001) and the AIDP electrophysiological classification (73% vs 31%, p < 0.001). In vivo, these IgG1 autoantibodies bound to the nodal regions, triggering complement-dependent nodal injury, voltage-gated sodium channel cluster disruption, and concomitant demyelination. These early pathogenic events preceded macrophage infiltration. INTERPRETATION: Anti-gelsolin-3 IgG1 represents a novel biomarker linking AIDP and BFP. Our results provide the first evidence that AIDP can be formally classified as a nodo-paranodopathy. This IgG1-mediated, complement-dependent nodal injury establishes a unifying paradigm across GBS: nodal complement activation represents a shared mechanism underlying conduction block despite targeting distinct domains-the axolemma in AMAN and myelin components at the axon-myelin interface in AIDP. ANN NEUROL 2026.