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
Wang et al. (Tue,) studied this question.