Complement‐Regulated Nodal Vulnerability in Guillain–Barré Syndrome and CIDP

The immunobiology of Guillain–Barré syndrome (GBS) has long been organized around a dichotomy: acute motor axonal neuropathy (AMAN) is an antibody‐mediated nodal disorder, whereas acute inflammatory demyelinating polyneuropathy (AIDP) has been interpreted mainly through T‐cell–mediated models of compact‐myelin injury. Four successive findings challenge this separation. Intraneural injection of GBS sera produced demyelination without transfer of immune cells; pathological studies in AIDP localized complement activation to the Schwann‐cell surface before macrophage‐associated myelin stripping. Serum IgG from a substantial subset of patients with AIDP bound nodal or paranodal surface domains; and identification of gelsolin‐3 defined an AIDP subset in which patient IgG, together with active complement, produced nodal disruption before internodal demyelination. Peripheral‐myelin‐reactive T cells further indicate that T‐cell–mediated and antibody‐mediated immunity may coexist. Within this evidence hierarchy, AMAN and a subset of AIDP have distinct initiating targets but converge on nodal dysfunction. CD55 and CD59 are membrane‐bound complement regulators: CD55 limits complement amplification, whereas CD59 prevents assembly of the membrane attack complex. Both are detectable in compact myelin but not at human nodes of Ranvier, revealing a localized discontinuity in complement control. This local absence of complement regulators may influence whether antibody binding progresses to conduction failure, axonal degeneration, or internodal demyelination, but should be regarded as a permissive substrate for injury rather than as evidence of lesion localization. Observations in chronic inflammatory demyelinating polyneuropathy (CIDP) suggest that antibody‐mediated functional injury may precede structural demyelination. This Review proposes complement‐regulated nodal vulnerability to integrate evidence across AMAN and subsets of AIDP and CIDP while preserving differences in targets, tempo, and mechanistic strength.