Can different autoantibodies affect distinct neural compartments without proving symptom causation from serum positivity alone?

Autoantibodies can produce anatomically selective injury when they recognize accessible, appropriately localized neural antigens. However, the claim as a whole is only partly established because direct evidence differs substantially by antibody class, and detection in serum is not equivalent to symptom causation.

Compartment-specific biological effects

• Neuronal-surface antibodies: The strongest example is LGI1. Patient antibodies can disrupt the LGI1–ADAM22/ADAM23 synaptic complex or promote its internalization, impairing synaptic signaling and increasing neuronal excitability. Hippocampal neuropil labeling and hippocampal experimental models support a corresponding neuronal/synaptic site of action.
• Ganglioside antibodies: GM1 is localized at nodal/paranodal axolemma and Schwann-cell membranes. Anti-GM1 antibodies have experimental support for complement-mediated nodal and glial injury, conduction failure, and secondary axonal damage. Anti-GM2 can bind Schwann cells and activate complement in vitro, though its pathogenic role is less firmly characterized.
• AQP4-IgG: AQP4 is concentrated at astrocyte endfeet at CNS vascular and pial interfaces. As an IgG1 antibody, AQP4-IgG activates classical complement, causing astrocyte injury; myelin and neuronal injury may then occur secondarily. This is not evidence that neurons are the primary target.

Cerebellar targets and interpretation

• Direct evidence was not identified for a distinct, validated class of cerebellar/Purkinje-target autoantibodies with demonstrated localization and pathogenic effects. Secondary cerebellar injury in AQP4-associated disease does not establish such antibodies.
• Serum findings require phenotype concordance and, when indicated, CSF and independent confirmation. Serum cell-based-assay-only positive predictive values ranged from 69.7% for NMDAR to 91.8% for LGI1, rising to 94.3%–100% after tissue-based confirmation.

Bottom line

• Antibody-mediated compartment-specific pathology is well supported for LGI1, GM1, and AQP4-IgG, but serum positivity alone cannot establish that a detected antibody is responsible for an individual’s symptoms.