AQP4 and MOG Characterize the Autoantibody Landscape of Checkpoint Blockade-Induced Optic Neuritis.

OBJECTIVE

The objective of this study was to investigate the autoantibody profile in immune checkpoint inhibitor (ICI)-induced optic neuritis (CBON) and identify key autoantibodies for diagnostic and therapeutic purposes.

METHODS

In this multicenter retrospective study (January 2020-June 2025), we screened 327 neuro-ophthalmic patients from a bio-repository of 2,321 ICI-treated individuals, identifying 88 patients with CBON across 3 independent cohorts (n = 25, 29, and 34). Longitudinal serum samples (pre-ICI, prodromal, onset, and follow-up) were available for 12 patients. A matched control group of 49 ICI-treated patients without neuro-ophthalmic symptoms was included. Serum samples were analyzed using cell-based assays for 25 neural-specific IgG autoantibodies. Longitudinal samples were assessed for antibody dynamics. Correlations between serostatus and clinical features were evaluated.

RESULTS

Autoantibody profiling revealed a highly focused immune response concentrated against aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG). Seropositivity rates for these antibodies ranged from 17.3% to 32.4% across cohorts, whereas other neural antibodies were detected at markedly lower frequencies (<12%). Longitudinal analysis demonstrated a clear seroconversion pattern, with antibodies undetectable at pre-ICI baseline but emerging at symptom onset, which remained detectable during follow-up in a subset of patients. These AQP4/MOG antibodies were virtually absent in control patients (0-2%).

INTERPRETATION: This study establishes AQP4 and MOG as the dominant autoantibodies in CBON, providing a serological framework for diagnosis and classification. The persistent antibody response following ICI-induced seroconversion offers direction for future mechanistic investigations. ANN NEUROL 2026;100:768-780.