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Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.

Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes