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

Abstract

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 Anti-Aquaporin 5 Autoantibody Production by Immunization with a Peptide Derived from the Aquaporin of Prevotella melaninogenica Leads to Reduced Salivary Flow in Mice

“…Therefore, instead of using recombinant PmAqp, we designed a peptide that contains both a T cell epitope and a conserved functional B cell epitope for immunization ( 17 ). Recently, Tsymala et al ( 36 ) reported a rat model that produces AQP4-reactive Abs by immunization with AQP4 mimotopes. These researchers screened a phage display peptide library to search for AQP4 mimotopes recognized by pathogenic AQP4-specific Abs from patients with neuromyelitis optica spectrum disorders ( 36 ).…”

“…Recently, Tsymala et al ( 36 ) reported a rat model that produces AQP4-reactive Abs by immunization with AQP4 mimotopes. These researchers screened a phage display peptide library to search for AQP4 mimotopes recognized by pathogenic AQP4-specific Abs from patients with neuromyelitis optica spectrum disorders ( 36 ). Our approach to identify a mimotope in a homologous bacterial protein was proven to be effective.…”

Autoantibodies in neurological disease

“…AQP4 antibody production was induced with active immunization in Lewis rats using AQP4 mimotopes, which mimic parts of the extracellular loops of AQP4 (ref. 124 ). Some work was also done with T cell transfer models in which highly encephalitogenic AQP4 268–285 -specific T cells infiltrated the CNS and reproduced some clinical features of NMO 77 .…”

Pathogenesis of autoimmune demyelination: from multiple sclerosis to neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody‐associated disease

“…Rats immunised with mimotopes of conformational AQP4 epitopes produce AQP4 Ab detectable in sensitive cell‐based assays; however, no concurrent pathology was observed 218 …”