Interferon-gamma controls pathogenic T-helper 17 and B cells in a new Aquaporin-4 induced experimental autoimmune encephalomyelitis

Abstract Background Neuromyelitis Optica (NMO) is an autoimmune disease of the Central Nervous System (CNS) mediated by Th17 cells and antibody response to the water channel protein Aquaporin 4 (AQP4), leading to chronic damage of the optic nerves and spinal cord. NMO animal models are substandard inducing disease inconsistently and weakly. Objectives Characterize a new NMO mouse model, which best represents the human disease in terms of incidence and chronicity of the disease, severity of symptoms and underlying molecular mechanisms. Methods C57BL/6 (WT) and IFN-γ receptor knockout (R-KO) mice were immunized subcutaneously with the AQP4201–220 peptide in Complete Freund Adjuvant and treated with pertussis toxin at day 0 and +2. WT were treated weakly with neutralizing anti-IFN-γ antibodies. mRNA expression and flow cytometry analysis of infiltrating CNS cells were performed. CNS histopathology was determined by immunofluorescence. In vivo B-cell depletion was made using anti-CD20 antibodies. Results WT mice treated with anti-IFN-γ and RKO mice showed ascendant paralysis starting from the tail to complete hind limb paralysis. Mice showed increased disease incidence and symptoms were more severe and chronic. CNS IL-17 expressing T cells and Th17 associated genes were upregulated in the absence of IFN-γ. CSN histological analysis showed an increased presence of T and B cells in lesion sites, associated with astrocytes and myelin loss. B-cell depletion in AQP4 primed RKO mice, diminished the incidence and severity of the disease confirming B cell pathogenicity. Conclusions AQP4 mouse model is strictly regulated by IFN-γ and its signaling, which control the disease progression and severity, by restraining pathogenic Th17 and B cells. Supported by grant from NIH (R21 Grant 12878760)