{"doi":"10.1093/brain/awad373","title":"Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder","abstract":"Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-β, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.","journal":"Brain","year":2023,"id":326338,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":764933,"name":"Eileah Loda","orcid":null,"position":1,"is_corresponding":false},{"id":303801,"name":"Yanan Chen","orcid":"0000-0001-5510-231X","position":2,"is_corresponding":false},{"id":741876,"name":"Tobias Neef","orcid":"0000-0002-8256-1455","position":3,"is_corresponding":false},{"id":449606,"name":"Andrew C. Cogswell","orcid":"0000-0002-6951-6713","position":4,"is_corresponding":false},{"id":1045886,"name":"Grant Primer","orcid":null,"position":5,"is_corresponding":false},{"id":1045887,"name":"Godwin Joy","orcid":null,"position":6,"is_corresponding":false},{"id":1045888,"name":"Kevin Kaschke","orcid":null,"position":7,"is_corresponding":false},{"id":1045282,"name":"Samantha M. Wills","orcid":"0000-0002-4307-9957","position":8,"is_corresponding":false},{"id":260784,"name":"Joseph R. Podojil","orcid":"0000-0002-5818-8515","position":9,"is_corresponding":false},{"id":303804,"name":"Brian Popko","orcid":"0000-0001-9948-2553","position":10,"is_corresponding":false},{"id":303803,"name":"Roumen Balabanov","orcid":"0000-0002-7235-2078","position":11,"is_corresponding":false},{"id":242015,"name":"Stephen D. Miller","orcid":"0000-0002-9556-0718","position":12,"is_corresponding":false},{"id":665970,"name":"Gabriel Arellano","orcid":"0000-0002-0656-5518","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:08:33.106703Z","pmid":"37931066","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}