title: Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS.
abstract: In neuromyelitis optica (NMO), astrocytes become targets for pathogenic aquaporin 4 (AQP4)-specific antibodies which gain access to the central nervous system (CNS) in the course of inflammatory processes. Since these antibodies belong to a T cell-dependent subgroup of immunoglobulins, and since NMO lesions contain activated CD4(+) T cells, the question arose whether AQP4-specific T cells might not only provide T cell help for antibody production, but also play an important role in the induction of NMO lesions. We show here that highly pathogenic, AQP4-peptide-specific T cells exist in Lewis rats, which recognize AQP4268-285 as their specific antigen and cause severe panencephalitis. These T cells are re-activated behind the blood-brain barrier and deeply infiltrate the CNS parenchyma of the optic nerves, the brain, and the spinal cord, while T cells with other AQP4-peptide specificities are essentially confined to the meninges. Although AQP4268-285-specific T cells are found throughout the entire neuraxis, they have NMO-typical "hotspots" for infiltration, i.e. periventricular and periaqueductal regions, hypothalamus, medulla, the dorsal horns of spinal cord, and the optic nerves. Most remarkably, together with NMO-IgG, they initiate large astrocyte-destructive lesions which are located predominantly in spinal cord gray matter. We conclude that the processing of AQP4 by antigen presenting cells in Lewis rats produces a highly encephalitogenic AQP4 epitope (AQP4268-285), that T cells specific for this epitope are found in the immune repertoire of normal Lewis rats and can be readily expanded, and that AQP4268-285-specific T cells produce NMO-like lesions in the presence of NMO-IgG.
authors.affiliation: Department for Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Bleranda
authors.initials: B
authors.lastname: Zeka
authors.affiliation: Department for Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Hastermann
authors.affiliation: Department for Neurology, Medical University Graz, Auenbruggerplatz 22, 8036, Graz, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hochmeister
authors.affiliation: Department for Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Kögl
authors.affiliation: Department for Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kaufmann
authors.affiliation: Clinical Department for Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schanda
authors.affiliation: Clinical Department for Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Simone
authors.initials: S
authors.lastname: Mader
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Misu
authors.affiliation: University Hospital for Neurology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Paulus
authors.initials: P
authors.lastname: Rommer
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fujihara
authors.affiliation: Department of Neurology, University of Southern Denmark, Sdr Boulevard 29, Odense, 5000, Denmark.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Illes
authors.affiliation: University Hospital for Neurology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Leutmezer
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.|Department of Neurology, Faculty of Medicine, University of Sao Paulo, Av. Dr. Arnaldo, 455-4th floor (sl 4110), 01246-903, São Paulo, Brazil.
authors.forename: Douglas Kazutoshi
authors.initials: DK
authors.lastname: Sato
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakashima
authors.affiliation: Clinical Department for Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.affiliation: Department for Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: Department for Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria. monika.bradl@meduniwien.ac.at.
authors.forename: Monika
authors.initials: M
authors.lastname: Bradl
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D009471:Neuromyelitis Optica / Q000276:immunology* / Q000473:pathology; D009900:Optic Nerve / Q000276:immunology / Q000473:pathology; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; C515934:Il17a protein, rat; D007074:Immunoglobulin G; D020381:Interleukin-17; D007371:Interferon-gamma
keywords: Aquaporin 4; CNS inflammation; ENMO; Neuromyelitis optica; T cells