title: Aquaporin 4-specific T cells and NMO-IgG cause primary retinal damage in experimental NMO/SD.
abstract: Neuromyelitis optica/spectrum disorder (NMO/SD) is a severe, inflammatory disease of the central nervous system (CNS). In the majority of patients, it is associated with the presence of pathogenic serum autoantibodies (the so-called NMO-IgGs) directed against the water channel aquaporin 4 (AQP4), and with the formation of large, astrocyte-destructive lesions in spinal cord and optic nerves. A large number of recent studies using optical coherence tomography (OCT) demonstrated that damage to optic nerves in NMO/SD is also associated with retinal injury, as evidenced by retinal nerve fiber layer (RNFL) thinning and microcystic inner nuclear layer abnormalities. These studies concluded that retinal injury in NMO/SD patients results from secondary neurodegeneration triggered by optic neuritis.However, the eye also contains cells expressing AQP4, i.e., Müller cells and astrocytes in the retina, epithelial cells of the ciliary body, and epithelial cells of the iris, which raised the question whether the eye can also be a primary target in NMO/SD. Here, we addressed this point in experimental NMO/SD (ENMO) induced in Lewis rat by transfer of AQP4268-285-specific T cells and NMO-IgG.We show that these animals show retinitis and subsequent dysfunction/damage of retinal axons and neurons, and that this pathology occurs independently of the action of NMO-IgG. We further show that in the retinae of ENMO animals Müller cell side branches lose AQP4 reactivity, while retinal astrocytes and Müller cell processes in the RNFL/ganglionic cell layers are spared. These changes only occur in the presence of both AQP4268-285-specific T cells and NMO-IgG.Cumulatively, our data show that damage to retinal cells can be a primary event in NMO/SD.
authors: Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, A-1090, Vienna, Austria.
authors: Bleranda
authors: B
authors: Zeka
authors: Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, A-1090, Vienna, Austria.
authors: Maria
authors: M
authors: Hastermann
authors: Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, A-1090, Vienna, Austria.
authors: Nathalie
authors: N
authors: Kaufmann
authors: Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Kathrin
authors: K
authors: Schanda
authors: Medical University Vienna, Section for Bioelectronics, Center for Brain Research, Vienna, Austria.
authors: Marko
authors: M
authors: Pende
authors: Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Tatsuro
authors: T
authors: Misu
authors: Department of Neurology, Medical University Vienna, Wien, Austria.
authors: Paulus
authors: P
authors: Rommer
authors: Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Kazuo
authors: K
authors: Fujihara
authors: Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Ichiro
authors: I
authors: Nakashima
authors: Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors: Charlotte
authors: C
authors: Dahle
authors: Department of Neurology, Medical University Vienna, Wien, Austria.
authors: Fritz
authors: F
authors: Leutmezer
authors: Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Markus
authors: M
authors: Reindl
authors: Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, A-1090, Vienna, Austria.
authors: Hans
authors: H
authors: Lassmann
authors: Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, A-1090, Vienna, Austria. monika.bradl@meduniwien.ac.at.
authors: Monika
authors: 0000-0003-2239-1586
authors: M
authors: Bradl
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D001369:Axons / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000378:metabolism*; D009471:Neuromyelitis Optica / Q000150:complications / Q000276:immunology* / Q000473:pathology; D011917:Rats, Inbred Lew; D012160:Retina / Q000276:immunology* / Q000473:pathology; D012173:Retinitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D007074:Immunoglobulin G