Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS

• Published in: Acta neuropathologica 2015-12, Vol.130 (6), p.783-798
• Main Authors: Zeka, Bleranda, Hastermann, Maria, Hochmeister, Sonja, Kögl, Nikolaus, Kaufmann, Nathalie, Schanda, Kathrin, Mader, Simone, Misu, Tatsuro, Rommer, Paulus, Fujihara, Kazuo, Illes, Zsolt, Leutmezer, Fritz, Sato, Douglas Kazutoshi, Nakashima, Ichiro, Reindl, Markus, Lassmann, Hans, Bradl, Monika
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antigens; Aquaporin 4 - genetics; Aquaporin 4 - metabolism; Aquaporins; Astrocytes - immunology; Astrocytes - pathology; Cell Line; Central Nervous System - immunology; Central Nervous System - pathology; Cytotoxicity; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Humans; Immunoglobulin G - immunology; Immunoglobulins; Interferon-gamma - metabolism; Interleukin-17 - metabolism; Lymphocytes; Medicine; Medicine & Public Health; Nervous system; Neurology; Neuromyelitis Optica - immunology; Neuromyelitis Optica - pathology; Neurosciences; Optic nerve; Optic Nerve - immunology; Optic Nerve - pathology; Original Paper; Pathology; Peptides; Rats, Inbred Lew; Spinal cord; T-Lymphocytes - metabolism; T-Lymphocytes - pathology
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-015-1501-5

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 AQP4 268–285 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 AQP4 268–285 -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 (AQP4 268–285 ), that T cells specific for this epitope are found in the immune repertoire of normal Lewis rats and can be readily expanded, and that AQP4 268–285 -specific T cells produce NMO-like lesions in the presence of NMO-IgG.