1. Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS.
- Author
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Zeka B, Hastermann M, Hochmeister S, Kögl N, Kaufmann N, Schanda K, Mader S, Misu T, Rommer P, Fujihara K, Illes Z, Leutmezer F, Sato DK, Nakashima I, Reindl M, Lassmann H, and Bradl M
- Subjects
- Animals, Aquaporin 4 genetics, Astrocytes immunology, Astrocytes pathology, Cell Line, Central Nervous System pathology, Encephalomyelitis, Autoimmune, Experimental pathology, Humans, Interferon-gamma metabolism, Interleukin-17 metabolism, Neuromyelitis Optica pathology, Optic Nerve immunology, Optic Nerve pathology, Rats, Inbred Lew, T-Lymphocytes pathology, Aquaporin 4 metabolism, Central Nervous System immunology, Encephalomyelitis, Autoimmune, Experimental immunology, Immunoglobulin G immunology, Neuromyelitis Optica immunology, T-Lymphocytes metabolism
- 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.
- Published
- 2015
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