Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654751/
https://www.ncbi.nlm.nih.gov/pubmed/26530185
http://dx.doi.org/10.1007/s00401-015-1501-5
_version_ 1782402095152889856
author 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
author_facet 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
author_sort Zeka, Bleranda
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-015-1501-5) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4654751
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-46547512015-11-27 Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS 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 Acta Neuropathol Original Paper 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-015-1501-5) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-11-03 2015 /pmc/articles/PMC4654751/ /pubmed/26530185 http://dx.doi.org/10.1007/s00401-015-1501-5 Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Paper
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
Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS
title Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS
title_full Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS
title_fullStr Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS
title_full_unstemmed Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS
title_short Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS
title_sort highly encephalitogenic aquaporin 4-specific t cells and nmo-igg jointly orchestrate lesion location and tissue damage in the cns
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654751/
https://www.ncbi.nlm.nih.gov/pubmed/26530185
http://dx.doi.org/10.1007/s00401-015-1501-5
work_keys_str_mv AT zekableranda highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT hastermannmaria highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT hochmeistersonja highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT koglnikolaus highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT kaufmannnathalie highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT schandakathrin highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT madersimone highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT misutatsuro highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT rommerpaulus highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT fujiharakazuo highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT illeszsolt highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT leutmezerfritz highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT satodouglaskazutoshi highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT nakashimaichiro highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT reindlmarkus highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT lassmannhans highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns
AT bradlmonika highlyencephalitogenicaquaporin4specifictcellsandnmoiggjointlyorchestratelesionlocationandtissuedamageinthecns