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

Bleranda Zeka, Maria Hastermann, Sonja Hochmeister, Nikolaus Kögl, Nathalie Kaufmann, Kathrin Schanda, Simone Mader, Tatsuro Misu, Paulus Rommer, Kazuo Fujihara, Zsolt Illes, Fritz Leutmezer, Douglas Kazutoshi Sato, Ichiro Nakashima, Markus Reindl, Hans Lassmann, Monika Bradl

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalActa Neuropathologica
Volume130
Issue number6
Pages (from-to)783-98
Number of pages16
ISSN0001-6322
DOIs
Publication statusPublished - Dec 2015

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Neuromyelitis Optica
Central Nervous System
Optic Nerve
Peptide T
Meninges
T-Lymphocyte Epitopes

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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. In: Acta Neuropathologica. 2015 ; Vol. 130, No. 6. pp. 783-98.
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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.",
author = "Bleranda Zeka and Maria Hastermann and Sonja Hochmeister and Nikolaus K{\"o}gl and Nathalie Kaufmann and Kathrin Schanda and Simone Mader and Tatsuro Misu and Paulus Rommer and Kazuo Fujihara and Zsolt Illes and Fritz Leutmezer and Sato, {Douglas Kazutoshi} and Ichiro Nakashima and Markus Reindl and Hans Lassmann and Monika Bradl",
year = "2015",
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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 & Bradl, M 2015, 'Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS', Acta Neuropathologica, vol. 130, no. 6, pp. 783-98. https://doi.org/10.1007/s00401-015-1501-5

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.

In: Acta Neuropathologica, Vol. 130, No. 6, 12.2015, p. 783-98.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS

AU - Zeka, Bleranda

AU - Hastermann, Maria

AU - Hochmeister, Sonja

AU - Kögl, Nikolaus

AU - Kaufmann, Nathalie

AU - Schanda, Kathrin

AU - Mader, Simone

AU - Misu, Tatsuro

AU - Rommer, Paulus

AU - Fujihara, Kazuo

AU - Illes, Zsolt

AU - Leutmezer, Fritz

AU - Sato, Douglas Kazutoshi

AU - Nakashima, Ichiro

AU - Reindl, Markus

AU - Lassmann, Hans

AU - Bradl, Monika

PY - 2015/12

Y1 - 2015/12

N2 - 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.

AB - 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.

U2 - 10.1007/s00401-015-1501-5

DO - 10.1007/s00401-015-1501-5

M3 - Journal article

C2 - 26530185

VL - 130

SP - 783

EP - 798

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 6

ER -