Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord

Satoru Oji, Eva-Maria Nicolussi, Nathalie Kaufmann, Bleranda Zeka, Kathrin Schanda, Kazuo Fujihara, Zsolt Illes, Charlotte Dahle, Markus Reindl, Hans Lassmann, Monika Bradl

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Abstract

Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.

Original languageEnglish
Article numbere0151244
JournalP L o S One
Volume11
Issue number3
ISSN1932-6203
DOIs
Publication statusPublished - 2016

Fingerprint

Neuromyelitis Optica
Interferon Type I
interferons
spinal cord
Interferons
Neurology
astrocytes
T-cells
Genes
blood-brain barrier
Autoimmune Experimental Encephalomyelitis
Central Nervous System
T-lymphocytes
encephalitis
Rats
lesions (animal)
central nervous system
Up-Regulation
Aquaporin 4
Aquaporins

Keywords

  • Animals
  • B-Lymphocytes
  • Blood-Brain Barrier
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental
  • Gene Expression Regulation
  • Interferon Type I
  • Lymph Nodes
  • Macrophages
  • Microglia
  • Neuromyelitis Optica
  • Neutrophils
  • Rats
  • Rats, Inbred Lew
  • Spinal Cord
  • T-Lymphocytes
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Oji, S., Nicolussi, E-M., Kaufmann, N., Zeka, B., Schanda, K., Fujihara, K., ... Bradl, M. (2016). Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord. P L o S One, 11(3), [e0151244]. https://doi.org/10.1371/journal.pone.0151244
Oji, Satoru ; Nicolussi, Eva-Maria ; Kaufmann, Nathalie ; Zeka, Bleranda ; Schanda, Kathrin ; Fujihara, Kazuo ; Illes, Zsolt ; Dahle, Charlotte ; Reindl, Markus ; Lassmann, Hans ; Bradl, Monika. / Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord. In: P L o S One. 2016 ; Vol. 11, No. 3.
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abstract = "Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.",
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Oji, S, Nicolussi, E-M, Kaufmann, N, Zeka, B, Schanda, K, Fujihara, K, Illes, Z, Dahle, C, Reindl, M, Lassmann, H & Bradl, M 2016, 'Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord', P L o S One, vol. 11, no. 3, e0151244. https://doi.org/10.1371/journal.pone.0151244

Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord. / Oji, Satoru; Nicolussi, Eva-Maria; Kaufmann, Nathalie; Zeka, Bleranda; Schanda, Kathrin; Fujihara, Kazuo; Illes, Zsolt; Dahle, Charlotte; Reindl, Markus; Lassmann, Hans; Bradl, Monika.

In: P L o S One, Vol. 11, No. 3, e0151244, 2016.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord

AU - Oji, Satoru

AU - Nicolussi, Eva-Maria

AU - Kaufmann, Nathalie

AU - Zeka, Bleranda

AU - Schanda, Kathrin

AU - Fujihara, Kazuo

AU - Illes, Zsolt

AU - Dahle, Charlotte

AU - Reindl, Markus

AU - Lassmann, Hans

AU - Bradl, Monika

PY - 2016

Y1 - 2016

N2 - Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.

AB - Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.

KW - Animals

KW - B-Lymphocytes

KW - Blood-Brain Barrier

KW - Disease Models, Animal

KW - Encephalomyelitis, Autoimmune, Experimental

KW - Gene Expression Regulation

KW - Interferon Type I

KW - Lymph Nodes

KW - Macrophages

KW - Microglia

KW - Neuromyelitis Optica

KW - Neutrophils

KW - Rats

KW - Rats, Inbred Lew

KW - Spinal Cord

KW - T-Lymphocytes

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pone.0151244

DO - 10.1371/journal.pone.0151244

M3 - Journal article

C2 - 26990978

VL - 11

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 3

M1 - e0151244

ER -

Oji S, Nicolussi E-M, Kaufmann N, Zeka B, Schanda K, Fujihara K et al. Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord. P L o S One. 2016;11(3). e0151244. https://doi.org/10.1371/journal.pone.0151244