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 - Illzs, Zsolt
AU - Dahle, Charlotte
AU - Reindl, Markus
AU - Lassmann, Hans
AU - Bradl, Monika
N1 - Funding Information:
SO, E-MN, NK, BZ, KS, ZI, MR and MB declare no conflict of interest. HL received honoraria for lectures from Teva, Biogen-Idec and Novartis. KF is on the Scientific Advisory Boards of Bayer Schering, Biogen Idec, Mitsubishi Tanabe, Novartis, Chugai, Ono, Nihon, Merck Serono, Alexion, Medimmune, and Medical Review; he received speaker honoraria from Bayer Schering Biogen Idec, Eisai, Mitsubishi Tanabe, Novartis, Astellas, Takeda, Asahi Kasei, Daiichi Sankyo, Nihon, and Cosmic Corporation, and research support from Bayer Schering, Biogen Idec, Asahi Kasei, Chemo-Sero-Therapeutic Research Institute, Teva, Mitsubishi Tanabe, Teijin, Chugai, Ono, Nihon, and Genzyme Japan. CD has received an unrestricted research grant from Biogen and Novartis. CD has received lecture honoraria from Biogen, Teva and Novartis. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.
Publisher Copyright:
© 2016 Oji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/3
Y1 - 2016/3
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.
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U2 - 10.1371/journal.pone.0151244
DO - 10.1371/journal.pone.0151244
M3 - Article
AN - SCOPUS:84962348999
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 3
M1 - e0151244
ER -