Publications by authors named "Norio Chihara"

31 Publications

Paraneoplastic Neuromyelitis Optica Spectrum Disorder Associated with Atypical Thymic Carcinoid: A Case Report.

Ann Thorac Cardiovasc Surg 2021 Apr 27. Epub 2021 Apr 27.

Division of Thoracic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease, occasionally accompanied by malignant tumors. Immunosuppressive therapy is the mainstay treatment for idiopathic NMOSD; no guidelines have been published for paraneoplastic NMOSD because it is rarely reported in the literature. We report a rare case of a 67-year-old man with paraneoplastic NMOSD associated with thymic carcinoid whose cells expressed aquaporin-4 antibody. After surgical resection, the patient's symptoms improved, and serum aquaporin-4 autoantibody turned negative. We believe that radiographic examination for mediastinal tumors in patients with NMOSD is necessary because thymic epithelial tumors could have a role in the pathogenesis of paraneoplastic NMOSD. After mediastinal tumor has been detected, they should be surgically resected to improve neurological symptoms.
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http://dx.doi.org/10.5761/atcs.cr.20-00354DOI Listing
April 2021

Efficacy for the Annual Relapse Rate after the Immunosuppressive Therapy in Patients Associated with Anti-AQP4 or Anti-MOG Antibody-Positive Optic Neuritis.

J Ophthalmol 2020 17;2020:8871146. Epub 2020 Nov 17.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Purpose: Although oral prednisolone is the first-line treatment for preventing recurrent optic neuritis (ON) after the completion of acute-phase treatment, especially anti-aquaporin 4 (AQP4) antibody-positive ON, and anti-myelin oligodendrocyte glycoprotein (MOG) antibody-positive ON, some patients experience relapses. Immunosuppressants could be effective in reducing the recurrence rate for neuromyelitis optica spectrum disorder and MOG antibody-related diseases, but there have been few studies addressing this issue focusing on the changes in ophthalmic parameters. The objective of the study was to analyze the impact of off-label uses of immunosuppressants to reduce recurrent ON.

Design: Retrospective observational study, clinical case series.

Methods: We reviewed the medical charts of 11 cases (22 eyes) who underwent immunosuppressive therapy in Kobe University Hospital and compared the annualized relapse rate (ARR) before and after immunosuppressive therapy. We also evaluated the dosage of prednisolone, complications of immunosuppressants, and other visual functional ophthalmologic parameters.

Results: Eleven cases in total had AQP4 antibody (9 cases) and/or MOG antibody (3 cases). One case was double positive for these antibodies. Nine patients received azathioprine and two received mycophenolate mofetil as an initial immunosuppressive therapy. The median duration of immunosuppressant treatment was 2.8 years. The median ON ARR before immunosuppressive therapy was 0.33, and this decreased significantly to 0 after the therapy ( = 0.02). The dose of prednisolone was reduced from 17.8 ± 7.1 mg/day before to 5.8 ± 2.2 mg/day after immunosuppressive therapy ( < 0.01). Although two patients presented with mild elevation of liver enzymes and nausea, all patients were able to continue taking the immunosuppressants.

Conclusions: Immunosuppressants can potentially decrease relapses and steroid dosage in patients with anti-AQP4 or MOG antibody-positive ON without severe adverse events and the exacerbation of visual acuities.
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http://dx.doi.org/10.1155/2020/8871146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883711PMC
November 2020

[A case of spinal cord infarction accompanied with neuromyelitis optica spectrum pathophysiology].

Rinsho Shinkeigaku 2021 Feb 26;61(2):127-131. Epub 2021 Jan 26.

Division of Neurology, Kobe University Graduate School of Medicine.

We report a 60-year-old woman who developed spinal cord infarction (SCI) with anti-aquaporin (AQP) 4 antibody seropositive. She was admitted to our hospital with acute onset of flaccid paraparesis and urinary disturbances that completed within a few minutes after acute pain in her lower back. Neurological examination revealed flaccid paraparesis, bladder and bowel dysfunction and dissociated sensory loss below the level of Th11 spinal cord segment. Diffusion weighted imaging (DWI) and T-wighted imaging (TWI) of thoracic spine MRI showed high signal intensity in the spinal cord between Th9 and Th12 vertebral levels with decreased apparent diffusion coefficient (ADC). We diagnosed her as having SCI. Thereafter the serum examination on admission was reported as positive for anti-aquaporin 4 (AQP4) antibody. Cerebrospinal fluid (CSF) analysis revealed pleocytosis, and the spinal cord lesions became enlarged in MRI on 12 days after the onset. We, therefore, suspected that the pathophysiology of neuromyelitis optica spectrum disorder (NMOSD) accompanied SCI. The patient underwent two courses of high dose intravenous methylprednisolone (IVMP) for three days (1 g/day). Her neurological symptoms did not improve significantly, but the size of TWI MRI high signal lesion improved to that of the initial MRI scan. Anti-AQP4 antibody seropositivity may have modified the SCI pathology in the present patient.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001535DOI Listing
February 2021

An IL-27-Driven Transcriptional Network Identifies Regulators of IL-10 Expression across T Helper Cell Subsets.

Cell Rep 2020 11;33(8):108433

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms, including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative (Irf9 and Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators, Prdm1 and Maf, that cooperatively drive the expression of signature genes induced by IL-27 in type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3 regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying ll10-deficient mice. Our work provides insights into IL-27-driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.
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http://dx.doi.org/10.1016/j.celrep.2020.108433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771052PMC
November 2020

At the dawn of personalised medicine in neuromyelitis optica spectrum disorder: the impact of the disease activity on pregnancy.

Authors:
Norio Chihara

J Neurol Neurosurg Psychiatry 2020 Nov 20. Epub 2020 Nov 20.

Neurology, Kobe Univerisity, Kobe, Japan

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http://dx.doi.org/10.1136/jnnp-2020-324602DOI Listing
November 2020

A case of neurosarcoidosis presenting with multiple cranial neuropathies.

Am J Ophthalmol Case Rep 2020 Sep 27;19:100796. Epub 2020 Jun 27.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Purpose: We report a case of neurosarcoidosis that presented simultaneously with oculomotor nerve palsy, contralateral abducens nerve palsy, and paresthesia of both lower limbs.

Observations: A 69-year-old Japanese woman who suffered from repeated diplopia and lower-limb paresthesia was referred to our hospital. Ophthalmic findings included oculomotor nerve and contralateral abducens nerve palsies. No remarkable abnormalities were detected via enhanced brain magnetic resonance imaging (MRI), chest X-ray, and cerebrospinal fluid analysis. Chest computed tomography (CT) was performed to exclude neoplastic lesions; this revealed right hilar lymphadenopathy, and positron emission tomography MRI showed strong 18-F fluorodeoxyglucose uptake in the hilar lymph node. Biopsy of the lymph node showed non-caseating epithelioid granulomatous tissue, leading to a diagnosis of probable neurosarcoidosis. After the initiation of oral prednisolone treatment, the patient experienced complete remission without any recurrence.

Conclusions And Importance: When examining a patient presenting with multiple cranial neuropathies of unknown cause, neurosarcoidosis should be considered as a differential diagnosis and chest CT should be performed even when the chest X-ray and angiotensin-converting enzyme appears normal.
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http://dx.doi.org/10.1016/j.ajoc.2020.100796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330492PMC
September 2020

Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Brain 2020 05;143(5):1431-1446

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.
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http://dx.doi.org/10.1093/brain/awaa102DOI Listing
May 2020

Eosinophilic Pneumonia Associated With Natalizumab In A Patient With Multiple Sclerosis: A Case Report And Literature Review.

Ther Clin Risk Manag 2019 1;15:1283-1289. Epub 2019 Nov 1.

Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.

We herein report the case of a 39-year-old Japanese female with eosinophilic pneumonia associated with natalizumab. The patient with bronchial asthma had multiple sclerosis and was treated using natalizumab. The patient was referred to our department because of a persistent cough. A chest computed tomography (CT) scan revealed bilateral patchy consolidation surrounded by ground-glass opacity. A bronchoalveolar lavage (BAL) was performed. Eosinophil levels in the BAL fluid were increased and the patient was consequently diagnosed as eosinophilic pneumonia associated with natalizumab. Therefore, natalizumab treatment was discontinued. Subsequent chest CT findings showed a remarkable improvement without any treatment.
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http://dx.doi.org/10.2147/TCRM.S225832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831985PMC
November 2019

Plasmablasts and neuroimmunological disorders.

Immunol Med 2019 Sep 29;42(3):103-107. Epub 2019 Aug 29.

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Neuroimmunological disorders are diseases of the nervous system, wherein the immune system contributes to tissue injury and repair. Autoantibodies are useful biomarkers for the diagnosis of neuroimmunological disorders and evaluating disease activity. Emerging evidence indicates that several autoantibodies are associated with neuroimmunological diseases. While the differential diagnostic process based on the positivity of autoantibodies has been established, the mechanisms underlying the production of these autoantibodies still need to be investigated. Autoantibodies are not necessarily pathogenic, and some are involved in immune regulation. Autoantibody-producing plasmablasts are involved in both pathogenicity and immune regulation of diseases. Thus, comparisons between these pathogenic and regulatory plasmablasts may give us clues understanding the machinery of autoantibody-related neuroimmunological diseases. Moreover, elucidating these mechanisms may allow the development of new immune-modulatory therapies to facilitate regulatory B cell function in neuroimmunological diseases. To this end, herein the roles of plasmablasts in neuroimmunological disorders are discussed.
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http://dx.doi.org/10.1080/25785826.2019.1659476DOI Listing
September 2019

Validation of the Guy's Neurological Disability Scale as a screening tool for cognitive impairment in multiple sclerosis.

Mult Scler Relat Disord 2019 Oct 12;35:272-275. Epub 2019 Aug 12.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Objectives: Cognitive impairment is a common symptom affecting daily activities of the patients with multiple sclerosis (MS). Various cognitive evaluation tests are available, yet most of them are complex and time-consuming to perform in outpatient clinics. In this study, we aimed to validate a Japanese version of the Guy's Neurological Disability Scale (GNDS) as a user-friendly tool to evaluate comprehensive disabilities in MS including cognitive function.

Methods: Questions of the GNDS were translated into Japanese and named GNDS-J. Forty-four patients were examined by the Expanded Disability Status Scale (EDSS), the Paced Auditory Serial Addition Test (PASAT), the Symbol Digit Modalities Test (SDMT), the vitality scale, and the GNDS-J in the same time at remission state.

Results: The GNDS-J scores correlated with the EDSS scores(r = 0.61), and inversely correlated with the PASAT2/1(r=-0.56/-0.49) scores and the SDMT scores (r=-0.68), whereas the GNDS-J did not show any correlation with the vitality scale. Furthermore, eleven patients were evaluated over 5 years for changes in these scores. Eight out of 11 patients had exacerbated GNDS, and all of these patients experienced clinical relapse during this period.

Conclusion: The GNDS-J is a valid tool to perform in outpatient clinics, which could provide a comprehensive scale for evaluating symptoms of MS, thus the disease activity by repeated measure.
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http://dx.doi.org/10.1016/j.msard.2019.08.012DOI Listing
October 2019

[Increased disease activity in a case of multiple sclerosis after switching treatment from fingolimod to natalizumab].

Rinsho Shinkeigaku 2019 Aug 23;59(8):536-540. Epub 2019 Jul 23.

Division of Neurology, Kobe University Graduate School of Medicine.

A 42-year-old woman diagnosed with multiple sclerosis (MS) at the age of 37 was initially treated with interferon-β IM. The frequency of clinical relapses was twice in 4 years. At the age of 41, due to difficulty in administering muscle injections, an oral medication fingolimod was started. However, it was discontinued after a month due to decreased lymphocyte count, following which natalizumab was administered. The number of relapses increased 3 times in eleven months, and the number of T lesions on the MRI increased from 12 to 23. Natalizumab was discontinued because the test for the anti-natalizumab antibody was positive. It was suspected that both, the rebound syndrome caused by fingolimod cessation and the drug neutralization by anti-natalizumab antibodies, were associated with the exacerbation of disease activity. Thus, careful attention should be paid to potential occurrence of these events post switching between disease-modifying drugs for treating MS with high activity.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001307DOI Listing
August 2019

Diaphragm involvement in immune checkpoint inhibitor-related myositis.

Muscle Nerve 2019 10 7;60(4):E23-E25. Epub 2019 Aug 7.

Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan.

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http://dx.doi.org/10.1002/mus.26640DOI Listing
October 2019

A 39-year-old female with cerebellar tumor and visual disturbance.

Brain Pathol 2018 11;28(6):1027-1028

Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

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http://dx.doi.org/10.1111/bpa.12668DOI Listing
November 2018

Paraneoplastic NMOSD associated with EG junction adenocarcinoma expressing unprotected AQP4.

Neurol Neuroimmunol Neuroinflamm 2018 Sep 9;5(5):e482. Epub 2018 Jul 9.

Division of Neurology (A.S., N.C., Y.T., T.U., K.S., T.T.), Kobe University Graduate School of Medicine; Department of Gastrointestinal Surgery (T.N.), Kobe University Graduate School of Medicine; and Department of Neurology (T.T.), Graduate School of Medicine, The University of Tokyo, Japan.

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http://dx.doi.org/10.1212/NXI.0000000000000482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039212PMC
September 2018

Induction and transcriptional regulation of the co-inhibitory gene module in T cells.

Nature 2018 06 13;558(7710):454-459. Epub 2018 Jun 13.

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4 T cells promotes autoimmunity, whereas sustained overexpression on CD8 T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4 and CD8 T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
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http://dx.doi.org/10.1038/s41586-018-0206-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130914PMC
June 2018

Japanese de novo mutation diagnosed by exome analysis: A case report.

Neurol Clin Neurosci 2017 07 29;5(4):131-133. Epub 2017 Jun 29.

Division of Neurology Kobe University Graduate School of Medicine Kobe Hyogo Japan.

A 40-year-old Japanese woman presented with slowly progressing parkinsonism in adulthood. She had a history of epilepsy with intellectual disability in childhood. In a head magnetic resonance scan, T2-weighted imaging showed low signal intensity areas in the globus pallidus and the substantia nigra; T1-weighted imaging showed a halo in the nigra. Because the patient's symptoms and history were similar to those of patients with neurodegeneration with brain iron accumulation, we ran an exome analysis to investigate neurodegeneration with brain iron accumulation-associated genes. We identified a c.700 C>T (p.Arg 234*) mutation in exon 9 of the gene, which had not been reported in Japanese patients with beta-propeller protein-associated neurodegeneration (a neurodegeneration with brain iron accumulation subtype). Sanger sequencing confirmed a heterozygous mutation in this patient that was absent in both her parents, so it was judged to be a de novo nonsense mutation.
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http://dx.doi.org/10.1111/ncn3.12132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575553PMC
July 2017

Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity.

J Exp Med 2016 10 26;213(11):2489-2501. Epub 2016 Sep 26.

Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115

Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation. CD4 T cells from PROCR low expressor mutant mice readily differentiated into Th17 cells, whereas addition of the PROCR ligand, activated protein C, inhibited Th17 differentiation in vitro. In addition, PROCR acted as a negative regulator of Th17 pathogenicity in that it down-regulated expression of several pathogenic signature genes, including IL-1 and IL-23 receptors. Furthermore, T cell-specific deficiency of PROCR resulted in the exacerbation of experimental autoimmune encephalomyelitis (EAE) and higher frequencies of Th17 cell in vivo, indicating that PROCR also inhibits pathogenicity of Th17 cells in vivo. PROCR thus does not globally inhibit Th17 responses but could be targeted to selectively inhibit proinflammatory Th17 cells.
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http://dx.doi.org/10.1084/jem.20151118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068226PMC
October 2016

Differentiation and Characterization of Tr1 Cells.

Curr Protoc Immunol 2016 Apr 1;113:3.27.1-3.27.10. Epub 2016 Apr 1.

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Regulatory T cell-mediated suppression serves as a pivotal mechanism of negative regulation of immune-mediated inflammation. Type 1 regulatory T cells (Tr1 cells) are an important subset of CD4+ T cells that prevent excessive inflammatory responses and maintain immune tolerance. The anti-inflammatory role of Tr1 cells is mediated in part by their production of interleukin 10 (IL-10), which dampens the function of both antigen-presenting cells and antigen-specific effector T cells. Additionally, Tr1 cells can kill effector and myeloid cells through the perforin-granzyme B pathway. Adoptive transfer of in vitro differentiated Tr1 cells can be used to suppress autoimmune tissue inflammation in vivo. This unit describes the in vitro stimulation of naïve murine CD4+ T cells using IL-27 to generate IL-10-producing Tr1 cells.
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http://dx.doi.org/10.1002/0471142735.im0327s113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933847PMC
April 2016

Dysbiosis in the Gut Microbiota of Patients with Multiple Sclerosis, with a Striking Depletion of Species Belonging to Clostridia XIVa and IV Clusters.

PLoS One 2015 14;10(9):e0137429. Epub 2015 Sep 14.

Department of Immunology, National Institute of Neuroscience, 4-1-1, Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.

The pathogenesis of multiple sclerosis (MS), an autoimmune disease affecting the brain and spinal cord, remains poorly understood. Patients with MS typically present with recurrent episodes of neurological dysfunctions such as blindness, paresis, and sensory disturbances. Studies on experimental autoimmune encephalomyelitis (EAE) animal models have led to a number of testable hypotheses including a hypothetical role of altered gut microbiota in the development of MS. To investigate whether gut microbiota in patients with MS is altered, we compared the gut microbiota of 20 Japanese patients with relapsing-remitting (RR) MS (MS20) with that of 40 healthy Japanese subjects (HC40) and an additional 18 healthy subjects (HC18). All the HC18 subjects repeatedly provided fecal samples over the course of months (158 samples in total). Analysis of the bacterial 16S ribosomal RNA (rRNA) gene by using a high-throughput culture-independent pyrosequencing method provided evidence of a moderate dysbiosis in the structure of gut microbiota in patients with MS. Furthermore, we found 21 species that showed significant differences in relative abundance between the MS20 and HC40 samples. On comparing MS samples to the 158 longitudinal HC18 samples, the differences were found to be reproducibly significant for most of the species. These taxa comprised primarily of clostridial species belonging to Clostridia clusters XIVa and IV and Bacteroidetes. The phylogenetic tree analysis revealed that none of the clostridial species that were significantly reduced in the gut microbiota of patients with MS overlapped with other spore-forming clostridial species capable of inducing colonic regulatory T cells (Treg), which prevent autoimmunity and allergies; this suggests that many of the clostridial species associated with MS might be distinct from those broadly associated with autoimmune conditions. Correcting the dysbiosis and altered gut microbiota might deserve consideration as a potential strategy for the prevention and treatment of MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137429PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569432PMC
June 2016

[A case of multiple sclerosis who relapsed early after fingolimod therapy introduced].

Rinsho Shinkeigaku 2015 ;55(6):417-20

Division of Neurology, Kobe University Graduate School of Medicine.

The patient was a 46-year-old woman having a history of multiple sclerosis (MS) for 14 years. She had been treated with interferon β-1b since 2001, but discontinued because of psychiatric problems in 2006. Thereafter relapses were observed 1-2 times a year, and EDSS became 2.5 to 6.5. In April 2012, relapse of MS was noticed and the patient received introduction of fingolimod (FTY) after methylprednisolone (mPSL) pulse therapy. Twenty days later, dysarthria and lower limb weakness were appeared. Brain MRI showed more than 20 several millimeter Gd enhanced lesions in periventricular white matter, juxta-cortical white matter, and cerebellum. Careful determination and observation are required upon the FTY administration into the MS with high frequency of relapse.
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http://dx.doi.org/10.5692/clinicalneurol.cn-000515DOI Listing
March 2016

Differential effects of fingolimod on B-cell populations in multiple sclerosis.

Mult Scler 2014 Sep 13;20(10):1371-80. Epub 2014 Feb 13.

Department of Immunology, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan Multiple Sclerosis Centre, National Centre Hospital, NCNP, Tokyo, Japan

Background: Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual patients indicates the need to evaluate its effects on other lymphoid cells.

Objective: To clarify the effects of fingolimod on B-cell populations in patients with MS.

Methods: We analysed blood samples from 9 fingolimod-treated and 19 control patients with MS by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts.

Results: The frequencies of each B-cell population in peripheral blood mononuclear cells (PBMC) were greatly reduced 2 weeks after starting fingolimod treatment. Detailed analysis revealed a significant reduction in activated memory B cells (CD38(int-high)), particularly those expressing Ki-67, a marker of cell proliferation. Also, we noted an increased proportion of activated plasmablasts (CD138(+)) among whole plasmablasts, in the patients treated with fingolimod.

Conclusions: The marked reduction of Ki-67(+) memory B cells may be directly linked with the effectiveness of fingolimod in treating MS. In contrast, the relative resistance of CD138(+) plasmablasts to fingolimod may be of relevance for understanding the differential effectiveness of fingolimod in individual patients.
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http://dx.doi.org/10.1177/1352458514523496DOI Listing
September 2014

Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica.

PLoS One 2013 10;8(12):e83036. Epub 2013 Dec 10.

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan ; Department of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan.

Neuromyelitis optica (NMO) is an inflammatory disease characterized by recurrent attacks of optic neuritis and myelitis. It is generally accepted that autoantibodies against aquaporin 4 water channel protein play a pathogenic role in neuromyelitis optica. We have recently reported that plasmablasts are increased in the peripheral blood of this autoimmune disease, and are capable of producing autoantibodies against aquaporin 4. Here, we demonstrate that CD138(+)HLA-DR(+) plasmablasts, a subset of IgG-producing cells, are increased in the peripheral blood and are enriched among the cerebrospinal fluid (CSF) lymphocytes during the relapse of neuromyelitis optica. Notably, these CD138(+)HLA-DR(+) plasmablasts overexpress CXCR3, whose ligands are present in the cerebrospinal fluid during the relapse of neuromyelitis optica. These results led us to speculate that plasmablasts producing anti-aquaporin 4 autoantibodies might traffic toward the central nervous system (CNS). Furthermore, we performed single-cell sorting of plasmablasts from peripheral blood and CSF samples from NMO and sequenced the complementarity-determining regions (CDRs) of the IgG heavy chain expressed by the sorted plasmablast clones. There were high frequencies of mutations in the CDRs compared with framework regions, indicating that these plasmablast clones would represent a post-germinal center B-cell lineage. Consistent with the preceding results, the plasmablast clones from the peripheral blood shared the same CDR sequences with the clones from the CSF. These results indicate that IgG-producing plasmablasts, which are guided by helper T-cells, may migrate from the peripheral blood preferentially to the CSF. Since migratory plasmablasts could be involved in the inflammatory pathology of NMO, the B-cell subset and their migration might be an attractive therapeutic target.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083036PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858367PMC
September 2014

Videofluorographic detection of anti-muscle-specific kinase-positive myasthenia gravis.

Am J Otolaryngol 2012 Nov-Dec;33(6):758-61. Epub 2012 Jun 4.

Department of Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan.

A 47-year-old woman with dysphagia and ptosis gradually developed dysarthria and muscular weakness. Magnetic resonance imaging, testing for anti-acetylcholine receptor antibodies, edrophonium chloride (EC) test, and electrophysiologic test revealed no abnormalities. A psychogenic reaction was suspected. Four months after disease onset, the patient presented to our hospital. In videofluoroscopic examination of swallowing (VF), there was no aspiration for swallowing of either liquid or soft food. It revealed, however, poor pharyngeal constriction, no epiglottis inversion, repeated swallowing movements, and large amounts of pharyngeal residue. Videofluoroscopic examination of swallowing after an intravenous injection of 10 mg EC showed improvements in all above observations; particularly, it was clear when swallowing soft food. Furthermore, the anti-muscle-specific kinase (MuSK) antibody titer was elevated, and anti-MuSK antibody-positive myasthenia gravis (MuSK-MG) was diagnosed. Thus VF during EC test may be helpful in diagnosing MuSK-MG in patients with dysphagia.
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http://dx.doi.org/10.1016/j.amjoto.2012.04.003DOI Listing
May 2013

Variable phenotypes in a family with mitochondrial encephalomyopathy harboring a 3291T > C mutation in mitochondrial DNA.

Neurol Sci 2011 Oct 24;32(5):861-4. Epub 2011 Aug 24.

Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai, Fuchu, Tokyo 183-0042, Japan.

We present a Japanese family suffering from mitochondrial encephalomyopathy associated with a T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 3291. Clinical manifestations of the patients include cerebellar ataxia with myopathy, recurrent headache, and myoclonus and epilepsy. The phenotypic variation among the affected members of a single family and the mutational analysis showing maternal inheritance in a heteroplasmic fashion are consistent with well-recognized phenomena associated with many pathogenic point mutations of mtDNA tRNA genes. The 3291 mutation is a rare mtDNA mutation whose clinical presentation had only been reported in three sporadic cases. This is the first report of a family segregating the 3291 mutation with multigenerational matrilinear recurrence of mitochondrial encephalopathy. Our findings provide conclusive evidence for the pathogenicity of the 3291T > C mutation in mtDNA and its characteristic clinical heterogeneity.
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http://dx.doi.org/10.1007/s10072-011-0719-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171650PMC
October 2011

Increase of Ki-67+ natural killer cells in multiple sclerosis patients treated with interferon-β and interferon-β combined with low-dose oral steroids.

J Neuroimmunol 2011 Jul 8;236(1-2):111-7. Epub 2011 Jun 8.

Division of Clinical Neurology, University of Nottingham, Nottingham, United Kingdom.

Interferon-β (IFN-β) is known to expand regulatory CD56(bright) natural killer (NK) cells in multiple sclerosis (MS). In this cross-sectional study we show that MS patients treated with IFN-β alone or in combination with low-dose prednisolone displayed increased proportion of all NK cell subsets in the active phase of the cell cycle (Ki-67+). There was no difference in NK cell apoptosis markers. In vitro experiments showed that both IFN-β and IFN-β in combination with corticosteroids increased the proportion of Ki-67(+) NK cells. This study, although limited, shows that treatment with IFN-β affects NK cell cycle without altering NK cell apoptosis in MS patients.
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http://dx.doi.org/10.1016/j.jneuroim.2011.05.005DOI Listing
July 2011

Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica.

Proc Natl Acad Sci U S A 2011 Mar 14;108(9):3701-6. Epub 2011 Feb 14.

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.

Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19(int)CD27(high)CD38(high)CD180(-) phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse. We also demonstrate that interleukin 6 (IL-6), shown to be increased in NMO, enhanced the survival of PB as well as their AQP4-Ab secretion, whereas the blockade of IL-6 receptor (IL-6R) signaling by anti-IL-6R antibody reduced the survival of PB in vitro. These results indicate that the IL-6-dependent B-cell subpopulation is involved in the pathogenesis of NMO, thereby providing a therapeutic strategy for targeting IL-6R signaling.
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http://dx.doi.org/10.1073/pnas.1017385108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048150PMC
March 2011

[Monthly low-dose immunoglobulin infusion as a maintenance therapy for multifocal motor neuropathy may reduce allergic adverse effects: a case report].

Rinsho Shinkeigaku 2010 Aug;50(8):561-5

Department of Neurology, National Center Hospital of Neurology and Psychiatry.

A 41-year-old man with multiple motor neuropathy developed weakness of the left hand at the age of 35 years. The weakness gradually progressed to his right hand. High-dose intravenous immunoglobulin (IVIg) therapy (0.4 g/kg for 5 consecutive days) improved the muscle weakness in the hands but led to the development of generalized severe pompholyx that spread to the skin over the entire body. Because muscle weakness of the hands worsened several months after IVIg therapy, we attempted another course of IVIg therapy. However, antiallergic agents and oral corticosteroids did not suppress the pompholyx induced by the high-dose IVIg. Hence, the treatment was switched to low-dose immunoglobulin therapy (0.4 g/kg for one day) once every month. After more than 8 months of low-dose therapy, only mild form of pompholyx remained and the muscle strength was maintained without further deterioration.
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http://dx.doi.org/10.5692/clinicalneurol.50.561DOI Listing
August 2010

[Severe kyphosis and esophagus hiatal hernia affected in the levodopa absorption of a patient with Parkinson's disease].

Rinsho Shinkeigaku 2009 Aug;49(8):493-6

Department of Neurology, National Center Hospital of Neurology and Psychiatry.

An 82 year-old woman with Parkinson's disease complained of a tendency to fall. She has had an extensive kyphosis since she was 66 years old. Over the last 6 months, she has repeatedly fallen. Even though she took anti-parkisonian drugs, she had also developed camptocormia. Her plasma levodopa concentration was analyzed for 4 hrs after administrating an oral dose of levodopa (200 mg) plus carbidopa (20 mg) at the time of fasting. The change in the plasma levodopa concentration showed bimodal peaks. The physical symptoms depended on the plasma concentration and improved twice. Esophageal tortuosity and esophageal hiatal hernia were detected by esophagography and upper gastric endoscopy. Such physical symptoms were speculated to have been caused by the transit disturbance of the drug in the gastrointestinal duct. During a second analysis of the plasma levodopa concentration, the patient was instructed to keep extending her back after consuming the same dose of drugs but with a greater amount of water than in the first analysis. A single and a higher peak were observed for the plasma levodopa concentration, and the physical symptoms, including camptocormia and parkinsonism, were improved. Hunched posture could influence the absorption of antiparkinsonian drugs.
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http://dx.doi.org/10.5692/clinicalneurol.49.493DOI Listing
August 2009

[Low dose pergolide induced systemic edema and pleural effusion in a patient with Parkinson's disease].

Rinsho Shinkeigaku 2008 Feb;48(2):143-5

Department of Neurology, Toranomon Hospital.

A 77-year-old woman was admitted to our department due to leg edema of 2-year duration. The patient has been suffered from Parkinson's disease for 12 years and prescribed levodopa, selegiline, and small dosage of pergolide (200 microg/day). Leg edema developed one year after she took pergolide. Bilateral peripheral effusion was shown without any findings for malignancy, infection, and heart failure. After discontinuation of pergolide, both pleural effusion and systemic edema were solved. Pergolide was reported to cause cardiac valve fibrosis, pleural effusion and fibrosis, and peritoneal fibrosis. This case suggests that low dose pergolide (200 microg/day: cumulative dose is about 200 mg) could cause severe pleural effusion and systemic edema.
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http://dx.doi.org/10.5692/clinicalneurol.48.143DOI Listing
February 2008