Publications by authors named "Youwei Lin"

21 Publications

  • Page 1 of 1

Real-world application of plasmapheresis for neurological disease: Results from the Japan-Plasmapheresis Outcome and Practice Patterns Study.

Ther Apher Dial 2022 Jun 29. Epub 2022 Jun 29.

Department of Neurology, Nagasaki Kawatana Medical Center, Kawatana, Japan.

Introduction: Plasmapheresis is a well-recognized treatment for autoimmune neurological diseases in Japan. However, the practice varies depending on the facility, and the actual treatment conditions are unclear.

Methods: To clarify real-world conditions, a prospective observational study was conducted on patients with neurological diseases who were scheduled to receive plasmapheresis. A dataset was analyzed that included 887 treatments from 210 patients with myasthenia gravis (MG), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and other diseases for 82, 30, 24, and 74 patients, respectively.

Results: The types of plasmapheresis performed included immunoadsorption plasmapheresis, plasma exchange, and double filtration plasmapheresis with 620, 213, and 54 treatments, respectively. Approximately, 60% of the treatments were performed using peripheral blood access alone. Non-serious adverse events were observed in 10 patients.

Conclusions: A statistically significant improvement was observed after plasmapheresis in patients with MG, MS, and NMOSD. These were evaluated using the modified Rankin Scale.
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http://dx.doi.org/10.1111/1744-9987.13906DOI Listing
June 2022

The impacts of surgical mask in young healthy subjects on cardiopulmonary function and muscle performance: a randomized crossover trial.

Arch Public Health 2022 May 17;80(1):138. Epub 2022 May 17.

Department of Rehabilitation Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, No. 621, Gangwan Road, Huangpu District, Guangzhou, 510700, China.

Objective: To explore the impacts of surgical mask in normal subjects on cardiopulmonary function and muscle performance under different motor load and gender differences.

Design: Randomized crossover trial.

Setting: The Fifth Affiliated Hospital of Guangzhou Medical University, June 16th to December 30th, 2020.

Participants: Thirty-one college students (age: male 21.27 ± 1.22 years; female 21.31 ± 0.79 years) were recruited and randomly allocated in two groups.

Interventions: Group 1 first received CPET in the mask-on condition followed by 48 h of washout, and then received CPET in the mask-off condition. Group 2 first received CPET in the mask-off condition followed by 48 h of washout, then received CPET in the mask-on condition. The sEMG data were simultaneously collected.

Main Outcome Measures: The primary outcome was maximum oxygen uptake (VO max) from CPET, which was performed on a cycle ergometer-this is the most important parameter associated with an individual's physical conditioning. The secondary parameters included parameters reflecting exercise tolerance and heart function (oxygen uptake, anaerobic valve, maximum oxygen pulse, heart rate reserve), parameters reflecting ventilation function (respiration reserve, ventilation volume, tidal volume, breathing frequency), parameters reflecting gas exchange (end-tidal oxygen and carbon dioxide partial pressure, oxygen equivalent, carbon dioxide equivalent, and the relationship between dead space and tidal volume) and parameters reflecting skeletal muscle function [oxygen uptake, anaerobic valve, work efficiency, and EMG parameters including root mean square (RMS)].

Results: Comparing the mask-on and mask-off condition, wearing surgical mask had some negative effects on VO/kg (peak) and ventilation (peak) in both male and female health subjects [VO/kg (peak): 28.65 ± 3.53 vs 33.22 ± 4.31 (P = 0.001) and 22.54 ± 3.87 vs 26.61 ± 4.03 (P < 0.001) ml/min/kg in male and female respectively; ventilation (peak): 71.59 ± 16.83 vs 82.02 ± 17.01 (P = 0.015) and 42.46 ± 10.09 vs 53.95 ± 10.33 (P < 0.001) liter in male and female respectively], although, based on self-rated scales, there was no difference in subjective feelings when comparing the mask-off and mask-on condition. Wearing surgical masks showed greater lower limb muscle activity just in male subjects [mean RMS of vastus medialis (load): 65.36 ± 15.15 vs 76.46 ± 19.04 μV, P = 0.031]. Moreover, wearing surgical masks produced a greater decrease in △tidal volume (VTpeak) during intensive exercises phase in male subjects than in female [male - 0.80 ± 0.15 vs female - 0.62 ± 0.11 l P = 0.001].

Conclusions: Wearing medical/surgical mask showed a negative impact on the ventilation function in young healthy subjects during CPET, especially in high-intensity phase. Moreover, some negative effects were found both in ventilation and lower limb muscle actives in male young subjects during mask-on condition. Future studies should focus on the subjects with cardiopulmonary diseases to explore the effect of wearing mask.

Trial Registration: Chinese Clinical Trial Registry ( ChiCTR2000033449 ).
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http://dx.doi.org/10.1186/s13690-022-00893-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9112472PMC
May 2022

Improved hydrogen production from pharmaceutical intermediate wastewater in an anaerobic maifanite-immobilized sludge reactor.

RSC Adv 2021 Oct 15;11(53):33714-33722. Epub 2021 Oct 15.

School of Forestry, Northeast Forestry University Harbin 150040 Heilongjiang China.

A novel anaerobic maifanite-immobilized sludge reactor (AMSR) was employed to investigate the feasibility and performance of continuous hydrogen production for the treatment of pharmaceutical intermediate wastewater (PIW) at different organic loading rates (OLR) (from 12 to 96 g COD L d) according to changes in the hydraulic retention time (HRT). A reactor without maifanite was also employed as a control. The results indicate that maifanite accelerates granular sludge formation and the AMSR presents more efficient and stable performance than the control in terms of the hydrogen production rate. In the AMSR, the highest hydrogen production rate of 11.2 ± 0.4 mmol L h was achieved at an optimum OLR of 72 g COD L d. The main metabolic route for hydrogen production was ethanol-type fermentation, which was reflected in the relative abundance of , which was dominant for all of the OLRs. The maximum energy conversion efficiency in the dual production of hydrogen and ethanol was determined to be 24.5 kJ L h at an OLR of 72 g COD L d.
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http://dx.doi.org/10.1039/d1ra02522hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9042261PMC
October 2021

The Japanese Society for Apheresis clinical practice guideline for therapeutic apheresis.

Ther Apher Dial 2021 Dec;25(6):728-876

The Japanese Society for Apheresis Guidelines Preparation Committee.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.
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http://dx.doi.org/10.1111/1744-9987.13749DOI Listing
December 2021

Th1 - CD11c B Cell Axis Associated with Response to Plasmapheresis in Multiple Sclerosis.

Ann Neurol 2021 10;90(4):595-611

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

Objective: Although plasmapheresis is a treatment option for patients with autoimmune neurological diseases, treatment response varies greatly among patients. The main objective of this study was to find out if biological/immune traits correlate with a beneficial response.

Methods: We thoroughly analyzed immune phenotypes in paired blood samples from a cohort of 31 patients with multiple sclerosis before and after plasmapheresis, in parallel with clinical evaluation of treatment response.

Results: The frequency of IFN-γ Th1 cells was persistently higher in those who obtained benefit from plasmapheresis (responders) than nonresponders. The Th1 cell frequency before plasmapheresis provided a high predictive value for beneficial response, achieving area under the curve (AUC) of 0.902. Plasmapheresis treatment decreased inflammation-related gene expressions in Th1 cells. Meanwhile, IFNG expression in Th1 cells positively correlated with the frequency of CD11c B cells, of which a pathogenic role has been suggested in several autoimmune diseases. In line with this, in vitro experiments showed that CD11c B cells would increase in response to exogenous IFN-γ compared to IL-4, and secrete high amounts of IgG. B cell receptor analysis indicated that clonal expansion of CD11c B cells takes place in patients with multiple sclerosis. Interestingly, CD11c B cells, which showed unique gene expression profile, decreased after plasmapheresis treatment along with all the immunoglobulin subsets in the circulation.

Interpretation: Taken together, we postulate that Th1 cell - CD11c B cell axis is involved in treatment response to plasmapheresis, giving us clues to better understanding of complicated pathogenesis of autoimmune diseases, and getting closer to a personalized therapy. ANN NEUROL 2021;90:595-611.
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http://dx.doi.org/10.1002/ana.26202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293420PMC
October 2021

Involvement of cytotoxic Eomes-expressing CD4 T cells in secondary progressive multiple sclerosis.

Proc Natl Acad Sci U S A 2021 03;118(11)

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

Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell-mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4 T cells expressing Eomes (Eomes Th cells) in SPMS pathogenesis-a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes Th cells circulate in RRMS patient peripheral blood ( = 44), primary progressive MS (PPMS) patients ( = 25), or healthy controls ( = 42), but Eomes Th cells were significantly increased in SPMS ( = 105, < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4 T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases ( < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.
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http://dx.doi.org/10.1073/pnas.2021818118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980371PMC
March 2021

Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis.

Brain 2019 04;142(4):916-931

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, Japan.

The mechanism underlying the progression of relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS), characterized by accumulating fixed disability, is yet to be fully understood. Although alterations in the gut microbiota have recently been highlighted in multiple sclerosis pathogenesis, the mechanism linking the altered gut environment with the remote CNS pathology remains unclear. Here, we analyse human CD4+ memory T cells expressing the gut-homing chemokine receptor CCR9 and found a reduced frequency of CCR9+ memory T cells in the peripheral blood of patients with SPMS relative to healthy controls. The reduction in the proportion of CCR9+ cells among CD4+ memory T cells (%CCR9) in SPMS did not correlate with age, disease duration or expanded disability status scale score, although %CCR9 decreased linearly with age in healthy controls. During the clinical relapse of both, relapsing-remitting multiple sclerosis and neuromyelitis optica, a high proportion of cells expressing the lymphocyte activating 3 gene (LAG3) was detected among CCR9+ memory T cells isolated from the CSF, similar to that observed for mouse regulatory intraepithelial lymphocytes. In healthy individuals, CCR9+ memory T cells expressed higher levels of CCR6, a CNS-homing chemokine receptor, and exhibited a regulatory profile characterized by both the expression of C-MAF and the production of IL-4 and IL-10. However, in CCR9+ memory T cells, the expression of RORγt was specifically upregulated, and the production of IL-17A and IFNγ was high in patients with SPMS, indicating a loss of regulatory function. The evaluation of other cytokines supported the finding that CCR9+ memory T cells acquire a more inflammatory profile in SPMS, reporting similar aspects to CCR9+ memory T cells of the elderly healthy controls. CCR9+ memory T cell frequency decreased in germ-free mice, whereas antibiotic treatment increased their number in specific pathogen-free conditions. Here, we also demonstrate that CCR9+ memory T cells preferentially infiltrate into the inflamed CNS resulting from the initial phase and that they express LAG3 in the late phase in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Antibiotic treatment reduced experimental autoimmune encephalomyelitis symptoms and was accompanied by an increase in CCR9+ memory T cells in the peripheral blood. Antibodies against mucosal vascular addressin cell adhesion molecule 1 (MADCAM1), which is capable of blocking cell migration to the gut, also ameliorated experimental autoimmune encephalomyelitis. Overall, we postulate that the alterations in CCR9+ memory T cells observed, caused by either the gut microbiota changes or ageing, may lead to the development of SPMS.
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http://dx.doi.org/10.1093/brain/awz012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439331PMC
April 2019

Application of immunotherapy for neurological manifestations in hypermobile Ehlers-Danlos syndrome.

Ther Adv Neurol Disord 2018 18;11:1756286418793766. Epub 2018 Aug 18.

Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

Ehlers-Danlos syndrome (EDS) is a heterogeneous heritable connective tissue disorder with various neurological manifestations, including chronic pain. The neurological manifestations in EDS are often regarded as being caused by the associated musculoskeletal disorders or polyneuropathy. Here, we present two patients with hypermobile EDS (hEDS), presenting with relapsing central nervous system (CNS) manifestations. Although the two patients showed relapsing signs of CNS manifestations like multiple sclerosis (MS) or spectrum disorder (NMOSD), they were unique in that they had widespread opioid-dependent chronic pain, which is not consistent with the symptoms of MS/NMOSD. Unexpectedly, the serious pain of unknown origin was remarkably mitigated by plasmapheresis, and magnetic resonance imaging (MRI) examinations conducted for one of the patients were negative. Collectively, we speculate that hEDS may be more susceptible to 'normal-appearing imaging, neuroimmunologically justified, autoimmune-mediated encephalomyelitis (NINJA).' Analysis of the presented cases and an additional three patients with EDS with chronic pain indicates that treatable immune-mediated mechanisms deserve considerations for neurological symptoms observed in hEDS.
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http://dx.doi.org/10.1177/1756286418793766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100124PMC
August 2018

Normal brain imaging accompanies neuroimmunologically justified, autoimmune encephalomyelitis.

Neurol Neuroimmunol Neuroinflamm 2018 May 2;5(3):e456. Epub 2018 Apr 2.

Department of Immunology (D.T., Y.L., W.S., H.O., M.N., M.A., T.Y.) and Department of Mental Disorder Research (M.O.), National Institute of Neuroscience, National Center of Neurology and Psychiatry; Department of Neurology (D.T., Y.L., M.A., T.O., Y.T.) and Department of Radiology (Y.K., N.S.), National Center Hospital, National Center of Neurology and Psychiatry; Multiple Sclerosis Center (D.T., Y.L., W.S., H.O., M.N., M.A., T.O., N.S., T.Y.), National Center of Neurology and Psychiatry, Tokyo, Japan.

Objective: To examine cases with a clinical course, signs, and symptoms mimicking MS, but without abnormalities on conventional MRI.

Methods: Among 550 people with a tentative diagnosis of MS or neuromyelitis optica spectrum disorder (NMOSD), we selected patients, who met the 2010 McDonald diagnosis criteria for MS, but did not show abnormal findings on conventional brain and spinal cord MRI. After evaluating their clinical data, we analyzed fractional anisotropy (FA) values in the brain white matter on diffusion tensor MRIs and the frequencies of B-cell subsets in the peripheral blood in the corresponding cases as compared to healthy controls.

Results: Eleven patients (age: 41.1 ± 8.0 years, 9 women and 2 men) met the selection criteria. They were functionally disabled, with a median expanded disability status scale score of 6.0 (2.0-8.0). CSF oligoclonal bands were negative in all cases. IV methylprednisolone and plasmapheresis (PP) were found to be efficacious. Diffusion tensor MRI analysis revealed extensive white matter abnormalities characterized by significantly decreased FA values. The frequency of plasmablasts in the peripheral blood was significantly increased in these patients similar to NMOSD.

Conclusions: The neurologic disabilities in these patients could be ascribed to brain white matter damage, as revealed by MRI analysis, whereas the efficacy of PP and B-cell abnormalities in the patients suggested an autoimmune-mediated pathogenesis. In the differential diagnosis of MS, we propose that this condition be referred to as, "Normal-appearing Imaging-associated, Neuroimmunologically Justified, Autoimmune encephalomyelitis."
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http://dx.doi.org/10.1212/NXI.0000000000000456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880628PMC
May 2018

Disrupted balance of T cells under natalizumab treatment in multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2016 Apr 3;3(2):e210. Epub 2016 Mar 3.

Department of Immunology, National Institute of Neuroscience (K.K., M.N., W.S., Y.L., T.Y.), and Multiple Sclerosis Center (W.S., T.O., M.A., Y.L., T.Y.) and Department of Neurology (Y.L., M.M.), National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo; and Department of Neurology (K.K., R.T.), Kyoto University Graduate School of Medicine, Japan.

Objective: To compare effects of natalizumab on inflammatory and regulatory T cells with regard to expression of α4-integrin (CD49d).

Methods: Twenty-seven natalizumab-naive and 8 natalizumab-treated patients with multiple sclerosis (MS), 7 patients with neuromyelitis optica (NMO) or NMO spectrum disorder, and 8 healthy controls were included. The positive rate of CD49d was analyzed and compared among T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells (CD49d+Th1, CD49d+Th17, and CD49d+Treg, respectively).

Results: Natalizumab treatment increased CD49d ratios, CD49d+Th1/CD49d+Treg, and CD49d+Th17/CD49d+Treg. This indicates larger reduction of the CD49d+ population in Treg cells than in Th1 or Th17 cells. The CD49d ratios of 2 patients who experienced exacerbation during natalizumab treatment were remarkably higher than those of the other natalizumab-treated patients. Natalizumab treatment increased the expression of TBX21, RORC, interferon (IFN)-γ, and interleukin (IL)-17A, and decreased the expression of FOXP3 in CD49d+ memory CD4 T cells. Natalizumab treatment also increased the amount of IFN-γ and IL-17A secreted by CD49d+ memory CD4 T cells.

Conclusions: The reduction rate of the CD49d+ population in Treg cells was larger than that in Th1 or Th17 cells. Although the large reduction in CD49d+ population is beneficial for MS, the proinflammatory state of residual CD49d+ cells might, in part, explain the presence of disease activity under natalizumab treatment.
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http://dx.doi.org/10.1212/NXI.0000000000000210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784802PMC
April 2016

[Animal models for multiple sclerosis].

Nihon Rinsho 2015 Sep;73 Suppl 7:73-80

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September 2015

[Experimental autoimmune encephalomyelitis: crosstalk with immunology and therapy].

Nihon Rinsho Meneki Gakkai Kaishi 2014 ;37(3):146-53

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

The immune network is a complex system comprising several types of inflammatory and regulatory cells. Autoimmune diseases occur because of dysregulation in host defenses caused by a cellular imbalance. The pattern of imbalance depends on the disease. Most autoimmune diseases are chronic, and the mechanism underlying this chronic nature is yet to be determined. Monoclonal antibody therapy is highly specific to the molecules targeted and is therefore highly effective. However, this therapy cannot be applied to all autoimmune diseases, since even the most effective therapy is incapable of completely inhibiting disease activity. Antigen-specific therapies have the ability to inhibit disease activity; however, their application is limited because of the presence of various disease-specific antigens. Regulatory cell therapies also have potential, but pose a plasticity problem. By focusing our research on experimental autoimmune encephalomyelitis (EAE), which is a multiple sclerosis (MS) model and normally initially has a relapse or remission course, followed by a progressive course, we can develop alternative therapies for the treatment of autoimmune diseases by exploring the mechanism of relapse and remission. It is safe to say that immunologic history is paced with EAE on which autoimmune disease therapy is based.
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http://dx.doi.org/10.2177/jsci.37.146DOI Listing
July 2015

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

CCR2(+)CCR5(+) T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis.

J Immunol 2012 Nov 15;189(10):5057-65. Epub 2012 Oct 15.

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

Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4(+) autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2(+)CCR5(+) T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2(+)CCR5(+) T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2(+)CCR5(+) T cells showed a higher invasive potential across an in vitro blood-brain barrier model compared with other T cells. Of note, the CCR2(+)CCR5(+) T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6(-), but not the CCR6(+), population within CCR2(+)CCR5(+) T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2(+)CCR5(+)CCR6(-) Th1 cells play a crucial role in the pathogenesis of MS.
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http://dx.doi.org/10.4049/jimmunol.1202026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496198PMC
November 2012

New-onset type 1 diabetes mellitus and anti-aquaporin-4 antibody positive optic neuritis associated with type 1 interferon therapy for chronic hepatitis C.

Intern Med 2012 15;51(18):2625-9. Epub 2012 Sep 15.

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

A 60-year-old woman developed type 1 diabetes mellitus and anti-aquaporin-4 antibody positive optic neuritis during type 1 interferon therapies for chronic hepatitis C. The diabetes mellitus was elicited by interferon-α plus ribavirin therapy, while the optic neuritis was induced after interferon-β treatment, followed by interferon-α and ribavirin therapy. It is possible that type 1 interferons lead to the onset of the two autoimmune diseases by inducing disease-specific autoantibodies. Autoimmune disease is an infrequent complication of type 1 interferon treatment; however, once it has occurred, it may result in severe impairments. Patients undergoing type 1 interferon therapy should therefore be carefully monitored for any manifestations of autoimmune diseases.
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http://dx.doi.org/10.2169/internalmedicine.51.7771DOI Listing
April 2013

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

[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

Suppression of experimental autoimmune encephalomyelitis by ghrelin.

J Immunol 2009 Aug 20;183(4):2859-66. Epub 2009 Jul 20.

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

Ghrelin is a recently identified gastric hormone that displays strong growth hormone-releasing activity mediated by the growth hormone secretagogue receptor. While this unique endogenous peptide participates in the regulation of energy homeostasis, increases food intake, and decreases energy expenditure, its ability to inhibit the production of proinflammatory cytokines in vitro indicates its role in the regulation of inflammatory process in vivo. Here we examine the effect of exogenous ghrelin on the development of experimental autoimmune encephalomyelitis (EAE), a representative model of multiple sclerosis. In the C57BL/6 mouse model of EAE induced by sensitization to myelin oligodendrocyte glycoprotein 35-55 peptide, we found that alternate-day s.c. injections of ghrelin (5 mug/kg/day) from day 1 to 35 significantly reduced the clinical severity of EAE. The suppression of EAE was accompanied by reduced mRNA levels of proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 in the spinal cord cellular infiltrates and microglia from ghrelin-treated mice at the peak of disease, suggesting the role of ghrelin as an antiinflammatory hormone. Consistently, ghrelin significantly suppressed the production of proinflammatory cytokines in LPS-stimulated microglia in vitro. These results shed light on the new role of ghrelin in the regulation of inflammation with possible implications for management of human diseases.
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http://dx.doi.org/10.4049/jimmunol.0803362DOI Listing
August 2009

Treatment of neuromyelitis optica: current debate.

Ther Adv Neurol Disord 2008 Jul;1(1):5-12

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

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that largely affects optic nerves and spinal cord. Recent studies have identified an elevation of serum anti-aquaporin 4 antibody as a hallmark of NMO. Typical cases of NMO significantly differ from multiple sclerosis (MS) in immunological markers, histopathology, and responses to therapy. In fact, plasma exchange may be more efficacious for NMO than MS, whereas interferon-ß is recommended for MS but not for NMO. An emerging idea that pathogenesis of NMO may involve an interaction of the newly identified helper T cell subset, Th17, with B cells offers potential targets of therapy.
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http://dx.doi.org/10.1177/1756285608093978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002541PMC
July 2008

Buprofezin susceptibility survey, resistance selection and preliminary determination of the resistance mechanism in Nilaparvata lugens (Homoptera: Delphacidae).

Pest Manag Sci 2008 Oct;64(10):1050-6

Key Laboratory of Monitoring and Management of Plant Disease and Insects, Ministry of Agriculture/Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China.

Background: Buprofezin has been used for many years to control Nilaparvata lugens (Stål). Assessment of susceptibility change in the insect is essential for maintaining control efficiency and resistance management.

Results: Eleven-year surveys showed that most field populations were susceptible before 2004. However, substantially higher levels of resistance (up to 28-fold) were found in most of the rice fields in China after 2004. A field population was collected and periodically selected for buprofezin resistance in the laboratory. After 65 generations (56 were selected), the colony successfully obtained 3599-fold resistance to buprofezin. Synergism tests showed that O,O-diethyl-O-phenyl phosphorothioate (SV1), piperonyl butoxide (PBO) and diethyl maleate (DEM) increased buprofezin toxicity in the resistant strain by only 1.5-1.6 fold, suggesting that esterases, P450-monooxygenases and glutathione S-transferases had no substantial effect on buprofezin resistance development.

Conclusion: The results from this study indicate that N. lugens has the potential to develop high resistance to buprofezin. A resistance management program with rotation of buprofezin and other pesticides may efficiently delay or slow down resistance development in the insect. Further investigation is also necessary to understand the resistance mechanisms in N. lugens.
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http://dx.doi.org/10.1002/ps.1606DOI Listing
October 2008

Neuropeptide Y (NPY) suppresses experimental autoimmune encephalomyelitis: NPY1 receptor-specific inhibition of autoreactive Th1 responses in vivo.

J Immunol 2003 Oct;171(7):3451-8

Department of Immunology, National Institute of Neuroscience, NCNP, Ogawahigashi, Kodaira, Tokyo, Japan.

Prior studies have revealed that the sympathetic nervous system regulates the clinical and pathological manifestations of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model mediated by Th1 T cells. Although the regulatory role of catecholamines has been indicated in the previous works, it remained possible that other sympathetic neurotransmitters like neuropeptide Y (NPY) may also be involved in the regulation of EAE. Here we examined the effect of NPY and NPY receptor subtype-specific compounds on EAE, actively induced with myelin oligodendrocyte glycoprotein 35-55 in C57BL/6 mice. Our results revealed that exogenous NPY as well as NPY Y(1) receptor agonists significantly inhibited the induction of EAE, whereas a Y(5) receptor agonist or a combined treatment of NPY with a Y(1) receptor antagonist did not inhibit signs of EAE. These results indicate that the suppression of EAE by NPY is mediated via Y(1) receptors. Furthermore, treatment with the Y(1) receptor antagonist induced a significantly earlier onset of EAE, indicating a protective role of endogenous NPY in the induction phase of EAE. We also revealed a significant inhibition of myelin oligodendrocyte glycoprotein 35-55-specific Th1 response as well as a Th2 bias of the autoimmune T cells in mice treated with the Y(1) receptor agonist. Ex vivo analysis further demonstrated that autoimmune T cells are directly affected by NPY via Y(1) receptors. Taken together, we conclude that NPY is a potent immunomodulator involved in the regulation of the Th1-mediated autoimmune disease EAE.
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http://dx.doi.org/10.4049/jimmunol.171.7.3451DOI Listing
October 2003
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