Yuji Kawano

Kyushu University, Hukuoka, Fukuoka, Japan

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Publications (73)281.28 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. A series of discovery and replication studies revealed that most identified CNVs were 5-50-kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio (OR) = 52.6), while deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0), and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    No preview · Article · Aug 2015 · Annals of Neurology
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    ABSTRACT: Objective Neuromyelitis optica (NMO) is an inflammatory disease in which NMO-immunoglobulin G (IgG) targeting aquaporin-4 (AQP4) is specifically detected. Although the main subclass of AQP4 antibody was reported to be in the IgG1 subclass, other subclasses have also been described, including IgG2 AQP4 antibody, as a second common subclass. NMO patients were analyzed to clarify the clinical features of NMO patients with IgG2 AQP4 antibody.Methods Serum samples from 58 NMO patients, who met the revised 2006 criteria for NMO, were analyzed for AQP4 antibody subclass expression using an established flow cytometric assay, and clinical features were compared according to the main AQP4 antibody subclasses.ResultsA total of 50 patients (86.2%) had IgG1 AQP4 antibodies, while eight (13.8%) expressed IgG2 AQP4 antibody as the main subclass. Those eight individuals exhibited younger age of onset (P = 0.0089), lower AQP4 antibody titers (P = 0.0024) and a more common fulfillment of Barkhof's criteria (P = 0.0466) than patients with IgG1 AQP4 antibody expression.Conclusions Results from the present study suggest that the characteristics of individuals with IgG2 AQP4 antibody as a main subclass are more similar to multiple sclerosis and somewhat distinct from NMO patients with IgG1 AQP4 antibody.
    No preview · Article · May 2015 · Clinical and Experimental Neuroimmunology
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    ABSTRACT: Background: Fingolimod efficiently reduces multiple sclerosis (MS) relapse by inhibiting lymphocyte egress from lymph nodes through down-modulation of sphingosine 1-phosphate (S1P) receptors. We aimed to clarify the alterations in peripheral blood T cell subsets associated with MS relapse on fingolimod. Methods/principal findings: Blood samples successively collected from 23 relapsing-remitting MS patients before and during fingolimod therapy (0.5 mg/day) for 12 months and 18 healthy controls (HCs) were analysed for T cell subsets by flow cytometry. In MS patients, the percentages of central memory T (CCR7+CD45RO+) cells (TCM) and naïve T (CCR7+CD45RO-) cells decreased significantly, while those of effector memory T (CCR7-CD45RA-) and suppressor precursor T (CD28-) cells increased in both CD4+T and CD8+T cells from 2 weeks to 12 months during fingolimod therapy. The percentages of regulatory T (CD4+CD25highCD127low) cells in CD4+T cells and CCR7-CD45RA+T cells in CD8+T cells also increased significantly. Eight relapsed patients demonstrated greater percentages of CD4+TCM than 15 non-relapsed patients at 3 and 6 months (p=0.0051 and p=0.0088, respectively). The IL17-, IL9-, and IL4-producing CD4+T cell percentages were significantly higher at pre-treatment in MS patients compared with HCs (p<0.01 for all), while the IL17-producing CD4+T cell percentages tended to show a transient increase at 2 weeks of fingolimod therapy (pcorr=0.0834). Conclusions: The CD4+TCM percentages at 2 weeks to 12 months during fingolimod therapy are related to relapse.
    Full-text · Article · Apr 2015 · PLoS ONE

  • No preview · Article · Oct 2014 · Journal of Neuroimmunology

  • No preview · Conference Paper · Jun 2014

  • No preview · Conference Paper · Jun 2014

  • No preview · Conference Paper · Jun 2014
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    ABSTRACT: Abnormal intrathecal synthesis of IgG, reflected by cerebrospinal fluid (CSF) oligoclonal IgG bands (OBs) and increased IgG index, is much less frequently observed in Japanese multiple sclerosis (MS) cohorts compared with Western cohorts. We aimed to clarify whether genetic and common infectious backgrounds influence CSF IgG abnormality in Japanese MS patients. We analyzed HLA-DRB1 alleles, and IgG antibodies against Chlamydia pneumoniae, Helicobacter pylori, Epstein-Barr virus nuclear antigen (EBNA), and varicella zoster virus (VZV) in 94 patients with MS and 367 unrelated healthy controls (HCs). We defined CSF IgG abnormality as the presence of CSF OBs and/or increased IgG index (>0.658). CSF IgG abnormality was found in 59 of 94 (62.8%) MS patients. CSF IgG abnormality-positive patients had a significantly higher frequency of brain MRI lesions meeting the Barkhof criteria compared with abnormality-negative patients. Compared with HCs, CSF IgG abnormality-positive MS patients showed a significantly higher frequency of DRB1*1501, whereas CSF IgG abnormality-negative patients had a significantly higher frequency of DRB1*0405. CSF IgG abnormality-positive MS patients had a significantly higher frequency of anti-C. pneumoniae IgG antibodies compared with CSF IgG abnormality-negative MS patients, although there was no difference in the frequency of anti-C. pneumoniae IgG antibodies between HCs and total MS patients. Compared with HCs, anti-H. pylori IgG antibodies were detected significantly less frequently in the total MS patients, especially in CSF IgG abnormality-negative MS patients. The frequencies of antibodies against EBNA and VZV did not differ significantly among the groups. CSF IgG abnormality is associated with Western MS-like brain MRI features. DRB1*1501 and C. pneumoniae infection confer CSF IgG abnormality, while DRB1*0405 and H. pylori infection are positively and negatively associated with CSF IgG abnormality-negative MS, respectively, suggesting that genetic and environmental factors differentially contribute to MS susceptibility according to the CSF IgG abnormality status.
    Full-text · Article · Apr 2014 · PLoS ONE
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    ABSTRACT: Objective Recent evidence has suggested the importance of an aberrantly activated monocyte system in amyotrophic lateral sclerosis (ALS) pathogenesis. However, the roles of each monocyte subset, namely CD14+CD16− classical monocytes, CD14dimCD16+ non-classical monocytes and CD14+CD16+ intermediate monocytes, in ALS remain unknown. We aimed to clarify the alterations in the monocyte subset proportions and the surface marker expressions on each monocyte subset in ALS. Methods Blood samples were collected from 19 ALS patients and 28 healthy controls (HC). The surface expressions of CCR2, CX3CR1, CD64 and CD62L were measured in the three monocyte subsets (classical, non-classical and intermediate) by flow cytometry. ResultsThe percentages of CCR2 and CD62L on CD14+CD16− classical monocytes were significantly lower in ALS patients than in HC (P = 0.0012 and P = 0.0296, respectively). No differences were found in CX3CR1 and CD64 on each monocyte subset. The percentage of intermediate monocytes showed a significant negative correlation with the revised ALS functional rating scale score (r = −0.631, P = 0.0038). Conclusions Reductions in chemotaxis- and adhesion-related molecules on classical inflammatory monocytes are present in ALS, further suggesting the involvement of an aberrant innate immune system in ALS pathogenesis.
    No preview · Article · Feb 2014 · Clinical and Experimental Neuroimmunology
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    ABSTRACT: Background Interleukin 2 receptor α subunit (IL2RA) is a genetic risk for multiple sclerosis (MS) in Caucasians. However, the association between MS and IL2RA in Japanese idiopathic demyelinating diseases of the central nervous system has not been examined. Objective To determine whether IL2RA gene polymorphisms confer risks of developing MS or neuromyelitis optica (NMO) in a Japanese population. Methods DNA samples were obtained from 115 MS patients, 75 NMO/NMO spectrum disorder (NMOSD) patients, and 238 healthy controls. The single nucleotide polymorphisms (SNPs) rs2104286, rs12722489, and rs7090512 were genotyped by real-time PCR using TaqMan SNP genotyping assays. Results No significant associations of the three IL2RA SNPs with the development of the diseases were observed. In MS patients only, the annualized relapse rates were significantly higher for the rs2104286-TT genotype than for the non-TT (CT+CC) genotype and for the rs12722489-CC genotype than for the non-CC genotype in females (p = 0.0138 for both), but not in males. Conclusions Although the possibility that IL2RA is a risk factor for MS development was not confirmed in this Japanese population, IL2RA gene polymorphisms were able to modify the disease activity in female MS patients, but had no influence on either susceptibility or disease phenotype in NMO/NMOSD patients.
    No preview · Article · Feb 2014 · Journal of the neurological sciences
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    ABSTRACT: Objectives To determine whether the non-synonymous 1425G/A polymorphism (rs2230500), an Asian-specific single nucleotide polymorphism that increases the kinase activity and affects the function of immune cells, of the protein kinase C-η gene (PRKCH) confers the risk of developing idiopathic demyelinating diseases of the central nervous system in a Japanese population. Methods Blood samples were collected from 96 multiple sclerosis (MS) patients, 52 neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) patients and 151 healthy controls. The polymorphism rs2230500 was genotyped by sequencing. ResultsNo significant association was observed between the PRKCH rs2230500 polymorphism and the risk of either MS or NMO/NMOSD. Clinical characteristics were also unaffected by the rs2230500 status. Conclusions Although the possibility that PRKCH has some effect on MS and NMO/NMOSD risk cannot be completely excluded because of the small study sample size, the polymorphism rs2230500 did not appear to confer disease susceptibility to MS or NMO/NMOSD in this Japanese population.
    Full-text · Article · Dec 2013 · Clinical and Experimental Neuroimmunology
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    ABSTRACT: Objectives There has been no large-scale study of methylprednisolone pulse therapy in Asian patients with multiple sclerosis (MS) or neuromyelitis optica (NMO), despite it being widely used for acute relapse. We aimed to clarify treatment response of MS and NMO patients to methylprednisolone pulse therapy and post-pulse oral corticosteroids in real clinical practice in a multicenter study in Japan. Methods Investigators at 28 institutions collected changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of completion of methylprednisolone pulse therapy carried out in 2010, and after post-pulse oral corticosteroids therapy, by retrospective review of medical records. ResultsIn 345 patients (95.1% of all registered patients), 457 series of methylprednisolone pulse therapy were carried out for treatment of acute relapse. EDSS scores improved by 0.8 ± 1.1 (mean ± SD) after the first course. The second and third courses also produced sufficient improvements (by 0.7 and 0.6, respectively), but much smaller improvements were observed thereafter. The target neurological symptoms and signs improved in 79.5% of patients. Improvement rates were 5–20% lower after a course of pulse therapy than after a series of pulse therapy. A half dose (500 mg/day) produced less improvement than a standard dose (1000 mg/day; 65.9 vs 79.5%). During post-pulse oral corticosteroid therapy, EDSS scores decreased by 0.6 ± 0.9. No significant adverse effects were observed. Conclusions Methylprednisolone pulse therapy is beneficial in nearly 80% of Japanese MS and NMO patients, and EDSS score improvements after therapy are compatible with those in Western MS patients.
    Full-text · Article · Dec 2013 · Clinical and Experimental Neuroimmunology

  • No preview · Article · Aug 2013 · Clinical and Experimental Neuroimmunology
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    ABSTRACT: Objectives Human peripheral blood monocytes comprise three different subtypes: CD14+CD16− (classical type), CD14lowCD16+ (non-classical type) and CD14+CD16+ (intermediate type). These subsets are known to have different functions, but little is known about their roles in multiple sclerosis (MS), especially for maintaining remission. We aimed to clarify the alterations in monocyte subsets in patients with MS and neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) in the remission phase. Methods Blood samples were collected from 19 MS patients and 10 NMO/NMOSD patients in the remission phase, and 42 healthy controls (HC). The surface expressions of CCR2, CX3CR1, CD64 (FcγR1) and CD62L were analyzed in the monocyte subsets by flow cytometry. ResultsCCR2 expression was significantly decreased in classical monocytes from MS patients, regardless of interferon-β (IFN-β) treatment, but not in those from NMO/NMOSD patients. CX3CR1 expression was also decreased in all monocyte subsets from MS patients receiving IFN-β, whereas CX3CR1 expression in classical monocytes was only decreased in NMO/NMOSD patients receiving prednisolone. In NMO/NMOSD patients on prednisolone, the percentages of CD14+CD16+ intermediate monocytes, CD14lowCD16+ non-classical monocytes and CD64+CD14+CD16+ monocytes among total monocytes were significantly lower than in HC. CD62L expression on the monocyte subsets showed no significant differences among the patients and HC. Conclusions Our findings suggest that alterations in chemokine receptor expressions on peripheral blood monocytes can occur in MS and NMO/NMOSD during the remission phase. Down-modulation of CCR2 in MS, and CX3CR1 in MS and NMO/NMOSD could partly contribute to sustained remission by preventing monocyte infiltration into the central nervous system.
    No preview · Article · Aug 2013 · Clinical and Experimental Neuroimmunology
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    Dataset: Table S4
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    ABSTRACT: Demographic features of MS patients without LESCLs according to the presence or absence of the HLA-DRB1*0405 allele. Exclusion of eight MS patients with LESCLs gave essentially the same results; MS patients positive for DRB1*0405 showed a significantly earlier age of onset and a significantly lower PI compared with those without this allele. (DOC)
    Preview · Dataset · Nov 2012
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    Dataset: Table S1
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    ABSTRACT: Frequency of HLA-DRB1 alleles among MS patients without LESCLs and healthy controls. Exclusion of eight MS patients with LESCLs gave essentially the same results; MS patients showed a significantly higher frequency of DRB1*0405, and lower frequency of DRB1*0901 compared with HCs. (DOCX)
    Preview · Dataset · Nov 2012
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    ABSTRACT: Background Nationwide surveys conducted in Japan over the past thirty years have revealed a four-fold increase in the estimated number of multiple sclerosis (MS) patients, a decrease in the age at onset, and successive increases in patients with conventional MS, which shows an involvement of multiple sites in the central nervous system, including the cerebrum and cerebellum. We aimed to clarify whether genetic and infectious backgrounds correlate to distinct disease phenotypes of MS in Japanese patients. Methodology/Principal Findings We analyzed HLA-DRB1 and -DPB1 alleles, and IgG antibodies specific for Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus, and Epstein-Barr virus nuclear antigen (EBNA) in 145 MS patients and 367 healthy controls (HCs). Frequencies of DRB1*0405 and DPB1*0301 were significantly higher, and DRB1*0901 and DPB1*0401 significantly lower, in MS patients as compared with HCs. MS patients with DRB1*0405 had a significantly earlier age of onset and lower Progression Index than patients without this allele. The proportion and absolute number of patients with DRB1*0405 successively increased with advancing year of birth. In MS patients without DRB1*0405, the frequency of the DRB1*1501 allele was significantly higher, while the DRB1*0901 allele was significantly lower, compared with HCs. Furthermore, DRB1*0405-negative MS patients were significantly more likely to be positive for EBNA antibodies compared with HCs. Conclusions Our study suggests that MS patients harboring DRB1*0405, a genetic risk factor for MS in the Japanese population, have a younger age at onset and a relatively benign disease course, while DRB1*0405-negative MS patients have features similar to Western-type MS in terms of association with Epstein-Barr virus infection and DRB1*1501. The recent increase of MS in young Japanese people may be caused, in part, by an increase in DRB1*0405-positive MS patients.
    Full-text · Article · Nov 2012 · PLoS ONE
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    Dataset: Table S3
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    ABSTRACT: Frequency of DRB1-DPB1 haplotypes. Compared with HCs, the haplotype frequencies in MS patients were significantly increased for the DRB1*0405-DPB1*0301 haplotype. (DOCX)
    Preview · Dataset · Nov 2012
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    Dataset: Table S2
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    ABSTRACT: Frequency of HLA-DPB1 alleles among MS patients without LESCLs and healthy controls. Exclusion of eight MS patients with LESCLs gave essentially the same results; MS patients showed a significantly higher frequency of DPB1*0301, and lower frequency of DPB1*0401 compared with HCs. (DOCX)
    Preview · Dataset · Nov 2012
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    ABSTRACT: Objective: To clarify whether genetic and common infectious backgrounds are distinct, according to anti-aquaporin 4 (AQP4) antibody status in Japanese patients with neuromyelitis optica (NMO). Methods: We analysed human leucocyte antigen (HLA)-DRB1 and HLA-DPB1 alleles, and IgG antibodies against Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus and Epstein-Barr virus nuclear antigen (EBNA) in 116 patients with NMO, including 39 patients with neuromyelitis optica spectrum disorder (NMOSD), 145 multiple sclerosis (MS) patients and 367 unrelated healthy controls. 77 NMO/NMOSD patients were seropositive for AQP4 antibody while 39 were seronegative. Results: Compared with healthy controls, NMO/NMOSD patients showed a significantly lower frequency of DRB1*0901 and significantly higher frequencies of DRB1*1602 and DPB1*0501, which conferred susceptibility to anti-AQP4 antibody positive NMO/NMOSD, but not antibody negative NMO/NMOSD. DRB1*0901 was a common protective allele, irrespective of the presence or absence of anti-AQP4 antibody. Anti-H pylori and anti-C pneumoniae antibodies were more commonly detected in anti-AQP4 antibody positive NMO/NMOSD patients than healthy controls. Antibody negative NMO/NMOSD patients did not differ from healthy controls regarding the presence of these antibodies. The presence or absence of antibodies against varicella zoster virus and EBNA did not vary among the groups. The frequencies of antibodies against these four pathogens were not significantly different between MS patients and healthy controls. Conclusions: Our results suggest that HLA-DRB1*1602 and DPB1*0501 alleles and H pylori and Chlamydia pneumonia infection are risk factors only for anti-AQP4 antibody positive NMO/NMOSD but not for anti-AQP4 antibody negative NMO/NMOSD.
    No preview · Article · Oct 2012 · Journal of neurology, neurosurgery, and psychiatry

Publication Stats

2k Citations
281.28 Total Impact Points

Institutions

  • 1996-2015
    • Kyushu University
      • Department of Neurology
      Hukuoka, Fukuoka, Japan
  • 2012
    • Ehime University
      • Department of Geriatric Medicine
      Matuyama, Ehime, Japan
  • 2009
    • Kumamoto University
      • Department of Immunogenetics
      Kumamoto, Kumamoto, Japan
  • 1999-2008
    • Fukuoka Institute of Technology
      Hukuoka, Fukuoka, Japan
  • 2004
    • Kyoto University
      • Institute for Virus Research
      Kioto, Kyōto, Japan
  • 1997
    • Tokyo Medical and Dental University
      • Department of Microbiology
      Edo, Tōkyō, Japan
    • Kitasato University
      • School of Science
      Edo, Tōkyō, Japan