Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Its early phase is characterized by a relapse-remitting disease course, followed by disability progression in the later stage. While chronic inflammation accompanied with degeneration is well-established as the key pathological feature, the pathogenesis of MS, particularly progressive MS, remains elusive. Sulfatide is a major glycolipid component of myelin, and previous studies in experimental autoimmune encephalomyelitis mouse models have demonstrated it to have immune-protective functions. Notably, sulfatide concentration is increased in the serum and cerebrospinal fluid of patients with MS, particularly those in a progressive disease course. Here, we show that the myelin-glycolipid sulfatide displays an ability to suppress the proliferation of polyclonally activated human T cells. Importantly, this suppressive effect was impaired in T cells obtained from MS patients having higher disability status. Therefore, it is plausible that progression of MS is associated with an escape from the immune-regulatory effect of sulfatide. Our study suggests that, although the precise mechanisms remain unrevealed, an escape of T cells from immunosuppression by sulfatide is associated with disease progression in the advanced stage. Further studies will provide novel insights into the pathogenesis of MS, particularly regarding disease progression, and help develop novel treatment strategies for this challenging disease.

DOI： 10.1007/s12035-022-02881-9

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Objective: Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Without reliable diagnostic biomarkers, the clinical and radiological heterogeneity of MS makes diagnosis difficult. Although magnetic resonance imaging (MRI) is a major diagnostic tool for MS, the association of MRI findings with the inflammatory profile in cerebrospinal fluid (CSF) has been insufficiently investigated. Therefore, we focused on CSF profile of MS patients and examined its association with MRI findings. Methods: Concentrations of 26 cytokines and chemokines were determined in CSF of 28 treatment-naïve MS patients and 12 disease-control patients with aquaporin-4 antibody-seropositive neuromyelitis optica spectrum disorder (NMOSD). Results: High levels of interleukin (IL)-6, IL-17A, B-cell activating factor (BAFF), a proliferation inducing ligand (APRIL), and CD40 ligand were correlated with the absence of at least one of the following three MRI findings in MS: an ovoid lesion, three or more periventricular lesions, and a nodular and/or ring-shaped contrast-enhancing lesion. The multivariate analysis revealed that elevated IL-17A was an independent predictor of absence of ovoid lesion and periventricular lesions less than three. MS patients were classified into a group with all three MRI findings (MS-full) and a group with less than three (MS-partial). The discriminant analysis model distinguished three groups: MS-full, MS-partial, and NMOSD, with 98% accuracy. Conclusion: The CSF inflammatory profile was associated with radiological findings of treatment-naïve MS. This result indicates the possible utility of combined CSF and MRI profiling in identifying different MS phenotypes related to the heterogeneity of underlying immune processes.

DOI： 10.3389/fneur.2022.1012857

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Language：English   Publisher：(一社)日本脳神経超音波学会  

下顎窓から測定した、内頸動脈(ICA)における脳血管反応性(CVR)診断の有用性について検討した。有効な側頭窓が確認された健常者25例(男性13例、女性12例、平均年齢39.9±13.7歳)を対象に、息こらえ試験を行い、CVR指標としてbreath holding index(BHI)を用い、息こらえ前後の平均血流速度からBHIを算出し、ICAで測定したBHI(BHIi)と同側中大脳動脈で測定したBHI(BHIm)との相関性を評価した。その結果、BHImおよびBHIiはそれぞれ平均0.93±0.29および平均0.92±0.32で、BHImとBHIiのSpearman相関係数は0.665であった。また、BHImにより決定されたCVR障害に対するBHIiのカットオフポイントは0.71で、感度と特異度はともに80%得られた。以上の結果から、側頭窓からの測定が不十分である場合には、下顎窓からのBHI測定が代替測定として有用であることが明らかにされた。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J02558&link_issn=&doc_id=20220113570003&doc_link_id=%2Fcn7neuro%2F2021%2F003403%2F003%2F0142-0147%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcn7neuro%2F2021%2F003403%2F003%2F0142-0147%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.msard.2021.103135

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ensci.2021.100346

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OBJECTIVE: To clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells. METHODS: A total of 24 immunotherapy-naive patients with anti-acetylcholine receptor (AchR) antibody-positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score. RESULTS: cTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOShighcTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOSlow cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement. CONCLUSIONS: Alternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.

DOI： 10.1212/NXI.0000000000000945

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BACKGROUND: Glomus tumors are soft tissue neoplasms comprised of glomus cells, vasculature, and smooth muscle cells, which occur commonly in a single subungual area of the digits, and their main clinical features include severe paroxysmal pain, localized tenderness, and cold hypersensitivity. CASE PRESENTATION: A 47-year-old Japanese man had suffered from chronic progressive paroxysmal shooting pain in his right leg since childhood. He avoided putting weight on his right foot whenever he walked. The frequency of paroxysmal pain and the number of tender points both gradually increased with age, and his right leg gradually atrophied. Magnetic resonance imaging of the lower extremity demonstrated multiple gadolinium-enhanced nodules that corresponded with his tender points. Excisional biopsy relieved his pain and provided a histopathological diagnosis of glomus tumors. CONCLUSION: This case suggests that small glomus tumors located in deep tissue may cause disuse atrophy because of their long delay before diagnosis. Clinicians should consider the potential for glomus tumors when patients exhibit unilateral lower limb muscular atrophy with pain.

DOI： 10.1186/s13256-020-02616-1

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Language：English   Publishing type：Research paper (scientific journal)  

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

DOI： 10.1038/s41598-020-79833-7

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Background: Multiple sclerosis (MS) is a relapsing, inflammatory, and demyelinating disease of central nervous system showing marked clinical heterogeneity. Many factors might influence the choice of relapse prevention drug, and treatment response varies among patients. Despite the enlargement of disease-modifying drugs for MS (MS-DMDs), some patients have been treated with corticosteroid and/or immunosuppressant (CS/IS). Objective: To clarify the radiological and laboratory features of MS treated with CS/IS for relapse prevention. Methods: Clinical records including radiological and laboratory findings, and drugs used for relapse prevention were reviewed retrospectively. Results: Out of 92 consecutive MS patients, 25 (27%) were treated with CS/IS. The followings were observed less frequently in patients treated with CS/IS than in those with MS-DMDs: three or more periventricular lesions, ovoid lesions, subcortical lesions, typical contrast-enhancing lesions, negative for serum autoantibodies, and positive for oligoclonal bands in the cerebrospinal fluid. Multiple logistic regression analysis revealed that the absence of typical contrast-enhancing lesions and positivity for serum autoantibodies were independent factors associated with CS/IS prescription (odds ratio 25.027 and 14.537, respectively). Conclusion: In this cohort of Japanese patients clinically diagnosed with MS, radiological and serological findings atypical of MS were observed more frequently in patients treated with CS/IS than in those with MS-DMDs as a part of MS therapy. The absence of contrast-enhancing lesions typical of MS and positivity for serum autoantibodies were independent factors strongly associated with CS/IS use.

DOI： 10.3389/fneur.2021.749406

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We describe a 61-year-old woman with bilateral parkinsonism caused by unilateral infarction limited to the territory of the lenticulostriate arteries. Although dopamine transporter imaging with single-photon emission computed tomography (DaTSPECT) demonstrated reduced putaminal tracer binding concordant with the size and location of the vascular lesion, the specific binding ratio was within the normal range. Five months after onset, the patient was free from parkinsonism without the use of any antiparkinsonian agents. When patients show bilateral parkinsonism, it is important to consider infarction of the lenticulostriate arteries. Additionally, DaTSPECT might be useful for predicting the prognosis of parkinsonism caused by infarction.

DOI： 10.1016/j.ensci.2020.100291

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal-dominant type of leukoencephalopathy caused by gene mutation of colony stimulating factor 1 receptor, which is expressed mainly on monocyte lineage cells such as monocytes in the peripheral blood and microglia in the brain. Hence, microglial dysfunction is regarded as critical in the pathogenesis of ALSP. However, functional changes in these cells have not been elucidated. In this study, we report the phenotypic and functional alterations of monocytes in four patients with ALSP. Flow cytometric analysis revealed altered expression of antigen presentation- and migration-related molecules, an inflammatory shift in cytokine production and phagocytic impairment in ALSP monocytes. We speculate that the observed altered features of monocytes are mostly shared by microglial cells, leading to the clinical history and pathological characteristics of ALSP. Our analysis of PB monocytes provides novel insights into the pathogenesis of ALSP.

DOI： 10.1016/j.nbd.2020.104867

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Multiple sclerosis (MS) is a worldwide disease with an uneven geographic distribution. There has been a sharp increase in MS prevalence over time almost throughout the world, including Japan. The reasons for the increase in the prevalence of MS are unknown. However, evidence suggests that genetic and environmental factors and their interaction contribute to the etiology of MS. Therefore, the increase in prevalence can be attributed in part to a greater exposure to certain environmental risk factors in genetically susceptible individuals and also to increased survival rates and improved assessment. To clarify whether the increase in MS prevalence reflects a real increase in disease frequency, it is essential to assess temporal and geographical differences in MS incidence and to compair incidence in different ethnic populations. However, epidemiological data on incidence are limited, and there are marked geographical disparities in available data, most of which were obtained from studies in Europe and North America. In addition, there are marked variabilities in methodology, objectives, and study periods. Further epidemiological studies with appropriate standardization are needed to determine whether the risk of MS has changed over time.

DOI： 10.11477/mf.1416201551

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal dominant neurodegenerative disorder caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We, herein, report the first Japanese case of ALSP caused by a de novo p.Phe849del mutation in CSF1R: a 44-year-old man who presented callosal disconnection symptoms. Brain MRI revealed dilation of the lateral ventricles, periventricular white matter hyperintensities, and thinning of the corpus callosum with hyperintensities on T2-weighted and FLAIR images. Brain single photon emission computed tomography (SPECT) showed hypoperfusion in the anterior corpus callosum. White matter lesions in MRI and hypoperfusion in SPECT increased with age. A brain biopsy at 44 years revealed axonal spheroids. Callosal disconnection symptoms and hypoperfusion in the anterior corpus callosum may be important indicators of ALSP, especially when caused by a p.Phe849del CSF1R mutation.

DOI： 10.1111/ncn3.12367

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Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.

DOI： 10.1111/neup.12614

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DOI： 10.11477/mf.1416201233

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/jnnp-2018-319376

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© 2018 Japanese Society for Neuroimmunology A multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study of BG00012 in participants from the Asia–Pacific region and other countries with relapsing–remitting multiple sclerosis (APEX), including Japan, established the efficacy of dimethyl fumarate (DMF) in preventing relapses and disease progression in patients with multiple sclerosis (MS). Consequently, in December 2016, DMF was approved as the second oral disease-modifying drug for MS in Japan. However, the new Japanese guidelines for MS and neuromyelitis optica published in 2017 did not include DMF. Later, after the committee discussed a guideline for DMF, a supplement of the new guidelines for MS and neuromyelitis optica, which included DMF, was published in June 2018; this supplement comprised the following four clinical questions: (i) is DMF effective in preventing relapses in patients with MS?; (ii) is DMF effective in preventing disease progression in patients with MS?; (iii) how to use DMF?; and (iv) what adverse events does DMF possibly cause? Furthermore, the supplement comprised answers to the questions and comments. Overall, this supplement is anticipated to contribute toward the treatment of Japanese MS patients with DMF.

DOI： 10.1111/cen3.12477

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12325-018-0788-8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press  

Background: B cells play an important role in the development of multiple sclerosis (MS), but can also exhibit regulatory functions through IL-10 production. Toll-like receptors (TLR) and CD40 signaling are likely to be involved in this process. Objective: To investigate the ability of MS B cells to produce IL-10 in response to TLR stimulation in the presence or absence of CD40 co-stimulation. Methods: Peripheral blood mononuclear cells obtained from 34 MS patients and 24 matched healthy participants (HS) were stimulated through either TLR4 or TLR9 alone, or together with CD40. Intracellular cytokine production was analyzed by flow cytometry. Results: The frequency of IL-10-producing cells in total B cells after either TLR9 or CD40 stimulation was significantly lower in MS than HS, regardless of disease phase. The frequency of IL-10 producing B cells after TLR4 stimulation did not differ significantly between HS and MS, regardless of disease phase. TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse. This effect was observed in both CD27− naïve and CD27+ memory B cells. The frequency of IL-10-producing B cells following CD40 stimulation was significantly higher in interferon-β responders than non-treated MS patients. Finally, we confirmed that the frequency of IL-10-producing B cells positively correlated with IL-10 production quantity by B cells using magnetic-isolated B cells. Conclusions: Cross-talk between TLR4 and CD40 signaling plays a crucial role in regulating IL-10 production by B cells during MS relapses, which may promote recovery from relapse. CD40 signaling in B cells is involved in the response to interferon-β in MS. Collectively, TLR4 and CD40 signaling in B cells may provide a promising target for MS therapy.

DOI： 10.1016/j.jaut.2017.10.011

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We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3+ T, F4/80+, and CD169+ cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS.

DOI： 10.1038/s41598-018-20390-5

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Language：English   Publisher：Wiley-Blackwell  

Many types of genetic variations have evolved in humans as a result of evolutionary adaptation to malaria. Steri et al. reported that a genetic variant that provided resistance to Plasmodium falciparum or Plasmodium vivax malaria might have increased the susceptibility to multiple sclerosis among Sardinians.

DOI： 10.1111/cen3.12412

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Language：English   Publisher：Wiley-Blackwell  

Multiple sclerosis (MS) is a complex immune-mediated disease characterized by recurrent demyelinating episodes of the central nervous system, which typically occurs in young adults. It is the most common disabling neurological disease of young people
however, pediatric MS, defined as onset of MS before the age of 18 years, has been increasingly recognized worldwide in the past two decades. Pediatric MS might represent up to 10% of all patients with MS. As in adults, the diagnosis of pediatric MS rests on the demonstration of dissemination of lesions in both space and time, and the exclusion of alternative diagnosis. However, it can be more difficult to distinguish MS accurately from other conditions in children compared with the adult population, because there is considerable overlapping of clinical and magnetic resonance imaging features between pediatric MS and other acquired demyelinating disorders of the central nervous system. In view of therapeutic strategies, although interferon-beta and glatiramer acetate are the most commonly used disease-modifying drugs for pediatric MS so far, none of the current available disease-modifying drugs were tested in pediatric MS by randomized controlled trials, and thus there is limited information regarding the efficacy and safety. The present review article describes the epidemiology, clinical features, consensus definition and treatment strategy of pediatric MS.

DOI： 10.1111/cen3.12347

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease. Fingolimod, a highly effective disease-modifying drug for MS, retains CCR7(+) central memory T cells in which autoaggressive T cells putatively exist, in secondary lymphoid organs, although relapse may still occur in some patients. Here, we analyzed the T cell phenotypes of fingolimod-treated, fingolimod-untreated patients, and healthy subjects. The frequency of CD56(+) T cells and granzyme B-, perforin-, and Fas ligand-positive T cells significantly increased during fingolimod treatment. Each T cell subpopulation further increased during relapse. Interestingly, T cells from fingolimod-treated patients exhibited interferon-gamma biased production, and more myelin basic protein-reactive cells was noted in CD56(+) than in CD56(-)T cells. It is likely that the altered T cell phenotypes play a role in MS relapse in fingolimod-treated patients. Further clinical studies are necessary to investigate whether altered T cell phenotypes are a biomarker for relapse under fingolimod therapy.

DOI： 10.1038/srep35314

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Background: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO).
Objective: To explain differences in treatment responses of MS and NMO patients to IVMP.
Methods: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases.
Results: In MS patients, decreased EDSS score was significant after the first (-0.80.9), second (-0.7 +/- 0.9), and third (-0.7 +/- 0.8) courses (p<0.05), but not after the fourth (-0.3 +/- 0.7) and fifth (-0.5 +/- 0.6). However, decreased EDSS score was only significant after the first course (-0.5 +/- 1.5, p<0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p<0.05), but not thereafter. Model analysis for EDSS score improvement at the first course, adjusting for covariates, showed significantly greater decreases in MS compared with NMO patients (p<0.05).
Conclusion: IVMP is effective in MS from the first to third courses, and in NMO at the first course. Additionally, IVMP is more efficacious in MS than NMO patients, even at the first course.

DOI： 10.1177/1352458515617248

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Language：English   Publisher：Wiley-Blackwell  

Multiple sclerosis (MS) is a complex immune-mediated disease of the central nervous system. Traditionally, it has been considered to be mediated primarily by T cells, and the contribution of B�cells in the pathogenesis of MS has long been debated. However, clinical trial results of B-cell depletion therapies have established the central role of B�cells in the pathogenesis of MS and their contribution to MS disease activity through antibody-independent pro-inflammatory function. One of the monoclonal antibodies targeting the B-cell surface antigen CD20, ocrelizumab, has shown efficacy in both relapsing–remitting and primary progressive MS in phase�III clinical trials, whereas the potential role of B�cells in compartmentalized central nervous system inflammation that might underlie tissue injury in progressive MS still continues to be debated. Furthermore, the failure of atacicept, which targets the B-cell survival factors and a proliferation-inducing ligand, suggests that B�cells potentially have a dual role in the pathogenesis of MS, and the role of B�cells in MS is highly complex. In the present review, we discuss the role of B�cells in the pathogenesis of MS and review available clinical efficacy data on B-cell-targeted therapy in MS.

DOI： 10.1111/cen3.12328

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

PURPOSE OF REVIEW: The present review aims to discuss the recent advances in inflammatory demyelinating diseases of the central nervous system in Asia. RECENT FINDINGS: Prevalence of multiple sclerosis (MS) in Asia is lower than that in Western countries, although it has been increasing recently. Meanwhile, there seems to be no major difference in neuromyelitis optica (NMO) prevalence in various regions or ethnicities. Thus, the ratios of NMO/NMO spectrum disorder (NMOSD) to MS are higher in Asia as compared with Western countries, indicating that the differential diagnosis between NMO/NMOSD and MS is a major challenge in Asia. Although the detection of aquaporin-4 (AQP4)-antibody is critical in distinguishing NMO/NMOSD from MS, some patients with NMO/NMOSD phenotype are seronegative for AQP4-antibody, and a fraction of those patients possess autoantibody against myelin oligodendrocyte glycoprotein. The clinical profile of Asian MS seems to be essentially similar to that in Western MS after careful exclusion of NMO/NMOSD, although some unique genetic and/or environmental factors may modify the disease in Asians. SUMMARY: MS prevalence has been low but is increasing in Asia. In contrast, NMO/NMOSD prevalence seems relatively constant in the world. Asian MS is not fundamentally different from Western MS, but some genetic and/or environmental differences may cause some features unique to Asian patients.

DOI： 10.1097/WCO.0000000000000328

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Language：English   Publisher：Wiley-Blackwell  

DOI： 10.1111/cen3.12297

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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DOI： 10.3995/jstroke.37.36

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1111/cen3.12168

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Multiple sclerosis (MS) is a complex immune mediated disease of the central nervous system. It is characterized by inflammatory and neurodegenerative processes that result in neuroaxonal damage. Its etiology is still unknown, and its pathogenesis is only partly understood. There have been major advances in the treatment of MS in the past two decades, and a wide range of immunomodulagtory and immunosuppressive therapies have been used for the management of MS. More recently, there has been a growing interest in immunotherapeutic strategies with selective actions that target biological molecules involved in MS pathogenesis. Thus, better understanding of the immunopathogenesis of MS is believed to result in the development of more efficacious treatment. However, in contrast to the successful introduced therapies, such as natalizumab and alemtuzumab, there have been a remarkable number of therapeutic failures as well. Despite the convincing immunological concepts and promising results from animal models of MS, some drugs showed no clinical efficacy or even worsened the disease. Clinical trial results of molecular targeted therapy that shed light on the improving understanding of the immunopathogenesis of MS are discussed in the present review. These trials include monoclonal antibodies against leukocyte differentiation molecules (anti-CD3 and anti-CD4 antibodies), tumor necrosis factor-α neutralization, targeting the interleukin (IL)-12/IL-23 pathways, immune cell-depleting ant-CD52 monoclonal antibody and targeting IL-2 receptor signaling.

DOI： 10.1111/cen3.12159

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Authorship：Lead author   Language：English   Publisher：Wiley-Blackwell  

The autoimmune regulator (Aire) is a key transcription factor that promotes promiscuous expression of tissue-specific antigens by medullary thymic epithelial cells (mTEC), and mediates a role in negative selection of autoreactive T cells. Tagawa et al. reported the central role of Aire in establishing central tolerance to myelin antigen, and its deficiency resulted in spontaneous autoreactivity against central nervous system myelin antigen. The role of mTEC-dependent tolerance in multiple sclerosis must await further study.

DOI： 10.1111/cen3.12145

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

BACKGROUND: 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. METHODOLOGY: 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). PRINCIPAL FINDINGS: 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. CONCLUSIONS: 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.

DOI： 10.1371/journal.pone.0095367

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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. Results In 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. © 2013 Japanese Society for Neuroimmunology.

DOI： 10.1111/cen3.12071

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The role of B cells in multiple sclerosis pathogenesis is being increasingly recognized. Although B cells certainly play a critical role in adaptive immunity through antibody secretion, what has received a lot of attention in multiple sclerosis is the antibody-independent B cell functions. © 2013 Japanese Society for Neuroimmunology.

DOI： 10.1111/cen3.12072

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BACKGROUND: To improve quality of life (QOL) in patients with multiple sclerosis (MS), it is important to decrease disability and prevent relapse. The aim of this study was to examine the causal and mutual relationships contributing to QOL in Japanese patients with MS, develop path diagrams, and explore interventions with the potential to improve patient QOL. METHODS: Data of 163 Japanese MS patients were obtained using the Functional Assessment of MS (FAMS) and Nottingham Adjustment Scale-Japanese version (NAS-J) tests, as well as four additional factors that affect QOL (employment status, change of income, availability of disease information, and communication with medical staff). Data were then used in structural equation modeling to develop path diagrams for factors contributing to QOL. RESULTS: The Expanded Disability Status Scale (EDSS) score had a significant effect on the total FAMS score. Although EDSS negatively affected the FAMS symptom score, NAS-J subscale scores of anxiety/depression and acceptance were positively related to the FAMS symptom score. Changes in employment status after MS onset negatively affected all NAS-J scores. Knowledge of disease information improved the total NAS-J score, which in turn improved many FAMS subscale scores. Communication with doctors and nurses directly and positively affected some FAMS subscale scores. CONCLUSIONS: Disability and change in employment status decrease patient QOL. However, the present findings suggest that other factors, such as acquiring information on MS and communicating with medical staff, can compensate for the worsening of QOL.

DOI： 10.1186/1471-2377-13-10

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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.

DOI： 10.1136/jnnp-2012-302925

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Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by monogenic mutations in the autoimmune regulator (AIRE) gene. No attention has been paid to muscle manifestations in this disorder. We aimed to uncover whether progressive myopathy is a component of this disorder. Methods: A case description and literature search for APECED cases presenting with myopathy and analysis of AIRE gene expression in biopsied muscles from 4 healthy volunteers and the patient by reverse transcriptase polymerase chain reaction. Results: A 52-year-old woman with APECED caused by AIRE gene mutations developed progressive myopathy involving proximal limb and paraspinal muscles. Muscle biopsy specimens showed myopathic changes without inflammatory cell infiltrate. We detected AIRE gene expression in all muscle tissues examined. An extensive literature search uncovered 5 cases of APECED with myopathy, all of whom had similar features. Conclusions: Progressive myopathy involvement could be a hitherto unknown manifestation of APECED. Muscle Nerve 45: 904-908, 2012

DOI： 10.1002/mus.23321

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PURPOSE: To evaluate health-related quality of life (HRQOL) in Japanese patients with multiple sclerosis (MS) and investigate associations between the results of these QOL assessments and disease severity. METHODS: One-hundred sixty-three Japanese MS patients completed a questionnaire battery comprising the Functional Assessment of MS (FAMS), the Nottingham Adjustment Scale-Japanese version (NAS-J), and the European QOL scale (EQ-5D). Additional five factors affecting QOL as identified by MS patients in a focus group interview were also investigated: employment status, change of income, availability of disease information, communication with medical staff, and care received. Disease severity was determined using the Expanded Disability Status Scale (EDSS). RESULTS: There was a strong negative correlation of the subscale scores for mobility, symptoms, emotional well-being, thinking and fatigue, and additional concerns on the FAMS with EDSS score. For the NAS-J, only acceptance of the condition was correlated with disease severity. Among the five additional aspects of the condition identified by patients, employment status, income, and disease information were shown to be important for maintaining QOL in patients with MS. CONCLUSIONS: Support for finding employment and having increased or maintained household income and readily available information about the disease contribute to improving QOL in Japanese MS patients.

DOI： 10.1007/s11136-010-9725-2

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Objective: To clarify brain-derived neurotrophic factor production by peripheral blood immunocytes and its relationship with clinical parameters in multiple sclerosis.
Methods: Serum brain-derived neurotrophic factor levels were measured by conventional enzyme-linked immunosorbent assay while brain-derived neurotrophic factor production by immunocytes was determined by an in situ enzyme-linked immunosorbent assay in 74 multiple sclerosis patients, 32 healthy controls, and 86 patients with other neurological diseases. The tyrosine kinase receptor TrkB expression level in peripheral blood mononuclear cells was measured by real-time polymerase chain reaction.
Results: Multiple sclerosis patients showed significantly higher serum brain-derived neurotrophic factor levels than healthy controls and patients with other neurological diseases. Multiple sclerosis patients with high brain-derived neurotrophic factor levels were younger, and showed fewer relapse numbers than those with low brain-derived neurotrophic factor levels. Brain-derived neurotrophic factor production by T cells increased with age in healthy controls, but not in multiple sclerosis patients. Interferon beta induced a significant increase in serum brain-derived neurotrophic factor levels. Brain-derived neurotrophic factor production from T cells and TrkB expression levels in peripheral blood mononuclear cells were significantly enhanced in interferon beta-treated multiple sclerosis patients compared with untreated ones. Conclusions: A high brain-derived neurotrophic factor level is related to early mild disease in young multiple sclerosis patients. Interferon beta potentiates brain-derived neurotrophic factor production and brain-derived neurotrophic factor receptor expression in peripheral blood mononuclear cells, which may act beneficially.

DOI： 10.1177/1352458510375706

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1212/WNL.0b013e3181a0fe74

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Objective Because Asian patients with opticospinal multiple sclerosis (OSMS) frequently have anti-aquaporin-4 (AQP4) antibody, complement-mediated disruption of astrocyte foot processes is proposed but not yet proven. We aimed to clarify whether complement consumption occurs at relapse in anti-AQP4 antibody-positive patients.
Methods We analyzed serum CH50, C3, C4, and C-reactive protein (CRP) levels and their relation to clinical phases in 118 MS patients with or without anti-AQP4 antibody. Serum CH50 levels were higher in 24 patients with anti-AQP4 antibody than in 39 OSMS and 54 conventional form of MS (CMS) patients without anti-AQP4 antibody at relapse (P(corr) < 0.05) but not in remission. The frequency of hypercomplementemia at relapse was also higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative CMS patients (70.4% vs 29.0%, P(corr) < 0.05). C3 and C4 levels did not differ significantly among the three groups at relapse. In patients with anti-AQP4 antibody, the coexistence of hypercomplementemia and high CRP values was more common at relapse than in the remission phase (36.0% vs 10.5%, P < 0.05). In patients with extensive central nervous system lesions, hypercomplementemia was significantly more common in anti-AQP4 antibody-positive patients than anti-AQP4 antibody-negative ones (88.9% vs 16.7%, P < 0.01). We consider that hypercomplementemia in anti-AQP4 antibody-positive patients may reflect a systemic inflammatory reaction at relapse. Multiple Sclerosis 2009; 15: 304-310. http://msj.sagepub.com

DOI： 10.1177/1352458508099139

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Background There are two distinct phenotypes of multiple sclerosis (MS) in Asians, manifesting as optic-spinal (OSMS) and conventional (CMS) forms. In Japan, four nationwide surveys of MS have been conducted. The first three were in 1972, 1982, and 1989, and we performed the fourth in 2004. Results The recent survey showed six main findings as follows: (1) a four-fold increase in the estimated number of clinically definite patients with MS in 2003 (9900; crude MS prevalence, 7.7/100,000) compared with 1972; (2) a shift in the peak age at onset from early 30s in 1989 to early 20s in 2003; (3) a successive proportional decrease in optic-spinal involvement in clinically definite patients with MS; (4) a significant north-south gradient for the CMS/OSMS ratio; (5) after subdivision of the mainland (30-45 degrees North) into northern and southern parts at 37 degrees N, northern-born northern residents (northern patients) showed a significantly higher CMS/OSMS ratio and higher frequency of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) than southern-born southern residents (southern patients); (6) among northern patients, the absolute numbers of patients with CMS and those with Barkhof brain lesions rapidly increased with advancing birth year. Conclusions These findings suggest that MS phenotypes are drastically altered by environmental factors, such as latitude and "Westernization." Multiple Sclerosis 2009; 15: 159-173. http://msj.sagepub.com

DOI： 10.1177/1352458508098372

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

There are two subtypes of multiple sclerosis (MS) in Asians: the opticospinal (OSMS) form that shows a selective involvement of the optic nerve and the spinal cord and the conventional (CMS) form that has disseminated lesions in the central nervous system including the cerebrum, cerebellum and brainstem. Both show distinct human leukocyte antigen (HLA) class II associations. OSMS has similar features to the relapsing form of neuromyelitis optica (NMO) in Western populations. Recently, it was shown that antibodies to aquaporin-4 (AQP4) are specifically detected in NMO patients and in some Japanese patients with OSMS or recurrent optic neuritis or myelitis. To clarify the immunogenetic background of anti-AQP4 antibody production, we studied HLA-DRB1 and -DPB1 gene polymorphisms in anti-AQP4 antibody-positive and -negative patients with idiopathic demyelinating diseases, such as MS, recurrent optic neuritis and recurrent myelitis. The phenotypic frequency of the HLA-DPB1*0501 allele was significantly increased in anti-AQP4 antibody-positive patients (89.5%, odds ratio = 4.8; 95% confidence interval = 1.6-14.3, n = 38, P(corr) = 0.032) compared with controls (64.0%, n = 125) but not in either anti-AQP4 antibody-negative OSMS (75.0%, n = 32) or CMS (69.2%, n = 52) patients. There was no significant correlation between any HLA-DRB1 allele and the existence of anti-AQP4 antibody. These findings suggest that the emergence of anti-AQP4 antibody is reinforced by the presence of the HLA-DPB1*0501 allele in Japanese.

DOI： 10.1111/j.1399-0039.2008.01172.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

juvenile Muscular atrophy of the distal upper extremity (JMADUE) is associated with airway allergy and hyperIgEaemia, suggesting the involvement of immunological processes. In this study we aimed to clarify the changes in various cytokines/chemokines in cerebrospinal fluid (CSF) from JMADUE patients. We simultaneously measured 17 cytokines/chemokines in sera and CSF from 6 patients with JMADUE before treatment and from 14 patients with cervical spondylosis (CS) as a disease control (mean age at examination 23 +/- 7 and. 57 +/- 16 years, respectively), using a fluorescent bead-based immunoassay. We also assayed CSF from a JMADUE patient before and after plasma exchanges. In sera, only an increase of MIP-1 beta (CCL3) in the JMADUE patients had a marginal significance as compared with the CS patients. In the CSF, IFN-gamma and MIP-1 beta (CCL3) were significantly elevated in JMADUE patients compared with controls (1.5 and 2-fold increases, respectively), while no other cytokines/chemokines showed any significant differences. Moreover, the upregulated cytokines decreased after plasma exchanges in accord with improvement of distal upper limb weakness. The intrathecal upregulation of proinflammatory Th1 cytokines/chemokines, such as IFN-gamma and MIP-1 beta (CCL3), in the CSF of JMADUE patients indicates the possible involvement of intrathecal immunological processes in this condition. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2008.07.020

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One of the major goals for the immunotherapy of autoimmune diseases is the induction of regulatory T cells that mediate immunologic tolerance. Parenteral administration of anti-CD3 monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We have found that oral administration of anti-CD3 monoclonal antibody is biologically active in the gut and suppresses experimental autoimmune encephalomyelitis both prior to disease induction and at the height of disease. Oral anti-CD3 antibody acts by inducing a unique type of regulatory T cell characterized by latency-associated peptide (LAP) on its cell surface that functions in vivo and in vitro via TGF-beta dependent mechanism. Orally delivered antibody would not have side effects including cytokine release syndromes, thus oral anti-CD3 antibody is clinically applicable for chronic therapy. These findings identify a novel and powerful immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

DOI： 10.1016/j.jns.2008.07.027

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: We reported the emergence of a distinct myelitis in patients with atopic diathesis (atopic myelitis [AM]) by a nationwide survey throughout Japan. Similar cases have recently been reported in Caucasians. Pathologic studies of biopsied spinal cord specimens revealed chronic active inflammation with eosinophilic infiltration.
Objective: To clarify the cytokine/chemokine alterations in CSF from patients with AM in comparison to other causes of myelitis.
Methods: We measured 27 cytokines, chemokines, and growth factors simultaneously in CSF from 22 patients with AM, 20 with opticospinal multiple sclerosis (OSMS), 11 with HTLV-1 associated myelopathy (HAM), 9 with Sjogren syndrome-related myelitis (SM), and 20 with other noninflammatory neurologic diseases (OND), using a fluorescent bead-based immunoassay.
Results: In patients with AM, CCL11 and interleukin (IL)-9 were significantly increased as compared with patients with OND and other myelitis while in patients with OSMS interferon-gamma and granulocyte-colony stimulating factor levels were significantly higher than in patients with OND and other causes of myelitis. Significant increase of IL-17 in comparison to patients with OND was found only in patients with OSMS, irrespective of presence or absence of anti-aquaporin- 4 (AQP4) antibody. In patients with HAM, CXCL10 and CCL5 were higher than in patients with OND and other myelitis. In patients with SM, CCL3 and CCL4 were higher than in patients with OND. In patients with AM, CCL11, IL-9, and IL-1 receptor antagonist (IL-1ra) showed positive correlations with the final Kurtzke Expanded Disability Status Scale scores while IL-1ra and IL-12(p70) had positive correlations with disease duration.
Conclusion: Intrathecal upregulation of CCL11 and Th2 cytokines is characteristic of atopic myelitis, which is distinct from interleukin-17/interferon-gamma-related autoimmune condition of opticospinal multiple sclerosis.

DOI： 10.1212/01.wnl.0000326589.57128.c3

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There are two distinct subtypes of multiple sclerosis (MS) in Asians: optic-spinal (OSMS) and conventional (CMS). Longitudinally extensive spinal cord lesions (LESCLs) extending over three or more vertebral segments are characteristic of patients with OSMS, yet in Asians, one-fourth of CMS patients also have LESCLs. To clarify the distinction between LESCLs in OSMS and CMS, and to characterize the relationship between the presence of LESCLs and brain magnetic resonance imaging (MRI) findings, we studied 142 patients with clinically definite MS of relapsing-remitting onset and 12 patients with primary progressive MS (PPMS) by MRI of the whole spinal cord and brain. The former was diagnosed by Poser criteria, including 57 with OSMS, 67 with CMS and 18 with brainstem-spinal form of MS, while the latter by McDonald criteria. The presence of LESCLs throughout the entire clinical course was significantly more common in OSMS patients than in CMS patients, while brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) were significantly more common in CMS patients than OSMS patients. LESCLs in OSMS patients most frequently affected the upper to middle thoracic cord, with either holocord or central gray matter involvement. By contrast, 70% of LESCLs in CMS patients predominantly affected the peripheral white matter of the mid-cervical cord. LESCLs in patients with PPMS also showed preferential involvement of the peripheral white matter of the mid-cervical cord. One-third of OSMS patients had neither LESCLs nor Barkhof brain lesions more than 10 years after disease onset, and showed significantly milder disability than OSMS patients with LESCLs. These findings suggest that LESCLs are heterogeneous between OSMS and CMS patients, and that there are distinct subtypes of MS in Japanese, according to clinical and MRI findings. (c) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2007.09.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

DOI： 10.1159/000120689

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We present two patients with primary lateral sclerosis-like upper motor neuron disease accompanying subclinical Sjogren's syndrome. Both patients showed progressive spastic quadriparesis, but neither sensory involvement nor detrusor dysfunction was noted. Lower motor neuron signs were detected only in their late follow-up period. Although sicca symptom was nearly absent, salivary labial gland biopsy revealed marked sialoadenitis in both patients. They also displayed a constellation of findings that suggested an autoimmune etiology closely related to Sjogren's syndrome, including germinal center formation in one patient, and markedly elevated levels of anti-nuclear antibody with abnormal sialography in the other. Both patients showed significant neurological improvement after the initial course of intravenous immunoglobulin therapy. We suggest that the evidence for subclinical Sjogren's syndrome should be sought in patients presenting with selective upper motor neuron involvement.

DOI： 10.2169/internalmedicine.47.0846

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We present two patients with primary lateral sclerosis-like upper motor neuron disease accompanying subclinical Sjogren's syndrome. Both patients showed progressive spastic quadriparesis, but neither sensory involvement nor detrusor dysfunction was noted. Lower motor neuron signs were detected only in their late follow-up period. Although sicca symptom was nearly absent, salivary labial gland biopsy revealed marked sialoadenitis in both patients. They also displayed a constellation of findings that suggested an autoimmune etiology closely related to Sjogren's syndrome, including germinal center formation in one patient, and markedly elevated levels of anti-nuclear antibody with abnormal sialography in the other. Both patients showed significant neurological improvement after the initial course of intravenous immunoglobulin therapy. We suggest that the evidence for subclinical Sjogren's syndrome should be sought in patients presenting with selective upper motor neuron involvement.

DOI： 10.2169/internalmedicine.47.0846

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Anti-CD3 monoclonal antibody (mAb) has been shown to induce tolerance and to be an effective treatment for diabetes both in animal models and in human trials. We have shown that anti-CD3 mAb given orally is biologically active in the gut and suppresses experimental autoimmune encephalitis by the induction of a regulatory T-cell that expresses latency-associated peptide (LAP) on its surface. In the present study, we investigated the effect of oral anti-CD3 mAb on the prevention of autoimmune diabetes in AKR mice in which the low-dose streptozocin (STZ) model induces autoimmunity to the beta-cells of the islets. We found that oral anti-CD3 mAb given at doses of 50 and 250 mu g/feeding suppressed the incidence of diabetes in this model with the best effects seen at the 50 mu g/dose. Associated with suppression, we observed decreased cell proliferation in the spleen and conversion of T-helper (Th)1 responses into Th2/Th3 responses in the periphery, including the pancreatic lymph nodes. Oral anti-CD3 mAb increased the expression of LAP on CD4(+) beta-cells, and these cells could adoptively transfer protection. Protection by oral anti-CD3 was transforming growth factor-beta dependent. Our results demonstrate that oral anti-CD3 is effective in the model of STZ-induced diabetes and may be a useful form of therapy for type 1 diabetes in humans.

DOI： 10.2337/db06-1632

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the II patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-Ib than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.

DOI： 10.1093/brain/awm027

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To address the immune mechanism of the long-term beneficial effects of interferon beta (IFN-beta), we measured the intracellular cytokine production patterns of IFN-gamma, IL-4 and IL-13 in peripheral blood CD4(+) and CD8(+) T cells, which previously displayed alterations during the early course of IFN-beta treatment, in 15 Japanese patients after long-term IFN-beta administration. The patients were treated with IFN-beta-1b 8 X 106 units given subcutaneously every other day for a mean period of 34.5 +/- 5.5 months (range: 26-43 months). During the follow-up period, 6 patients experienced 33 relapses, while the other 9 were relapse-free. The results revealed the following cytokine alterations: (1) type 2 cytokine, such as IL-4 and IL-13, were significantly increased in producing cell percentages in both CD4(+) (p=0.0356 and p=0.0007, respectively) and CD8(+) (p=0.0231 and p=0.0170, respectively) T cells while IFN-gamma, a representative type I cytokine, was significantly decreased in the absolute producing cell numbers (p=0.0125 in CD4(+) T cells and p=0.0022 in CD8(+) T cells) even after approximately 3 years of IFN-beta administration; (2) the intracellular IFN-gamma / IL-4 ratio tended to decrease in both CD4+ and CD8+ T cells (p=0.0535 and p=0.0783, respectively), reflecting a strong downmodulation of type I cytokine producing cells; and importantly (3) alterations such as the decreased intracellular IFN-gamma / IL-4 ratio in CD4(+) T cells and increased percentage of CD8(+) IL-13(+) Tcells compared with the pretreatment levels were only statistically significant in MS patients without relapse during IFN-beta therapy (p=0.0152 and p=0.0078, respectively). Therefore, we consider that cytokine deviation toward the Th2 and Tc2 sides is linked to a long-term favorable response to IFN-beta, while a higher intracellular IFN-gamma / IL-4 ratio is associated with treatment failure. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2006.02.008

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

DOI： 10.1038/nm1408

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

SJL mice are highly susceptible to proteolipid protein (PLP) 139-151-induced experimental allergic encephalomyelitis (EAE). The disease is characterized by a relapsing-remitting type of paralysis. However, the mechanism by which animals recover from EAE is poorly understood. Here, we investigated the role of regulatory T cells in the recovery from disease. We found that Forkhead box P3-expressing CD4(+)CD25(+) T cells were increased in the blood, draining lymph node and spleen of EAE-recovered SJL mice. These cells were anergic and inhibited proliferation of CD4(+)CD25(-) T cells to PLP 139-151 or anti-CD3 antibody stimulation. Depletion of CD4(+)CD25(+) T cells during the recovery phase exacerbated disease, resulted in the expansion of IA(s)/PLP 139-151-tetramer-positive cells and enhanced IFN-gamma production. In addition, transforming growth factor-beta (TGF-beta) was shown to be involved in the recovery from EAE as the percentage of CD4(+) cells expressing TGF-beta latency-associated peptide (LAP) on the cell surface increased significantly in blood and spleen of EAE-recovered mice as compared with the naive mice and in vivo neutralization of TGF-beta abolished recovery from disease. Taken together, our results demonstrate that both CD4(+)CD25(+) and CD4(+)LAP(+) regulatory T cells mediate recovery from PLP 139-151-induced EAE in SJL mice in which TGF-beta plays an important role.

DOI： 10.1093/intimm/dxh390

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The patient was a 55-year-old man who had shown progressive dysarthria and unsteady gait since 48 years of age. Neurologically, pure cerebellar ataxia without either pyramidal or extrapyramidal signs was seen. He had been diagnosed as having cortical cerebellar atrophy (CCA) at age 53. Polysomnography was carried out at June 17 th, 2003, because of snoring and sleep apnea had occurred since January 2003. The results showed central dominant sleep apnea with an apnea index (AI) of 16.6. Apnea occurred during shallow sleep, stages I and II, while the length of REM sleep was almost normal, occupying 17.7% of total sleep time. The rhythm of his sleep was well preserved. Brain MRI showed cerebellar atrophy without any brainstem abnormality. Except for the central type sleep apnea, no other autonomic symptoms were found. We considered that the diagnosis of CCA remained applicable to the patient because of the presence of pure cerebellar symptoms over a 7-year-course, and the absence of brainstem atrophy on MRI. Sleep apnea seen in the present patient was distinct from MSA in which central type sleep apnea dominated, and that the sleeping rhythm including REM was preserved.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 74-year-old woman suffered from progressive muscle atrophy and weakness of her arms since she was seventy two years old. Before referral to our department, she was diagnosed as having cervical spondylotic myeloradiculopathy and received spinal fusion. Though spinal decompression was successful, muscle weakness of her upper limbs were progressive even after the surgery. On admission, neurological examinations revealed marked atrophy and weakness of her bilateral upper limbs with absent deep tendon reflexes showing man-in-the-barrel syndrome. Her lower extremities had normal muscle strength, but fasciculations were seen in her all four limbs. Electrophysiologically, motor nerve conduction velocity was almost normal but the amplitude was remarkably decreased, conduction block was not detected, and electromyography showed neurogenic patterns on her all extremities. Spinal progressive musclar atrophy (SPMA) accompanied with Sjögren's syndrome was the likely diagnosis. Because 50 kDa anti-neuronal antibodies were found in her serum, we assumed that anterior horn cells were impaired by an autoimmune mechanism. Thus we treated her with corticosteroid pulse therapy, plasma exchange (PE) and intravenous immunoglobulin infusion therapy (IVIG). Although steroid pulse therapy only had a minimal effect, PE and IVIG promoted a remarkable improvement on her weakness, and the effect lasted for about three months. This is the first case of SPMA with Sjögren's syndrome which showed good response to PE and IVIG in the early course of the disease. We considered that some SPMA-like motor neuron syndrome accompanied with autoimmune features may require immunomodulating therapies.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We evaluated the association of the platelet-activating factor receptor (PAFR) gene polymorphism (A224D) with the susceptibility and severity of multiple sclerosis (MS) in a Japanese population. DNA was collected from 162 Japanese patients with clinically definite 'conventional' MS (MS) and 245 healthy controls. The missense mutation A224D that impairs PAF-PAFR signaling was determined by polymerase chain reaction restriction fragment length polymorphism. The frequency of the AD/DD genotypes was significantly higher in MS patients (21.0%) than in healthy controls (13.5%) (p=0.045; odds ratio (OR), 1.71; 95% confidence interval (0), 1.01-2.89). Moreover, the frequency of D allele in MS patients (11.7%) was also significantly higher than those in healthy controls (6.9%) (p=0.019; OR, 1.78; 95% Cl, 1.10-2.89). These findings suggest that the PAFR gene missense mutation has a relation to the susceptibility for MS. (C) 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jneuroim.2004.12.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Juvenile muscular atrophy of the distal tipper extremity (JMADUE) is considered to be a type of flexion myelopathy: however,. we recently reported cases of JMADUE associated with airway allergy successfully treated by plasma exchange. To further characterize;he allergo-immunological features of JMADUE, 11 consecutive JMADUE patients in the neurology clinic at Kyushu University Hospital were studied. Past and present together with family histories of common allergic disorders were investigated. Total serum NE was measured by an enzyme linked immunosorbent assay (ELISA) and allergen-specific IgE by a liquid phase enzyme immunoassay. Intracellular interferon (IFN)gamma-, interleukin(IL)-4-, IL-5- and IL-13-producing T cells in peripheral blood were analyzed by flow cytometry. Data from 42 healthy subjects were used as controls for allergological studies. Flow cytometric data from 21 healthy subjects were also used for comparison. The patients exhibited significantly higher frequencies of coexisting airway allergies such as allergic rhinitis (p=0.0057) and pollinosis (p=0.0064), family histories of allergic disorders (p=0.0075). and mite antigen specific IgE (p=0.0361) compared with the healthy subjects. Patients with JMADUE had a significantly higher percentage of IFNgamma(-)IL-4(+)CD4(+) T cells (p=0.0017), but not IL-5- or IL-13-producing CD4(+) T cells. and a reduced intracellular IFNgamma/IL-4 ratio in CD4(+) T cells (p=0.002) compared to the controls. These findings suggest that JMADUE has a significant T helper 2 (Th2) shift, which may in part contribute to the development of spinal cord damage. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2004.10.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Interferonbeta-1b (IFNbeta-1b) is commonly used for relapsing-remitting multiple sclerosis (MS). We report a 23-year-old woman with childhood onset relapsing-remitting MS treated with IFNbeta-1b who developed overt chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) immediately after therapy. A baseline conduction study before IFNbeta-1b therapy revealed decreased motor conduction velocities and prolonged F wave latencies in several nerves, but there was no neurological sign indicating neuropathy. The existence of subclinical demyelinating neuropathy before IFNbeta-1b treatment was suggested, although the clinical criteria for CIDP were unfulfilled. Following two months of IFNbeta-1b therapy, numbness of her right upper and lower limbs progressively worsened and all tendon reflexes were depressed. Electrophysiologically, F waves were not evoked in any limbs except for the left ulnar and tibial nerves, which showed marked prolongation of F wave latencies. Moreover, subclinical hyperthyroidism developed in association with high titers of anti-thyroglobulin and antithyroid peroxydase antibodies, which were negative before IFNbeta-1b therapy. These findings indicated that peripheral demyelination worsened at the nerve roots after IFNbeta-1b therapy. In addition to the development of autoimmune thyroid disease, the patient now fulfilled the criteria for probable CIDP. Along with the results of a previous report demonstrating IFNbeta-induced CIDP development in patients with childhood MS, this case underscores IFNbeta as a potential risk factor for CIDP in patients with childhood onset MS.

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Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objective: A recent nationwide survey of myelitis with atopic diathesis in Japan disclosed that the disease frequently shows a chronic persistent course. A neuropathological study of the spinal cord also revealed chronic active inflammation. Since the effects of various immunotherapies have not been studied extensively in this condition, we evaluated the efficacies of various immunotherapies in patients with myelitis with atopic diathesis.
Patients and methods: Forty-two treatments in 26 patients with myelitis with atopic diathesis were retrospectively analyzed. One of the following therapies was administered: (1) corticosteroids (CS) (pulse therapy followed by oral administration with gradual tapering); (2) intravenous immunoglobulin (IVIG) (400 mg/kg/day for 5 consecutive days); (3) plasma exchanges (PE); or (4) PE followed by IVIG or CS (PE+IVIG/CS). The therapeutic efficacies were evaluated by thorough neurological examination and laboratory tests including MRI, somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs).
Results: Objective neurological findings improved in 89% of the PE group and 90% of the PE+IVIG/CS group, compared with only 72% of the CS and 60% of the IVIG groups. Improvement determined by laboratory tests was seen in 57% of the PE and 57% of the PE+IVIG/CS groups, compared with only 15% of the CS and none of the IVIG groups. Thus, the improvement rate determined by laboratory tests was significantly greater for therapies including PE than for those without PE (p=0.0187).
Conclusions: These data suggest that immunotherapy is effective in myelitis with atopic diathesis despite a chronic persistent course, and that PE is the most beneficial immunotherapy. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2004.08.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objectives: To investigate the frequency of allergic disorders in myasthenia gravis (MG) patients and characterize the features of MG associated with allergic disorders.
Methods: Frequencies of past and present common allergic disorders in 160 MG patients who visited the Department of Neurology, Kyushu University Hospital from April 2000 to July 2003 and in 81 neurological normal controls were studied.
Results: Among various allergic disorders, the frequency of allergic conjunctivitis (AC) was significantly higher in MG patients (39/160, 24.4%,p(corr)=0.0112), especially with MG without thymoma (36/123, 29.3%,p(corr)=0.0016), in comparison to the controls (6/81, 7.4%). MG patients with AC showed a significantly higher rate of seronegative MG (43.6% vs. 17.4%, p=0.008) and a higher tendency of ocular MG (43.6% vs. 28.1%, p=0.071). Moreover, MG with AC had significantly lower anti-acetylcholine receptor antibody titers (median 6.8 nmol/l vs. median 23.6 nmol/l, p=0.0359) as well as a lower rate of coexisting thymoma (7.7% vs. 17.4%, p=0.016). The incidence of myasthenic crisis was also lower in MG with AC than without AC, yet the difference was not significant (7.7% vs. 15.7%).
Conclusion: There was a significant association of AC with MG especially for ocular or seronegative MG in cases without thymoma. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2004.06.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To address the immune mechanism sustaining interferon beta (IFNbeta) efficacy in multiple sclerosis (MS), we longitudinally analyzed expressions of IFN-gamma, IL-4, IL-5 and IL-13 in CD4(+) T cells and CD8(+) T cells in 22 Japanese MS patients (16 patients with conventional MS and 6 with opticospinal MS) undergoing IFNbeta using flow cytometry. During the 48-week observation period, five opticospinal MS patients (83%) relapsed compared to only four conventional MS patients (25%); the frequency of relapsed patients was significantly higher in the former (p = 0.046). The effects of IFNbeta on individual cytokines were time-dependent and altered cytokine productions were particularly evident in CD4(+) rather than CD8(+) T cells. A decreased intracellular IFN-gamma/IL-4 ratio in CD4(+) T cells was thus evident soon after the initiation of therapy, and persisted for the entire 1 year follow-up period, regardless of whether or not the patient relapsed (p < 0.01). IFNbeta treatment resulted in a rapid increase in the percentage of IFN-gamma(-) IL-4(+) and IL-13(+) CD4(+) T cells 1 week after the initiation of therapy and high values were sustained for 6 months but declined to the baseline over 1 year. Later, the percentage of IFN-gamma(+) IL-4(-) CD4(+) T cells decreased significantly from weeks 24 through 48 of therapy (p < 0.01). When comparisons with the pretreatment values were made for each subtype of MS, a significant reduction of IFN-gamma(+) IL-4(-) CD4(+) T cell percentages was shown in conventional MS (p < 0.0001), but not in opticospinal MS. Moreover, when such a comparison was made by the presence or absence of relapse during therapy, a significant reduction of IFN-gamma(+) IL-4(-) CD4(+) T cell percentages was observed in MS patients without relapse (p < 0.01). Thus, a reduction of IFN-gamma(+) IL-4(-) CD4(+) T cell percentages in the late phase of therapy is considered important for reducing relapse in conventional MS. When the expression patterns of IFN-gamma IL-4, IL-5 and IL-13 in CD4(+) T cells and CD8(+) T cells were compared between patients with and without relapse during therapy, the only significant difference was an increase in the IL-13(+) CD4(+) T cell percentages in patients with relapse compared to those without (p < 0.05). The results indicate that in CD4(+) T cells IL-4 was preferentially up-regulated in the early course and IFN-gamma was down-regulated in the late phase of IFNbeta therapy. The net effect of IFNbeta on the immune balance was entirely toward type 2 immune deviation, possibly contributing to its beneficial effects on MS. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2004.04.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Two adult females developed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and psoriasis. Both showed chronic progressive paraparesis and sharply demarcated erythematous scaling plaques on their extremities and trunk. One patient had polymyositis while in the other anti-thyroid antibodies, antinuclear antibodies and SS-A antibody, all autoantibodies, were positive. Both patients were treated by intramuscular injections of interferon-alpha for 2 to 4 weeks, resulting in amelioration of paraparesis. After the therapy psoriasis and polymyositis markedly improved in one patient without any additional therapy, while in the other simultaneous use of topical corticosteroids was effective. This is the first report to describe occurrences of psoriasis in HAM/TSP patients. Although there are several reports indicating interferon-a induces or exacerbates psoriasis, our experience suggests that psoriasis associated with HAM/TSP can be successfully managed even during interferon-a therapy. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2004.02.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We evaluated the association of the plasma platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphism (G(994)-->T) and PAF-AH activity with susceptibility and severity of multiple sclerosis (MS) in Japanese. DNA was collected from 216 patients with clinically definite MS (65 opticospinal MS (OS-MS) and 151 conventional MS (C-MS)) and from 213 healthy controls. The missense mutation G(994)-->T that disrupts the PAF-AH activity was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No statistically significant difference in the frequency of genotypes and alleles of the plasma PAF-AH polymorphism was observed among OS-MS patients, C-MS patients and healthy controls. However, the missense mutation tended to be associated with the severity of OS-MS, especially in females (GT/TT genotypes; 51.7% in female rapidly progressive OS-MS vs. 26.6% in female controls, p = 0.0870). Moreover, PAF-AH activities were significantly lower in MS than in controls, irrespective of clinical subtypes, among those carrying the identical polymorphism in terms of nucleotide position 994 of the PAF-AH gene. These findings suggest that the PAF-AH gene missense mutation has no relation to either susceptibility or severity of C-MS, yet its activity is down-regulated, and that the mutation has no relation with susceptibility of OS-MS, yet it may confer the severity of female OS-MS. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.neuroim.2004.01.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Bone marrow transplantation (BMT) is accepted as an efficient therapy for X-linked adrenoleukodystrophy (ALD). To clarify the mechanisms of this treatment, we examined the effects of hematopoietic cell transplantation (HCT) in an ATP-binding cassette, subfamily D, member 1 (ABCD1) knock out mice and co-culture of ALD patient fibroblasts with normal cells. We treated ABCD1 knock out mice with HCT using lacZ-transgenic mice as donors, which enabled us to detect donor-derived cells. We also examined the effects of co-culturing a normal microglia cell line (N9) with ALD fibroblasts. beta-Galactosidase (beta-GAL) activity was higher in spleen, lung and kidney than in liver, brain and spinal cord of the recipient ABCD1 knock out mice. HCT reduced the accumulation of very long chain fatty acid (VLCFA) in those tissues. The reduction of the VLCFA ratio was significant in spleen and lung; tissues with higher beta-GAL activity. ABCD1 was detectable in spleen from HCT mice. Co-culture of ALD fibroblasts with normal fibroblast cells reduced VLCFA accumulation in ALD cells. This effect was not observed when the cells were co-cultured while separated by a filter membrane. Our data suggest that supplying normal cells for ABCD1 knockout mouse by HCT corrects metabolic abnormalities in ALD tissues through a cell-mediated process. The correction requires direct cell-to-cell contact for recovering normal cell function.

DOI： 10.1016/j.jns.2003.11.006

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Language：English   Publisher：Fukuoka Medical Association  

DOI： 10.15017/19209

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Other Link： http://search.jamas.or.jp/link/ui/2005246038

Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: Superantigens are considered to exacerbate autoimmune inflammation through the expansion of autoreactive T cells; however, the immune response to bacterial superantigens has not been extensively studied in any type of myelitis. We recently reported the occurrence of a distinct type of myelitis in patients with atopic diathesis, which in a recent nationwide survey was reported to be widespread in Japan. The aim of this study was to investigate the presence of IgE antibodies to bacterial superantigens and the proportion of IL-13- or IL-5-producing CD4+ or CD8+ T cells in patients with myelitis and atopic diathesis. Methods: Twenty-four myelitic patients with and 12 myelitic patients without hyperlgEemia, 28 patients with multiple sclerosis (MS) and 34 healthy controls were enrolled in this study. IgE antibodies to staphylococcal enterotoxins A ( SEA) and B (SEB) in sera were measured using a liquid-phase enzyme immunoassay, and the intracellular production of IL-5 and IL-13 in peripheral blood CD4+ and CD8+ T cells was measured by flow cytometry. Results: The myelitic patients with hyperlgEemia showed significantly higher positive rates of serum SEA/SEB-specific IgE antibodies (41.7 and 62.5%, respectively) than the healthy controls (5.9 and 8.8%), patients with MS (0 and 21.4%) and those with normolgEemic myelitis (0 and 0%). Moreover, IL-13- producing CD4(+) T cells and CD8(+) T cells increased significantly in the myelitic patients with hyperlgEemia compared to the controls, while IL-5-producing CD4(+) or CD8+ T cells did not. Conclusions: The IgE response to staphylococcal superantigens is heightened in myelitic patients with atopic diathesis, which might contribute to increases in IL-13- producing T cells and thus the development of myelitis. Copyright (C) 2004 S. Karger AG, Basel.

DOI： 10.1159/000077532

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We recently reported the occurrence of myelitis in patients with atopic disorders and its pathology to be eosinophilic inflammation. Because similar cases have been reported, we conducted a nationwide epidemiological survey (NES) of myelitis with atopy in Japan. We compared the clinicolaboratory features of the 30 NES cases with the 49 cases at Kyushu University Hospital (KU). Although the NES cases were distributed throughout Japan, the NES and KU cases shared common characteristics. We therefore combined all of the cases identified. The average onset age was 35.8 +/- 13.4 years, and the male/female ratio was 1:0.65. The onset mode was subacute/chronic in half the patients, and stepwise progression or symptom fluctuation was frequent (69.6%). The most common lesion site was determined clinically and by MRI to be the cervical cord, and paresthesia and/or dysesthesia were the most common symptoms initially (74.7%) and throughout the entire course (83.5%). Cerebrospinal fluid (CSF) abnormalities were infrequent and mild. These findings suggest that myelitis associated with atopy has mild but prolonged symptoms and occurs throughout Japan. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-510X(02)00441-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

Histologically proven eosinophilic myelitis has rarely been reported except in connection with parasitism. To clarify its clinicopathological features, we conducted a nationwide survey of biopsy-proven eosinophilic myelitis of unknown cause throughout Japan. Six such cases were collected and studied immunologically and pathologically. All were young to middle-aged men. All showed a protracted and fluctuating course with mild disability for 3-25 (mean 12.5) months before biopsy. Magnetic resonance imaging revealed localized lesions of T2-high and T1-iso signal intensity with a partial gadolinium enhancement in all cases. Cerebrospinal fluid (CSF) examinations were completely normal except for modest pleocytosis in two cases. Eosinophilia was present in the peripheral blood in two cases but was absent from the CSF of all cases. In spite of the chronic nature of the disease, spinal cord pathology revealed very active lesions with marked cell infiltration consisting mainly of CD8(+) T cells and varying numbers of eosinophils in the perivascular areas and the parenchyma. Both the myelin and axons were severely disrupted in all cases. Moreover, cosinophil cationic protein (ECP), an activated eosinophil product, was heavily deposited in the tissues. All but one case had hyperIgEemia and mite antigen-specific IgE in the sera, and two had accompanying atopic disorders. The present study thus revealed idiopathic eosinophilic myelitis to be a localized and persistent inflammation of the spinal cord. with distinct clinicopathological features, that has a possible link to atopic diathesis.

DOI： 10.1007/s00401-002-0645-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Juvenile muscular atrophy of the distal upper extremity (JMADUE) is postulated to be a type of flexion myelopathy. However, patients with typical clinical features of JMADUE but without evidence of flexion myelopathy have been reported. We recently reported a significant association of, JMADUE with airway allergy. Here we report the successful treatment by plasma exchange (PE) of two patients with both airway allergy and JMADUE without evidence of flexion myelopathy. Patient 1 had a 5-year history of allergic rhinitis and high titers of mite antigen-specific IgE, and patient 2 had an 8-year history of pollinosis and high titers of cedar pollen-specific IgE. Both patients noted progressive distal muscle atrophy and weakness of the upper extremities: patient I for 3 months and patient 2 for 3 years. Neurologically, both showed asymmetric intrinsic hand muscle atrophy, oblique atrophy of the forearm muscles, and weakness and contraction fasciculation (minipolymyoclonus) of these muscles without any sensory impairment. Neither had any evidence of flexion myelopathy on magnetic resonance imaging (MRI) in a flexed position. Both were subjected to PE three times. Soon after the PEs, both showed improvement of distal muscle weakness of the upper extremities and marked reduction of contraction fasciculation of the forearm muscles. Patient I showed marked reduction in ongoing denervation potentials in the distal muscles on needle electromyography, while patient 2 showed marked improvement of F wave persistence of bilateral median and ulnar nerves. Serum total and allergen-specific IgE decreased after PEs in both patients. PE was thus considered to be effective in these two patients having JMADUE without evidence of flexion myelopathy. These observations may suggest the involvement of an immune-mediated process in the neural damage of JMADUE without evidence of flexion myelopathy, especially in patients with atopic diathesis, and may support the notion that JMADUE is etiologically heterogeneous. (C) 2002 Elsevier Science B.V. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective To study subclinical involvement of the peripheral nerves in myelitis with hyperIgEaemia and mite antigen-specific IgE (atopic myelitis: AM).
Material and Methods We carried out a nerve conduction study of the median, ulnar, tibial, and sural nerves in 21 patients with AM and in 28 patients with clinically definite or laboratory-supported definite multiple sclerosis (MS).
Results The patients with AM showed a significantly higher frequency of abnormal records than the MS patients in the sensory nerve conduction study (52.4% vs. 14.3%, p=0.0106). The frequency of abnormal records in the motor nerve conduction study in AM patients was twice as high as in MS patients (38.1% vs. 17.9%), but the difference was not statistically significant. Abnormality in the F-wave-evoked frequency in the median nerve was also significantly more common in AM patients than in MS patients (57.9% vs. 10.7%, p=0.0016).
Conclusions These findings suggest that subclinical peripheral neuropathy is frequent in patients with AM.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

A 62-year-old man who developed akinetic mutism with delayed white matter demyelination after hypoxia was treated with hyperbaric oxygen (HBO). HBO in the subacute period markedly improved the patient's activity in daily life, cognitive function and organization on EEG. H-1-MRS showed a recovery of aerobic metabolism of the neurons. However, dementia and cerebral atrophy slowly progressed despite HBO treatment. Thus, HBO had a beneficial effect on the activity of depressed neurons but did not improve the prognosis. (C) 2002 Elsevier Science B.V. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

In the present study, we flow cytometrically analyzed the intracellular production of interleukin (IL)-5 and IL-13 in peripheral blood CD4(+) and CD8(+) T cells from patients with multiple sclerosis (MS), human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and healthy controls. IL-13-producing T cells were significantly increased in both T cell subsets in MS at relapse, markedly in the conventional form of MS and modestly in the optocospinal form of MS, and returned to normal at remission. However, IL-5-producing T cells did not vary regardless of clinical phase or type. HAM/TSP showed no significant change in the number of IL-5- and IL-13-producing cells. A distinct profile of IL-13 and IL-5 production by disease and by phase of MS suggests an active involvement of these type 2 cytokines in central nervous system (CNS) inflammation. (C) 2002 Elsevier Science B.V. All rights reserved.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Hashimoto's encepbalopathy (HE) is a rare autoimmune disease associated with Hashimoto's thyroiditis (HT). To identify the HE-related autoantigens, we developed a human brain proteome map using two-dimensional electrophoresis and applied it to the immuno-screening of brain proteins that react with autoantibodies in HE patients. After sequential MALDI-TOF-MASS analysis, immuno-positive spots of 48 kDa (pI 7.3-7.8) detected from HE patient sera were identified as a novel autoirnmuno-antigen, alpha-enolase, harboring several modifications. Specific high reaetivities against human a-enolase were significant in HE patients with excellent corticosteroid sensitivity, whereas the patients with fair or poor sensitivity to the corticosteroid treatment showed less reactivities than cut-off level. Although a few HT patients showed faint reactions to a-enolase, 95% of HT patients, patients with other neurological disorders, and healthy subjects tested were all negative. These results suggest that the detection of anti-alpha-enolase antibody is useful for defining HE-related pathology, and this proteomic strategy is a powerful method for identifying autoantigens of various central nervous system diseases with unknown autoimmune etiologies. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(02)03307-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC PUBL  

We examined the mechanism of action of nitrosoureas as represented by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) with respect to p53 and the G(2)M cell cycle checkpoint using two glioblastoma cell lines: U251MG and U373MG, with mutated p53. At log-phase cell growth, fresh medium containing ACNU (final concentration, 3, 10, or 30 mug/ml) was added. After 24 h of incubation, cells were harvested for flow cytometric or Western analysis. In both lines, cell numbers in the G0/G1 phase decreased with ACNU treatment. Cells accumulated in G(2)M and S phases, and the peak was shifted from G(2)M to the S phase in a concentration-dependent manner. In both cell lines, the amount of Cdc2 protein phosphorylated at the tyrosine 15 residue was increased 2- to 6-fold by treatment with ACNU compared with untreated control cells. Expression of cyclin B protein was suppressed in cells treated with 30 mug/ml ACNU. Protein abundance for total Cdc2, Cdc2 phosphorylated at the threonine 161 residue, Wee 1, Myt 1, Chk 1, and 14-3-3sigma was not affected by treatment with ACNU in either cell line. We suggest that a low concentration of ACNU should be used with adjuvant therapies that act upon cells in the G(2)M phase. A high concentration of ACNU should be used with adjuvant therapies that act upon cells in the S phase.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Our aim was to localize the generator site of parasagittal epileptiform discharges in a patient with epilepsia partialis continua (EPC) in the right leg. We examined a 32-year-old woman with EPC whose conventional EEG did not show any epileptic discharge. We performed the jerk-locked back averaging (JLA) of EEG and magnetoencephalography (MEG) to localize the dipole source of sharp transients. The myoclonic discharges in the right soleus muscle were used as a trigger pulse. JLA revealed consistent EEG and MEG sharp transients that coincided consistently and constantly preceded the myoclonic jerks. JLA of EEG demonstrated sharp waves paradoxically distributed over the vertex and right hemisphere. However, the estimated dipoles of MEG were localized in a restricted area in the primary leg motor area in the left hemisphere, which was closely located in the abnormal lesion on the brain MRI. JLA of MEG is considered to be a useful noninvasive method for localizing the epileptogenic area in EPC even when paradoxical lateralization of electroencephalographic discharges was noted. (C) 2002 Elsevier Science B.V. All rights reserved.

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Objective - To clarify the association between past and present history of allergic disorders and neurologic diseases. Methods - The past and present history of common allergic disorders together with family history was prospectively studied in all out-patients at the Department of Neurology at Kyushu University Hospital from March 1998 to February 2000. Results - Among 3113 out-patients, 2152 (69.1%) completed a questionnaire. Myelitis showed a statistically significant increase of concomitant atopic dermatitis (P = 0.006) and concomitant and past atopic dermatitis (P = 0.014), as compared with neurologically healthy controls. Moreover, patients with lower motoneuron disease (LMND) had a statistically significant increase of past and concomitant asthma (P = 0.007). None of the other common neurologic diseases showed any increase of allergic disorders when compared with controls. Conclusions - The present study supports the significant association between allergic disorders and such spinal cord diseases as myelitis and LMND in Japanese patients.

DOI： 10.1034/j.1600-0404.2002.1o028.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To elucidate the T helper 1 (Th1)/T helper 2 (Th2) balance in various inflammatory neuropathies, we measured the ratio of intracellular interferon-gamma (IFN-gamma)-positive to IL-4-positive cells (intracellular IFN-gamma /IL-4 ratio) by flow cytometry in peripheral blood CD4(+) T cells of 14 patients with mononeuritis multiplex (MNM), 12 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 patients with Guillain-Barre syndrome (GBS), 23 patients with neurodegenerative disorders and 36 healthy controls by intracellular labeling. The patients with MNM showed a significantly lower intracellular IFN-gamma /IL-4 ratio (P <0.05) and higher IL-4(+)/IFN-gamma (-) cell percentages (P < 0.05) than the controls. The increase of IL-4(+)/IFN-gamma (-) cell percentages was especially prominent in MNM of unknown etiology (P < 0.005). The patients with CIDP also showed significantly higher IL-4(+)/IFN-gamma (-) cell percentages (P < 0.05) than the controls. The IL-4(+)/IFN-gamma (-) cell percentages were increased in some patients with GBS, but the difference was not significant compared with the controls. Thus, our results suggest that a Th2 shift is a characteristic of MNM and may play an important role in the development of the disease. (C) 2001 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-510X(01)00603-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BRITISH MED JOURNAL PUBL GROUP  

Juvenile muscular atrophy of the distal upper Limb (Hirayama disease) is a rare disease predominantly affecting the anterior horn cells of the cervical spinal cord in young men. Although the disease is considered to be a type of cervical myelopathy, the mechanism remains unknown. An immunological study of five consecutive patients with this disorder who were examined in the neurology clinic at Kyushu University Hospital during the past 2 years were performed. Ah developed distal muscular atrophy and weakness of one or both upper limbs in the second decade, and showed forward displacement of the dural sac and passive dilatation of the posterior venus plexus at the lower cervical portion on MRI during neck flexion. Four of the five patients had one or more coexistent airway allergies, such as allergic rhinitis, pollinosis, and asthma, and all five patients had a family history of atopic or allergic disorders in close relatives. Four of the five patients had mild eosinophilia. All five patients commonly had IgE specific to two mite antigens, Dermatophagoides pteronyssinus and Dermatophagoides farinae, whereas three of them also showed a raised total serum IgE concentration. The frequency of mite antigen specific IgE was significantly higher in the present patients with Hirayama disease than in 82 healthy controls (26/82, p <0.005). These findings suggest that atopy may be one of the contributing factors for Hirayama disease.

DOI： 10.1136/jnnp.70.6.798

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Language：English   Publisher：BRITISH MED JOURNAL PUBL GROUP  

DOI： 10.1136/jnnp.70.2.265

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We report the neuropathological findings of spinal cord specimens obtained from two patients who had localized myelitis with hyperIgEemia and mite antigen specific IgE (atopic myelitis). Both cases showed mild spinal cord dysfunction, and the gadolinium-enhanced area of the isolated spinal cord lesion observed on MRI was biopsied, respectively. Neuropathologically, both cases showed many perivascular lymphocyte cuffings associated with disrupted vessels, and the infiltration of eosinophils in the spinal cord lesions. Both myelin and axons were lost in the lesions, which were associated with astrogliosis. These findings suggest that an allergic mechanism may play a role in this condition. (C) 2001 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-510X(00)00475-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

Objective To clarify the clinical features of myelitis associated with atopic disorders in Japanese patients. Subjects and Methods We retrospectively studied the clinical, immunological and electrophysiological features of 68 consecutive patients with myelitis of acute or subacute onset diagnosed at Kyushu University Hospital during the past 20 years. Results While only 2 of 28 (7% ) patients with myelitis diagnosed between 1979 and 1993 had either atopic dermatitis (AD) or bronchial asthma (BA), 19 of 40 (48%) patients with myelitis diagnosed between 1994 and 1998 did. Among the 40 patients with myelitis diagnosed between 1994 and 1998, 19 patients with either AD or BA as well as 21 patients without either disease showed a significantly higher level of serum total IgE, higher frequency of hyperIgEaemia and higher frequency of mite antigen-specific IgE than 82 healthy controls. Myelitis patients with AD presenting as persistent paresthesia/dysesthesia in all four limbs showed cervical cord lesions on MRI and abnormalities in upper limb motor evoked potentials but no abnormalities in the cerebrospinal fluid (CSF), while myelitis patients with BA showed preferential involvement of the lower motor neurons clinically and electromyographically. In addition, 12 patients with myelitis who had hyperIgEaemia and mite antigen-specific IgE but neither AD nor BA showed incomplete transverse myelitis with mild motor disability and few CSF abnormalities. Conclusion The clinical features of myelitis associated with atopic disorders were in part distinguished by the type of preceding atopic disorder, and also were different from those of hyperIgEaemic myelitis with no preceding atopic disorders.

DOI： 10.2169/internalmedicine.40.613

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In Japanese, susceptibility to the conventional form of multiple sclerosis (C-MS) is associated with the HLA-DRB1 *1501-DRB5*0101 haplotype while susceptibility to the opticospinal form of MS (OS-MS) is associated with HLA-DPA1 *0202-DPB1*0501. To clarify the characteristics of T cells autoreactive to myelin proteins in each MS subtype, we established T-cell lines reactive to such myelin antigens as myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) from 5 of 10 OS-MS patients, 6 of 11 C-MS patients and 7 of 13 healthy controls (HCs), and T-cell epitopes and their restriction molecules were determined. We found that (a) intermolecular epitope spreading was found to be significantly more frequent in MS patients than in HCs (P=0.0128), (b) intramolecular epitope spreading also tended to occur more frequently in MS patients than in HCs (P=0.0584), (c) in OS-MS, HLA-DR-restricted and MOG-autoreactive T cells were more frequently established as compared with those reactive to MBP or PLP epitopes and (d) in C-MS, HLA-DQ-restricted and PLP-autoreactive T cells dominated those autoreactive to MBP or MOG epitopes. A DPB1*0501-restricted MBP-reactive T-cell clone from a patient with OS-MS provided evidence that the first HLA class II anchor amino-acid of peptide bound to disease-susceptible DP5 molecule was distinct from that for the DR2 molecule. Taken together, these differences in specificities of myelin-autoreactive T cells between C-MS and OS-MS as well as the difference in the anchor motif of the binding peptides between each MS subtype-susceptible HLA class II molecule may contribute to the development of distinct clinical phenotypes.

DOI： 10.1034/j.1399-0039.2001.057005447.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

CD5(+) B-l cells are known to be unresponsive to B cell receptor (BCR)-mediated growth signals but instead undergo apoptosis, However, the B-1 cells from Lyn kinase-deficient (Lyn(-/-)) mice exhibited an enhanced proliferative response upon BCR cross-linking. It has been reported that BCR-mediated signaling in B-1 cells is negatively regulated by signals from CD22, CD5 and CD72 co-receptors, and that Lyn kinase plays a crucial role in tyrosine phosphorylation of immunoreceptor tyrosine-based inhibitory motifs on the CD22 and CD72, which recruits SHP-1 to the BCR complex. We found that Lyn kinase is also essential for the tyrosine phosphorylation of CD5 and subsequent recruitment of SHP-1 in B-1 cells upon cross-linking of BCR, Moreover, a distinct subpopulation of B-1 cells was found to express cell surface Ly49, which is known as a MHC class 1-binding negative regulatory receptor on NK cells. Ly49 was rapidly tyrosine phosphorylated upon cross-linking of BCR and SHP-1 was found to, recruit to the phosphorylated Ly49, Addition of F(ab')(2) fragments of anti-ly49 antibodies partially blocked negative signals In B-1 cells, Thus two co-receptors, CD5 and Ly49, which are unique to B-1 cells, play a role in the regulation of B-1 cell activation. These results indicate that BCR-mediated signals in B-1 cells are strictly and negatively regulated through multiple pathways, that are dependent on Lyn kinase activity.

DOI： 10.1093/intimm/12.10.1417

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We examined the alterations of memory CD4(+) T cell subsets bearing surface receptors linked to either Th1 or Th2 cytokine production as well as natural killer (NK) cell subsets by three color flow cytometry in the peripheral blood from 36 patients with clinically definite multiple sclerosis (MS), 27 patients with HAM/TSP, 13 patients with hyperIgEaemic myelitis who had mite antigen-specific IgE and 25 healthy controls (HC). The patients with MS were clinically classified into an optico-spinal form of MS (Asian type, MS-A) and the conventional form of MS (Western type, MS-W). MS-A showed a significant increase of CD4(+)CD45RA(-)CCR5(+) cells (Th1 cells) through the relapse and remission phases in comparison to HC, while MS-W showed a significant increase of CD4(+)CD45RO(+)CD62L(-) cells (Th1 cells) only at the relapse phase. HAM/TSP showed a significant increase of CCR5(+) and CD62L(-) memory CD4(+) T cells as well as CD30(+) memory CD4(+) T cells (Th2 cells) in comparison to HC. On the other hand, a selective increase of CD4(+)CD45RO(+)CD30(+) cells was found in hyperIgEaemic myelitis. The percentage of mature NK cells (CD3(-)CD16(+)CD56(+) cells) as well as double negative T cells (CD3(+)CD4(-)CD8(-) cells) decreased significantly in HAM/TSP in comparison to HC. Our findings therefore suggest a flow cytometric analysis of Th1/Th2-associated markers on memory CD4(+) T cells as well as NK cell subsets to be useful for differentiating various inflammatory neurologic conditions. (C) 2000 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0022-510X(00)00322-1

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DOI： 10.1016/0022-510X(95)00166-Y

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞進行型多発性硬化症(PMS)に対するオクレリズマブとシポニモドの有効性が証明されたことで,PMS治療は新たな時代となった。しかし,これらの薬剤の主たる作用機序は抗炎症作用で,神経変性に対する作用は弱い。本論では,既存の疾患修飾薬の二次性(SPMS)に対する効果を概説し,治療介入にもかかわらず進行が抑制できないSPMSに対する治療法を考えたい。

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(株)総合医学社  

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Language：Japanese   Publisher：(株)医事出版社  

【背景】フマル酸ジメチル(DMF)は、本邦では2016年に承認された経口の多発性硬化症(MS)治療薬であり、MSの治療歴のない患者への使用も認められている。DMFの安全性と有効性は国内外の臨床試験と欧米を中心とした実臨床研究で多く報告されているが、MS治療歴のない患者を含め、日本人の実臨床データは十分でない。【目的】DMFの国内実臨床下での安全性と有効性を把握するために実施している使用成績調査からの中間解析データを用いて行った、MS治療歴有無別のサブグループ解析結果を報告する。【方法】使用成績調査は本邦にてDMFによる治療を受けた患者全例を対象に実施中であり、本中間解析には2017年2月の調査開始から2020年3月までのデータを用いた。安全性評価項目は有害事象、重篤な有害事象、リンパ球数減少、白血球減少等、有効性評価項目は年間再発率、身体機能障害スケール(EDSS)スコアの平均値の推移、身体障害が3ヵ月以上改善・維持・進行した患者の割合、等とした。【結果】安全性解析対象は1253名、有効性解析対象は1241名であり、そのうちMS治療歴なしの患者は安全性解析対象で346名、有効性解析対象で338名であった。DMF投与期間の中央値は364.0日であった。有害事象は全体集団で866名(69.1%)、MS治療歴なし集団で226名(65.3%)、MS治療歴あり集団で640名(70.6%)であった。重篤な有害事象は全体集団で116名(9.3%)、MS治療歴なし集団で28名(8.1%)、MS治療歴あり集団で88名(9.7%)に認められた。有害事象の内容は、いずれも全体集団と同様の傾向であった。リンパ球数はいずれの集団でも60%以上の患者で正常下限値(1000/mm3)以上が維持された。年間再発率はいずれの集団でも投与開始前1年間と比べて投与開始後1年目で有意に減少し(p<0.0001)、投与開始後12ヵ月時のEDSSスコアにより評価した身体障害の進行度はいずれの集団でも90%以上の患者で「維持」または「改善」であった。【結論】報告された安全性、有効性データは既報の全体集団と同様であり、新たな安全性の懸念は認められなかった。本報告は中間報告のため、本調査の最終的な安全性、有効性の評価には継続した調査が必要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J01205&link_issn=&doc_id=20211006080019&doc_link_id=%2Fag6niria%2F2021%2F007910%2F019%2F1580-1588%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2021%2F007910%2F019%2F1580-1588%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞急性散在性脳脊髄炎は,多巣性の神経症候が急性ないしは亜急性に出現する中枢神経の炎症性脱髄疾患である。感染やワクチン接種などの先行事象を認めることが多く,免疫介在性疾患と考えられている。主に小児に発症し,通常は単相性であるが,稀に再発し多相性のことがある。急性期治療の第一選択はステロイドパルス治療であり,長期予後はおおむね良好である。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J04871&link_issn=&doc_id=20210517450012&doc_link_id=10.11477%2Fmf.1416201787&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1416201787&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞多発性硬化症の有病率や患者数は世界的に増加傾向であり,特に若年女性での増加が著しい。女性を中心に見られたライフスタイルの変化が増加に関係している可能性が考えられるが,単一の生活環境因子は明らかになっていない。一方で,罹患率については報告が少ないものの,横ばいないしは低下傾向とする報告も少なくない。発症リスクの推移を追跡するためには,同一手法を用いて標準化された罹患率調査を継続する必要がある。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J04871&link_issn=&doc_id=20200529420004&doc_link_id=10.11477%2Fmf.1416201551&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1416201551&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：日本神経免疫学会  

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Language：English   Publisher：日本神経免疫学会  

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Language：Japanese   Publisher：(株)日本医事新報社  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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＜文献概要＞多発性硬化症は免疫介在性の中枢神経疾患である。炎症性脱髄に伴う中枢神経症候が再発と寛解を繰り返しながら経過し,次第に慢性進行性となる。そのため,比較的強い障害が残る例が少なくなく,早期から疾患修飾薬により再発を予防し進行を抑制することが重要である。また,近年の研究から,運動により症状の軽減や機能回復が期待できることが明らかとなり,運動療法は非薬理学的疾患修飾療法の1つに位置付けられている。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2019&ichushi_jid=J04871&link_issn=&doc_id=20190204270009&doc_link_id=10.11477%2Fmf.1416201233&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1416201233&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：エーザイ(株)  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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DOI： 10.20837/12018071661

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Language：Japanese   Publisher：(株)日本医事新報社  

＜Point＞▼多発性硬化症(MS)は中枢神経白質を侵す慢性炎症性脱髄疾患である▼若年成人に好発する。世界的に患者数・有病率ともに増加傾向で、特に若年女性での増加が著しい▼中枢神経髄鞘抗原に対するT細胞が介在する自己免疫疾患と考えられているが、真の原因は不明である▼脱髄に伴う中枢神経症候が再発と寛解を繰り返しながら経過(時間的・空間的多発性)し、しだいに慢性進行性の経過となることが多い▼障害は身体機能のみならず高次脳機能にも及び、日常生活や社会生活が大きく制限されることも少なくない(著者抄録)

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Language：Japanese   Publisher：(一社)日本脳神経超音波学会  

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DOI： 10.3143/geriatrics.55.158

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Language：Japanese   Publisher：愛媛医学会  

われわれは2006年から開始している抗加齢ドックのデータを基にした加齢に伴う認知症発症リスクに対する検討を行っている。根本的な治療薬のない現在「可能な限り早期に認知症および認知症予備群を発見して適切な生活への介入を行うこと」が求められている。近年、正常加齢と認知症の境界領域と考えられる軽度認知障害(Mild cognitive impairment:MCI)が注目されており、MCIと関連するファクターを探索し、それらに対する介入を試みることは臨床面からも有用であると考えられる。MCIは65歳以上の高齢者の約5%にみられ、年間約10-15%がADに移行することが知られている。われわれはMCIの診断には「MCI screen」を用いている。このテストを用いて2017年に2本の論文がpublishされた。論文1)高齢者のMCI診断におけるSAFの有用性 AGEs(Accumulation of advanced glycation endproducts)の蓄積と認知症の発症の関連性が示唆されている。しかしながら認知症発症の前段階と考えられるMCI(mild cognitive impairment)とAGEsの関連を検討した報告は少ない。そこで本研究では健常高齢者におけるMCIと皮膚に蓄積したAGEsとの関連について検討した。本研究から非侵襲的なAGEs測定法であるSAFは健常者におけるMCIスクリーニングを行う上で有用なバイオマーカーである可能性が示唆された。論文2)高齢者におけるエクオール産生能と認知機能低下の関連 豆イソフラボン摂取による心血管疾患の予防効果が知られているが、認知機能予防効果については愚論のあるところである。個人差がある原因として大豆イソフラボンの代謝産物である「エクオール」(Equol)産生能の有無が関連している可能性がある。本研究結果からは1)エクオール産生者では有意にタッチパネル式認知機能検査の点数が高い2)エクオール非産生者では有意にMCIの存在率が高い、ことからエクオール産生者では認知機能の予防効果がある可能性がある。(著者抄録)

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Language：Japanese   Publisher：(株)最新医学社  

米国食品医薬品局によって承認された多発性硬化症(MS)に対する疾患修飾薬は,すでに13種類に上る.また,再発寛解型MSを対象とした第III相臨床試験の結果が公表されている薬剤には,ダクリズマブやラキニモド,オクレリズマブがある.さらに,フィンゴリモドより高い受容体サブタイプ選択性を持つ新たな薬剤の開発も進んでいる.今後は,オクレリズマブやビオチンのような進行型MSに対する治療薬の開発も期待されている.(著者抄録)

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Language：Japanese   Publisher：(株)最新医学社  

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Other Link： http://search.jamas.or.jp/link/ui/2016383429

Language：Japanese   Publisher：日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2016&ichushi_jid=J02615&link_issn=&doc_id=20170202470054&doc_link_id=10.15082%2Fjsnt.33.3_466&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.33.3_466&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

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DOI： 10.15082/jsnt.33.3_466

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多発性硬化症(Multiple Sclerosis:MS)の診断は、時間的および空間的多発性を臨床症候によって証明し、かつ他の疾患を十分に除外することが基本である。しかし、近年のMRIの普及によって無症候性病変の鋭敏な検出が可能となり、臨床的には初発の段階であっても、時間的および空間的多発性に関する一定のMRI基準を満たせばMSと診断できるようになった。このため従来よりも早期の診断が可能となり、早期に治療を開始できるようになった。しかし、現在のMRI基準は欧米の典型的なMS患者のデータを基に作成されているため、遺伝的や環境的要因の異なるわが国の患者に適用した場合の妥当性については、今後の検証が必要である。アドヒアランスを良好に保つことは治療効果に直結する重要な問題である。治療の目的と期待される治療効果、予測される有害事象とその対処法など、治療開始前から繰り返し説明することが重要である。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2015028818

Language：Japanese   Publisher：(株)医学書院  

多発性硬化症では最大70%の患者に認知機能障害が認められる。注意や情報処理速度,作業記憶の障害が認められやすく,患者の生活の質や社会生活に大きく影響することも少なくない。多発性硬化症患者の認知機能を正しく評価し,認知機能障害に対して介入することは極めて重要であるが,有効性が確立された対処法がないのが現状である。治療研究の発展が期待される。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2014&ichushi_jid=J04871&link_issn=&doc_id=20141016190011&doc_link_id=1390002209995671424&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390002209995671424&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

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多発性硬化症治療では、急性増悪期の治療と並んで、早期より再発予防治療を開始し、将来の身体機能障害の進行を抑制することが重要である。この目的で使用される薬剤は病態修飾薬と呼ばれ、わが国では2種類の注射剤のインターフェロンβ製剤と、経口カプセル剤であるフィンゴリモドの合計2剤形3種類の薬剤が使用されている。また、2014年3月には注射剤であるナタリズマブが製策販売承認を受け、現在発売に向けての準備が進んでいる。それぞれの薬剤の特徴を理解したうえで、患者のライフスタイルに合った治療法を選択することが重要である。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2013121521

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We report a 45-year-old man with myositis associated with clonal expansion of γδ T cells. He was referred to our hospital because of slowly progressive (over 10 years) muscle weakness. On neurological examination, weakness and muscle atrophy were noted in the proximal upper and lower limbs. The level of creatinine kinase (CK) was 1,436U/L. Neutropenia and monoclonal gammopathy were found in the peripheral blood. Flow cytometric analysis of peripheral blood and bone marrow revealed proliferation of CD3+CD4-CD8+ and CD3+CD4-CD8- γδ T cells, and Southern blotting demonstrated a clonally rearranged T-cell receptor Jγ gene in peripheral blood and bone marrow. A biopsy of the right quadriceps muscle showed variations in muscle fiber size, and endomysial mononuclear cell infiltration. The expression of MHC Class I antigen was increased on the surfaces of most of muscle fibers, and TCRδ1 positive-lymphocytes invaded nonnecrotic muscle fiber. After starting treatment with cyclosporin A and steroids, his muscle weakness gradually ameliorated, the CK level decreased and neutrophils increased. Although reports of myositis associated with clonal expansion of γδ T cells are extremely rare, the present case suggests that γδ T cells might play a role in mediating myositis. © 2012, Societas Neurologica Japonica. All rights reserved.

DOI： 10.5692/clinicalneurol.52.227

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Language：Japanese   Publishing type：Book review, literature introduction, etc.   Publisher：(株)医学書院  

Neuromyelitis optica (NMO) is a unique inflammatory condition characterized by selective involvement of the optic nerves and spinal cord. The cardinal features of NMO and a tendency of recurrence led to the classification of NMO as a subtype of multiple sclerosis (MS); however, it can be distinguished from MS on the basis of clinicoradiological and serological findings. In particular, NMO is characterized by the presence of spinal cord lesions that are longer than the total length of 3 vertebral segments and presence of anti-aquaporin 4 antibodies. Secondary progression of this condition is usually not observed, and therapy for NMO patients is designed to prevent acute exacerbations and limit irreversible neurological disability. Intravenous administration of a high dose of methylprednisolone is a standard treatment for patients with acute exacerbations of this condition, and patients with refractory cases are often responsive to plasmapheresis. To reduce the frequency of relapses and severity, standard therapies for MS, such as interferon-beta therapy, are not effective; further, a long-term immunosuppressive therapy is required for NMO patients. Immunosuppressive therapies often involve oral administration of prednisolone with or without azathioprine; patients who are refractory to the oral therapy may be treated by parental administration of cyclophosphamide, mitoxantrone, or rituximab. At present, there is no cure for NMO; early and precise diagnosis is critical to initiate immunosuppressive therapy for prevention of relapse.

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Language：Japanese   Publisher：(株)南江堂  

NMO-IgG(抗AQP4抗体)の発見により、MSとNMOの免疫病態が異なる疾患であることが明らかとなった。両者の鑑別には、両者の臨床的特徴を理解するとともに抗AQP4抗体の測定が有用である。NMOの急性増悪期にはステロイドパルス療法が行われるが、無効であったり効果が不十分な場合には血液浄化療法が有効である。NMOでは再発予防治療が重要で、経口prednisolone単独やazathioprineとの併用療法が行われることが多い。これらの治療が無効の場合は、さらに強力な免疫抑制治療が行われる。(著者抄録)

DOI： 10.15106/J00974.2010193463

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「経口免疫寛容」とは、古典的には動物にあらかじめ抗原を経口的に投与することにより、その抗原に対する正の免疫応答(細胞増殖や抗体産生など)が抑制される現象として理解される。そのため、食物成分に由来する多種多様な非自己抗原に対して食物アレルギーなどを示さないのは、各抗原に対して「経口免疫寛容」が成立しているからだとされる。最近では、経鼻あるいは経気道的に抗原を投与した場合にも、同様の免疫寛容状態が誘導されることが示されており、「粘膜免疫寛容」と総称されることもある。本稿では、まず腸管免疫と経口免疫寛容について概説し、経口免疫寛容を応用した多発性硬化症(multiple sclerosis:MS)の免疫制御について解説する。(著者抄録)

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Clinically definite MS連続113例において抗AQP4抗体と頭部脊髄MRIを評価した。視神経脊髄型(OSMS)で抗AQP4抗体は27.1%、通常型(CMS)で5.6%に認めたが、脳幹脊髄型や対照群では陰性だった。抗体陽性MSは全例女性で、抗体陰性OSMSと同様に抗体陰性CMSに比べて発症年齢が高く、重篤な視神経炎や横断性脊髄炎、長大な脊髄病巣(LESCL)が有意に多かった。LESCLは抗体陽性MSでは主として胸髄灰白質に限局した。一方、抗体陰性OSMSでは頸髄から胸髄に拡がり、灰白質から白質に及んだ。また抗体陽性MSでNMO基準を満たす群は脳病巣やSSA/SSB陽性例が多く、インターフェロンβの効果が乏しい点がLESCLを伴う抗体陰性OSMSと異なった。多変量解析では抗AQP4抗体はLESCLやOSMSには関連がなかった。日本人MSには抗AQP4抗体陽性MSとLESCLを伴う抗体陰性OSMSが存在した。臨床病型と抗AQP4抗体によりLESCLは異なった特徴を呈し、その形成機序はheterogeneousと思われた。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内科学会  

54歳女、両下肢の痺れを主訴とした。潰瘍性大腸炎(UC)を発症したが治療により寛解状態であった。右前胸部痛と主訴が出現し、入院時、右下肢の筋力低下、両下肢の感覚障害、痙性歩行を認め、脊髄MRIでTh6-7レベルの右後索〜側索にT2延長域を認めた。UCに関連した脊髄炎と診断し、ステロイドパルス療法の後、経口プレドニゾロンを漸減、中止した。筋力の正常化と感覚障害の軽快が得られ、その後も再発なく、6ヵ月後のMRIで病巣の縮小を確認した。

DOI： 10.2169/naika.96.1703

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Guillain-Barre症候群(GBS)には様々な亜型が存在し、Fisher症候群(FS)、FSとGBSの重複症候群などが含まれる。今回、眼筋麻痺・失調・腱反射消失といったFS様症候と球麻痺症状で発症したが、経過中に四肢筋力低下や呼吸筋麻痺を生じ、最終的にFS/GBSと考えられた症例を経験した。患者は42歳の男性、急性期の血液検査で抗GQ1b抗体と抗GT1a抗体が陽性を示し、両抗体とも症状の改善に伴い陰性化した。FSは通常予後良好とされているが、本例のように病変の範囲が広い場合には重症化しやすいと考えられ、とくに球麻痺を呈する場合には呼吸不全に陥りやすいと思われた。

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J-GLOBAL

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Language：Japanese   Publisher：日本神経免疫学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(株)マッキャンヘルスケアワールドワイドジャパン  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap