Yuri Nakamura

Copy number variations in multiple sclerosis and neuromyelitis optica

To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases.

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study

BackgroundHigher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS.MethodsWe enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42–45° north), and 187 MS patients and 235 HCs from the southern half (33–35° north) of the Japanese archipelago (33–45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke’s Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity.ResultsThe HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (pcorr = 0.0004 and pcorr = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p < 0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p = 0.0415, p = 0.0026, and p < 0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1*04:05 allele (p = 0.0198).ConclusionsLiving at a higher latitude and carrying the DRB1*04:05 allele independently lessens MS symptom severity as defined by MSSS. However, these factors influence the frequency of Barkhof brain lesions and CSF IgG abnormalities in opposite ways; higher latitude increases the frequency of Barkhof brain lesions and CSF IgG abnormalities, whereas DRB1*04:05 decreases them.

HLA-DRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis

Background: Cortical lesions (CLs) frequently observed in Caucasian patients with multiple sclerosis (MS) contribute to disability. However, it remains unclear whether CLs are associated with clinical features and genetic risk factors, such as HLA-DRB1*15:01 and -DRB1*04:05 in Asian MS patients. Objective: To elucidate the frequency of CLs and their association with HLA-DRB1 and DPB1 alleles in Japanese MS patients. Methods: Three-dimensional double inversion recovery imaging and clinical information were retrospectively obtained from 92 Japanese MS patients. Results: CLs of any type, intracortical lesions (ICLs), and leukocortical lesions (LCLs) were detected in 39.1%, 26.1%, and 28.3% of patients, respectively. MS patients with ICLs had a significantly higher frequency of secondary progression and greater Expanded Disability Status Scale (EDSS) scores than those without ICLs. Similar trends were observed with CLs and LCLs. The number of all three lesion types positively correlated with EDSS scores. The frequency and number of ICLs were significantly higher in HLA-DRB1*15:01 carriers than in HLA-DRB1*15:01 non-carriers, but significantly lower in HLA-DRB1*04:05 carriers than in HLA-DRB1*04:05 non-carriers. Multivariate logistic regression analysis revealed a negative association of HLA-DRB1*04:05 with ICLs. Conclusion: ICLs are associated with greater disease severity in Japanese MS patients and are partly suppressed by the HLA-DRB1*04:05 allele.

Association of Decreased Percentage of Vδ2+Vγ9+ γδ T Cells With Disease Severity in Multiple Sclerosis

We recently reported that deletion-type copy number variations of the T cell receptor (TCR) γ, α, and δ genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR γδ gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify γδ TCR repertoire alterations and their relationship to clinical and immunological parameters in MS patients by comprehensive flow cytometric immunophenotyping. Peripheral blood mononuclear cells obtained from 30 untreated MS patients in remission and 23 age- and sex-matched healthy controls (HCs) were stained for surface markers and intracellular cytokines after stimulation with phorbol 12-myristate 13-acetate and ionomycin, and analyzed by flow cytometry. MS patients showed significantly decreased percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells (pcorr = 0.0297 and pcorr = 0.0288, respectively) and elevated Vδ1/Vδ2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-γ+Vδ2+ and interleukin (IL)-17A+IFN-γ+Vδ2+ cells in γδ T cells, as well as IFN-γ+ cells in Vδ2+ γδ T cells, were significantly lower in MS patients than in HCs (pcorr < 0.0009, pcorr = 0.0135, and pcorr = 0.0054, respectively). The percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells were negatively correlated with both the Expanded Disability Status Scale score (r = −0.5006, p = 0.0048; and r = −0.5040, p = 0.0045, respectively) and Multiple Sclerosis Severity Score (r = –0.4682, p = 0.0091; and r = –0.4706, p = 0.0087, respectively), but not with age at disease onset, disease duration, or annualized relapse rate. In HCs, the percentages of Vδ2+ and Vδ2+Vγ9+ cells of total CD3+ T cells had strong positive correlations with the percentage of CD25+CD127low/− cells in CD4+ T cells (r = 0.7826, p < 0.0001; and r = 0.7848, p < 0.0001, respectively), whereas such correlations were totally absent in MS patients. These findings suggest that decreased Vδ2+Vγ9+ γδ T cells are associated with disability in MS. Therefore, the Vδ1/Vδ2 ratio might be a candidate biomarker for predicting disease severity in MS.

Recurrent Hemorrhagic Venous Infarctions Caused by Thrombosis of a Pontine Developmental Venous Anomaly and Protein S Mutation

A 34-year-old man presented with an acute onset of upbeat nystagmus, slurred speech, and limb and truncal ataxias. The patient had a history of limb ataxia and gait disturbance previously treated as brainstem encephalitis with corticosteroids 3 years previously. Brain magnetic resonance imaging showed pontine developmental venous anomaly (DVA) and hemorrhagic infarction within the drainage territory of the DVA. Three months later, the patient exhibited recurrent limb ataxia, double vision, and numbness of the left side of the body. The brain magnetic resonance imaging revealed recurrent hemorrhagic venous infarction within the same territory of the pontine DVA. Laboratory tests disclosed a hypercoagulable state owing to a decrease of protein S activity despite the normal antigen level. Genetic testing indicated that the patient was a homozygous carrier of protein S Tokushima. The patients severe disability remained unchanged in spite of treatment with anticoagulation therapy using warfarin. We propose that further research on hereditary coagulopathy be carried out in patients with recurrent episodes of DVA-related infarction.

Peripheral blood T cell subset characteristics of multiple sclerosis in remission phase correlate with annualized relapse rates

A large number of disease‐modifying drugs are available for multiple sclerosis (MS); however, there is no established biomarker to predict long‐term disease severity and future relapses in MS. We aimed to clarify the alterations in peripheral blood T cell subsets that are associated with MS relapse and disease severity, according to cytokine production profiles in the remission phase.

HLA genotype and cortical lesions: Response to the letter from Spencer et al.

We sincerely appreciate the letter from Spencer et al.1 commenting on our recently published study, in which we reported an association of certain HLA class II gene alleles with cortical lesions detected by threedimensional double inversion recovery (DIR) imaging in Japanese patients with multiple sclerosis (MS).2 The association of human leukocyte antigen (HLA) genotype with cortical lesion load had not been identified until their neuropathological study reported that HLADRB1*15, the strongest susceptible HLA class II gene allele for MS in Caucasians, was significantly associated with increased inflammation and larger areas of demyelination in the motor cortex of autopsied MS patients.3

The 32nd European Committee for Treatment and Research in Multiple Sclerosis

The 32nd European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and 21st Annual Conference of Rehabilitation in Multiple Sclerosis were held at the ExCeL London, London, UK, from 14 September to 17 September 2016 (Figs 1,2). An exciting scientific program was presented in 65 sessions during 4 congress days. A total of over 9300 participants from almost 100 countries attended, and 2036 abstracts were submitted in this year’s meeting. There were many impressive presentations about multiple sclerosis (MS), neuromyelitis optica spectrum and other neuroinflammatory diseases. Here, we review and share some of the interesting studies reported at this meeting.

Minocycline-induced human herpesvirus 6 encephalomyelitis with drastically disseminated contrast-enhanced lesions

The reactivation of human herpesvirus 6 (HHV-6) occurs as a reaction to several drugs including minocycline. Such reactivation induces drug-induced hypersensitivity syndrome (DIHS) characterized by fever, lymphadenopathy, hepatitis and exanthematous rash [1]. Limbic system lesions detected by magnetic resonance imaging (MRI) have been reported in several cases with DIHS and HHV-6 encephalitis after hematopoietic stem cell transplantation [2–4]. Here, we report a case of HHV-6 encephalomyelitis, triggered by minocycline, with drastically disseminated gadolinium-enhanced lesions in the brain and spinal cord. The patient was an immunocompetent 19-year-old female. She had a fever and mild consciousness disturbance (Glasgow coma scale, E3V5M6) 2 days after the initiation of minocycline treatment for atypical pneumonia, which proved to be Mycoplasma pneumoniae pneumonia by antibody titers of paired sera. Minocycline was immediately stopped and her consciousness temporarily improved. However, she fell into a semi-coma 6 days later and was referred to our hospital. On admission, she had a high fever (39.0°C), was mildly hypertensive (152/ 74 mmHg, but not requiring drug treatment) and had a maculopapular erythematous rash on her left gluteal region. Neurological examination revealed a Glasgow coma scale score of E2V2M4, conjugate eye deviation toward the left, hyper-reflexia and extensor plantar response bilaterally, but no meningeal signs. Complete blood counts were normal with no anemia (lowest hemoglobin, 116 g/L), atypical lymphocytosis or eosinophilia. Serum chemistry revealed elevated hepatic transaminases (aspartate aminotransferase, 57 IU/L; alanine aminotransferase, 133 IU/L) and hyperIgEemia (7992 IU/mL). Arterial blood gas was normal. Hepatosplenomegaly

The 8th Pan-Asian Committee for Treatment and Research in Multiple Sclerosis

The 8th Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS) was held at the Conrad Seoul, in Seoul, Korea, from 19 to 21 November 2015. Seoul is the capital city of Korea and, with a population of over 10.5 million, is regarded as one of the most important financial and cultural centers in East Asia. PACTRIMS was established in 2007 to provide neurologists and other healthcare professionals the opportunity to exchange findings regarding research and clinical care of individuals with multiple sclerosis (MS) and related disorders among Asian–Pacific countries. At this year’s meeting, there were many impressive presentations about MS, neuromyelitis optica (NMO) and other neuroinflammatory diseases. Here, we would like to introduce some of the intriguing studies reported at this meeting (Fig. 1).