Yusei Miyazaki

Memory and naïve B-cell subsets in patients with multiple sclerosis.

Memory and naïve B cells are considered to play distinct roles in immune regulation. However, the roles of memory and naïve B-cell subsets in multiple sclerosis (MS) have not yet been elucidated. In this study, we examined whether memory and naïve B-cell subsets differ between patients with MS and healthy subjects and whether interferon beta (IFNbeta)-1b can affect these subsets in patients with MS. We also studied these subsets in relapsing and remitting stages of MS. Subjects included 31 patients with relapsing-remitting MS in the remitting stage, of which 15 were treated with IFNbeta-1b and 16 were not treated, and 22 healthy control subjects. For 11 of the 16 untreated patients, blood samples were also obtained in the relapsing stage. Expression of CD5, CD80, CD86, CCR5, CXCR3, CD11a, and CD49d in memory and naïve B cells in blood samples was examined by flow cytometry. The percentages of CD86(+) cells and CCR5(+) cells in the naïve B-cell subset were significantly higher in untreated patients than in control subjects or IFNbeta-treated patients. In patients with MS, the percentages of CD86(+) cells and CCR5(+) cells in the naïve B-cell subset and the percentage of CD5(+) cells in the memory B-cell subset were significantly greater in the remitting stage than in the relapsing stage. These results indicate that memory and naïve B-cell subsets, especially CD86(+) naïve B cells, CCR5(+) naïve B cells, and CD5(+) memory B cells, might be useful in the study of the pathogenesis of and therapy for MS.

TNF-related apoptosis inducing ligand (TRAIL) gene polymorphism in Japanese patients with multiple sclerosis

TNF-related apoptosis inducing ligand (TRAIL) has been reported to induce apoptosis of autoreactive T cells and other inflammatory cells, and thus, it is a strong candidate gene for involvement in the development of autoimmune diseases. We investigated single nucleotide polymorphisms (SNPs) in the coding region of the gene at position 1595 in exon 5 in 128 Japanese patients with conventional/classical multiple sclerosis (MS) and 158 healthy controls. Patients with optico-spinal MS (OSMS) or atypical clinical attacks were excluded from the study. The frequency of CC genotype at position 1595 was significantly different between patients and controls (p=0.0027), and the C allele was more prevalent in the patients than in the controls (p=0.0138, OR=1.546, 95% CI=1.092-2.188). Logistic analysis, adjusted for HLA-DRB1*1501-positivity, revealed the independent association of the CC genotype with susceptibility to MS (p=0.0006, OR=2.393, 95% CI=1.453-3.943). There were no significant associations between +1595 polymorphism and the clinical features of MS. The results indicate that the presence of the CC genotype at position 1595 in exon 5 represents a higher risk of MS.

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

The chief therapeutic mechanism of fingolimod in multiple sclerosis (MS) is considered to be sequestration of pathogenic lymphocytes into secondary lymphoid tissues. B cells have recently been recognized as important immune regulators in MS. In this study, the effects of fingolimod on B cells in MS patients were analyzed. MS patients treated with fingolimod (MS-F) had a significantly lower number of B cells in the circulation. The remaining B cells in the blood of MS-F had a reduced proportion of memory B cells and an increased proportion of naïve B cells, expressed lower levels of the costimulatory molecule CD80, and produced less tumor necrosis factor-α and more interleukin-10. These observations in MS-F were based on an increased proportion of the transitional B-cell subpopulation within the naïve B-cell compartment. The observed findings in B cells of MS-F might be related to the therapeutic effect of this drug in MS.

Apathy/depression, but not subjective fatigue, is related with cognitive dysfunction in patients with multiple sclerosis

BackgroundCognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue. This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression.MethodsThe Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education. The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively. Student’s t-test was used to compare MS patients and healthy controls. Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score.ResultsIn all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N. Patients with MS had higher AS (p < 0.001), FQ (p < 0.0001), and BDI-II (p < 0.0001) scores than controls. In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ.ConclusionsCognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS. Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy. However, subjective fatigue is not related with cognitive impairment. Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS.

A case of acute urinary retention caused by periaqueductal grey lesion

Diseases of the central nervous system often cause disturbances in micturition. These diseases include lesions in the spinal cord, pons, cerebellum, hypothalamus, basal ganglia, and cerebrum. Of these regions, the dorsomedial pontine tegmentum (pontine micturition centre, PMC), frontal lobe, and sacral spinal cord are considered important in controlling micturition. Recent studies in healthy humans using positron emission tomography (PET) have shown a significant increase in blood flow in the PMC and midbrain periaqueductal grey (PAG) during micturition and urine storage.1–3 Thus, in addition to the PMC, the PAG may play an important role in micturition control. However, to our knowledge, there is no clinical report that identifies the role of the PAG in micturition. Here we report a case of acute urinary retention caused by a small lesion in the PAG. A favourable response to steroid therapy resulted in the normalisation of micturition. A 31 year old man had sudden voiding …

HLA-DPB1*0501 is not uniquely associated with opticospinal multiple sclerosis in Japanese patients. Important role of DPB1*0301

Apart from its unique lesion distribution pattern, the opticospinal form of multiple sclerosis (OSMS) is distinct among Japanese patients who satisfy the diagnostic criteria of MS. OSMS has been suggested to be strongly associated with HLA-DPB1*0501 in Japanese. However, association of DPB1*0301 with non-OSMS and lack of DPB1*0301 in OSMS were also reported. To verify the role of DPB1*0501 and DPB1*0301 in Japanese MS patients we determined the frequencies of these alleles in 26 patients with OSMS, 167 with non-OSMS and 156 normal subjects, who were all residents of Hokkaido, the northernmost island of Japan. All (100%) OSMS were negative for DPB1*0301 while 32 (19%) of the non-OSMS were positive for the allele. In DPB1*0301-negatives, the frequencies of DPB1*0501 in OSMS (85%) and non-OSMS (82%) were similar, but both were higher than in the controls (66%). In DPB1*0301-positives, the frequency of DPB1*0501 was low but similar in non-OSMS (12/32; 38%) and controls (6/14; 43%). Periventricular white matter lesions (PVL) were noted in 31 of 32 (97%) DPB1*0301-positive non-OSMS patients but in only 22 out of 135 (16%) DPB1*0301-negative non-OSMS patients and two out of 26 (8%) OSMS patients. Our findings indicate that DPB1*0501 plays an important role in the development of MS in general, but not in OSMS. The strong association of DPB1*0501 with OSMS may be due to the over-representation of the DPB1*0301 allele among individuals in the non-OSMS group. In addition, DPB1*0301 might be relevant to the development of periventricular lesions in Japanese patients with MS.

Expansion of CD4+CD28− T cells producing high levels of interferon-γ in peripheral blood of patients with multiple sclerosis

CD4+ T cells that lack surface expression of the CD28 co-stimulatory molecule (CD4+CD28− T cells) were expanded in peripheral blood of patients with multiple sclerosis (MS) [5.20 ± 1.67% vs 13.00 ± 2.68% (healthy controls (HC) versus patients with MS)]. Both the CD4+CD28+ and CD4+CD28− T-cell populations of patients with MS produced higher levels of interferon (IFN)-γ compared with those in HC. In particular, the proportion of IFN-γ+ cells among CD4+CD28− T cells from patients with MS was considerably high. However, expression of co-stimulatory molecules including inducible costimulator (ICOS), activating natural killer receptors, or members of tumor necrosis factor receptor family that replace CD28 in CD4+CD28− T cells of patients with MS could not be identified. A unique subpopulation bearing the CD45RAhighCCR7− phenotype was identified among the CD4+CD28− T cells of some patients with MS. Because only MS samples contained this CD45RAhighCCR7− population attributed to terminally differentiated effector memory cells and lacked naive CD45RAhighCCR7+ cells, we suggest that CD4+CD28− T cells of patients with MS represent a cell population which is in more differentiated state than healthy subjects. In patients treated with IFN-β-1b, IFN-γ production from CD4+CD28+ T cells was suppressed compared with that in untreated patients. On the contrary, in the CD4+CD28− population, production of IFN-γ in IFN-β-1b-treated patients was not significantly suppressed compared with that in untreated patients with MS. Thus, an additional treatment strategy that specifically targets this cell population may enhance the beneficial effect of IFN-β on MS.

Decreased serum vitamin D levels in Japanese patients with multiple sclerosis

Data regarding vitamin D in multiple sclerosis (MS) in Asia are limited. We investigated whether Japanese MS patients show decreased serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and vitamin D-binding protein (DBP) during winter. Mean serum 25(OH)D and 1,25(OH)2D levels were significantly lower in MS patients than in controls. There were no significant differences in serum 25(OH)D, 1,25(OH)2D, and DBP levels between patients or between controls from northern Japan (Hokkaido) and southern Japan (Kyushu). Serum vitamin D levels were low in Japanese MS patients but did not differ in patients from northern and southern Japan.

CSF pleocytosis and expansion of spinal lesions in Japanese Multiple sclerosis with special reference to the new diagnostic criteria

New diagnostic criteria for multiple sclerosis (MS) were recently proposed from the international panel on the diagnosis of MS, and they include exclusion criteria, such as lesions extending over more than two vertebral segments on spinal MRI and CSF pleocytosis of more than 50/mm3. We reviewed the clinical features of 158 patients who satisfied the diagnostic criteria for MS except for having the above atypical paraclinical findings. All patients exhibited two or more clinical attacks and objective clinical evidence of multiple lesions without any evidence of other disorders. Thirty–three (20.9%) patients had one or both atypical paraclinical findings. Twenty–one out of the 33 patients were classified as having optico–spinal MS (OSMS), and the other 12 as non–OSMS patients with atypical large expanding or destructive cerebral, cerebellar or brainstem lesions on MRI as well as one or both atypical paraclinical findings. Based on this heterogeneity in clinical findings in MS, there is an urgent need to develop a common general concept of the “MS” syndromes, and the ethnic–related heterogeneity should be considered in the revised criteria for the diagnosis of MS.

Spinal Magnetic Resonance Image alterations in human T-lymphotropic virus type I-associated myelopathy patients before and after immunomodulating treatments.

Sirs: Previous reports have been that most of the spinal cord lesions of Human T-lymphotropic virus type I associated myelopathy (HAM) were atrophy induced by the chronic inflammatory processes, and that these changes seldom showed alterations in MRI signal intensity [1–3]. In contrast, we present here two cases of HAM patients in whom the spinal cord showed moderate swelling both with gadolinium-DTPA enhancement and faint high T2 signal intensities, and in whom these alterations were partially resolved after interferon-alpha and steroid treatments. Case 1: A 66-year-old woman noticed paresthesia in her left arm and walking difficulty about eight months prior to admission. Suspected of having cervical and thoracic myelopathy, she underwent decompression of the cervical and thoracic spine at another hospital. Her neurological symptoms did not significantly improve, and in fact, there was gradual worsening. Neurological examination revealed marked spasticity of the lower extremities, and slight spasticity of the upper limbs. Deep tendon reflexes were hyperactive, and pathological reflexes were easily elicited. Serum antibody for HTLV-I was elevated to x8132, as was that of CSF x32. Additionally, Western blot analysis demonstrated P19 and p24 in the CSF. Protein in the CSF was elevated to 55 mg/dl, and IgG was 7.7 mg/dl (normal; 4 mg/dl >). No pleocytosis was seen (3/mm3). Both oligoclonal bands and MBP (myelin basic protein) were negative. On the basis of these findings, the patient was diagnosed as having HAM. Previous T2-weighted MRI performed prior to operation demonstrated high signal intensity in the patient’s cervical and thoracic cord (Fig. 1A,B). Moreover, the spinal cord showed faint Gdenhancement. Cranial MRI did not show white matter lesions, which are well known to be associated with HAM. As the initial treatment, we administered three million units of interferon-alpha intramuscularly daily for twenty-eight days. Following the interferon treatment, pulsed steroid therapy was employed, and oral steroid dose was gradually tapered. Then, the frequency of the tonic spasms in the lower extremities decreased. Intriguingly, MRI showed that T2 high signal intensity and gadolinium-DTPA enhancement of the spinal cord had almost disappeared (Fig. 1C,D). Case 2: A 51-year-old woman was transferred to our department because she had had walking difficulty and dull pain over both her lower extremities for about four months prior to admission. Neurologically, the spasticity of her extremities was prominent, and deep tendon reflexes were markedly hyperactive. Pathological reflexes were easily elicited. She also showed a markedly unsteady gait. Her serum anti-HTLV-I antibodies were highly elevated (x16384). Since her CSF examination had also revealed a high titer of HTLV-I antibody (x1024), and Western blotting had demonstrated p19 and p24 proteins, we concluded that she was suffering from HAM. MRI demonstrated cervical and thoracic cord swelling with faint T2 high signal intensities (Fig. 2A,B,C). Additionally, gadolinium-DTPA enhancement in the cervical cord revealed high signal areas in the lateral columns, which resembled “owl eyes” (Fig. 2D). Cranial MRI was regarded as normal. The spinal fluid showed slightly elevated protein 46 mg/dl and mild pleocytosis (33/mm3). IgG in the CSF was 6.7 mg/dl (normal; 4.0 mg/dl >). Neither oligoclonal bands nor MBP were found. The patient was initially administered steroid (1 mg/kg), and the dose was gradually tapered. In addition to the steroid treatment, interferon-alpha was administered every day for twenty-eight days. Her spasticity appeared to decrease, DTR became slightly hyperactive, and bilateral pathological reflexes showed weakly positive. Her walking speed increased, and a steadier gait was seen. MRI revealed a less swollen spinal cord, and the previously observed T2 high signal in the cervical cord had disappeared (Fig. 2E). Despite the improvement in cord swelling, T2 high signal intensities within the thoracic cord remained (Fig. 2F). In spite of intensive investigation including auto-antibody analysis, systemic CT and scintigrams, no other systemic disorders which could generate myelopathies were found in either case. However, we cannot completely exclude the possibility that protruding cervical disks at C5/6 and C6/7 in case1 and LETTER TO THE EDITORS