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Masaaki Niino

Publications and source records attributed to Masaaki Niino.

At least 19 recordsLinked to original sources
PubMed2026

Multiancestry genome-wide association and multiomics analyses elucidate spatiocellular features of multiple sclerosis genetics.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination disseminated in space and time. Here we performed a genome-wide association study (GWAS) using 688 MS cases and 205,199 controls from the Japanese population and identified significant associations in the major histocompatibility complex region and a population-specific risk variant in 11q24. Through cross-population GWAS meta-analyses using a total of 29,374 cases and 1,843,563 controls from 4 ancestral populations, we identified 22 novel susceptibility loci. Integration of GWAS and single-cell and single-nucleus RNA sequencing of peripheral blood mononuclear cells and subcortical lesions from patients with MS revealed enrichment of genetic risk factors for MS in CD4+ T helper cell lineage and regulatory T cells, as well as in endothelial cells. Furthermore, spatial transcriptomics of subcortical lesions demonstrated spatial and temporal heterogeneity in associations with MS genetic risk. Our study demonstrates the value of investigation of spatiocellular features of disease genetics across diverse populations and omics modalities.

Humans↗
PubMed2006

Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.

BACKGROUND: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an alpha4beta(1) integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection. OBJECTIVE: To test the effect of natalizumab treatment on the CD4(+)/CD8(+) T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood. DESIGN: Prospective longitudinal study. SETTING: Academic and private multiple sclerosis centers. PATIENTS: Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients. MAIN OUTCOME MEASURES: CD4(+) and CD8(+) T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound alpha4 integrin on peripheral blood CD4(+) and CD8(+) T cells was analyzed before and after natalizumab therapy. RESULTS: Natalizumab therapy decreased the CSF CD4(+)/CD8(+) ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients. CD4(+)/CD8(+) ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4(+)/CD8(+) ratios normalized. The expression of unbound alpha4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4(+) vs CD8(+) T cells. CONCLUSIONS: Natalizumab treatment alters the CSF CD4(+)/CD8(+) ratio. Lower expression of unbound alpha4 integrin on CD4(+) T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

Adolescent↗
PubMed2006

Natalizumab effects on immune cell responses in multiple sclerosis.

OBJECTIVE: Our objective was to study in vivo biological effects of natalizumab on immune cell phenotype and function in multiple sclerosis (MS) patients. METHODS: Blood was obtained before and after serial monthly natalizumab infusions to track functional expression of VLA-4 and migratory capacity of immune cells. The impact of infusion on activation thresholds of immune cells was evaluated. RESULTS: Preinfusion VLA-4 expression differed across immune cell subsets. Natalizumab significantly, albeit partially, diminished VLA-4 expression on circulating immune cells. Cell subsets were differentially affected. Treatment significantly decreased migratory capacity of immune cells, correlating well with changes in VLA-4 expression. Effects of a single dose were not saturating and did not persist through the monthly dose interval. Infusion effect varied across patients but was remarkably stable in individual patients, over multiple infusions. Treatment significantly modulated proliferative responses of immune cells. INTERPRETATION: To our knowledge, we provide first proof of concept that natalizumab diminishes migratory capacity of immune cells. Our prospective study further shows that effects of therapy likely (1) differ for distinct immune cell subsets, (2) are not sustained over current dose interval, (3) have unique profiles in individual patients, and (4) include modulation of activation threshold of immune cells. Monitoring these parameters could be relevant to ongoing safety and efficacy considerations.

Antibodies, Monoclonal↗
PubMed2005

Platelet-activating factor receptor gene polymorphism in Japanese patients with multiple sclerosis.

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 (CI), 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% CI, 1.10-2.89). These findings suggest that the PAFR gene missense mutation has a relation to the susceptibility for MS.

Adult↗
PubMed2005

Comparison of the clinical courses of the opticospinal and conventional forms of multiple sclerosis in Japan.

We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.

Adult↗
PubMed2004

CTLA-4 gene polymorphism is not associated with conventional multiple sclerosis in Japanese.

We investigated the polymorphisms of exon 1 (+49A/G) and promoter (-318C/T and -651C/T) regions of the CTLA-4 gene in 133 Japanese patients with conventional/classical multiple sclerosis (MS) and 156 healthy controls. Patients with optico-spinal MS (OSMS) or atypical clinical attacks were excluded from the study. There was no significant difference in the distribution of polymorphisms between patients and controls. Furthermore, there were no associations between polymorphisms and clinical characteristics, such as age at onset, disease prognosis, and HLA profiles. Our results suggest that CTLA-4 gene polymorphisms are neither conclusively related to susceptibility nor to the clinical characteristics of MS, especially in Japanese patients with conventional/classical form and clinical features identical to those of their counterparts in Western countries.

Adolescent↗
PubMed2004

Attack-related severity: a key factor in understanding the spectrum of idiopathic inflammatory demyelinating disorders.

Understanding the spectrum of idiopathic inflammatory demyelinating disorders (IIDD) is a fundamental issue for the diagnosis and treatment of these disorders as well as for the approach to their pathogenesis. The spectrum of IIDD is usually classified according to clinical course and lesion distribution. We compared the demographic features, clinical characteristics, laboratory findings, and genetic backgrounds between 193 Japanese patients with and without clinically or radiographically fulminant attacks who all satisfied the diagnostic criteria for multiple sclerosis (MS). "Fulminant attacks" in the current study represent attack-related clinically or radiologically severe relapses but do not necessarily mean severe disability. Patients with fulminant attacks were clinically and immunogenetically distinct from those free of such attacks, and the previously described characteristics of the opticospinal form of MS (OSMS) or neuromyelitis optica (NMO) were mostly shared by patients with fulminant attacks. HLA profiles were similar among patients with fulminant attacks irrespective of the lesion distributions. The GG homozygous and G alleles of the CTLA4 gene A/G coding SNP at position 49 in exon 1 were significantly more common in patients with fulminant attacks than in those without. Attack-related severity may be an important factor if validated by prospective studies defining criteria and establishing relationships to disease course and treatment regimens.

Adolescent↗
PubMed2004

Platelet-activating factor acetylhydrolase gene polymorphism and its activity in Japanese patients with multiple sclerosis.

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.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

The prevalence and clinical characteristics of MS in northern Japan.

In Japan, there is a low prevalence rate (PR) of multiple sclerosis (MS; 0.8-4.0/100,000) but a relatively high frequency of "optic-spinal form" MS (OS-MS). There have been no intensive epidemiologic frequency studies, however, in over 30 years. We performed a province-wide prevalence study of MS in the Tokachi province of Hokkaido, the northernmost island of Japan, and compared the observed clinical features with other populations in Japan and Western countries. Prevalence was determined on March 31, 2001. The primary sources for the case ascertainment were 13 hospitals that treated patients with neurologic diseases including MS in Tokachi. Patients were classified according to Poser's criteria. The prevalence rate of clinically definite or laboratory-supported definite MS (LSDMS) was 8.57 per 100,000 [31/361,726; male/female ratio=1:2.9, and age at onset=29.1+/-14.2 (mean+/-SD) years]. Out of the 31 patients, 5 (16%) were classified as OS-MS. The prevalence rate of MS in the Tokachi province was the highest reported in Orientals to date, although still low in comparison with Western communities at a similar latitude. In contrast to the previous reports in Japan, there was a relatively low frequency of OS-MS in Hokkaido.

Adolescent↗
PubMed2003

Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons.

Proteasomal dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). We examined the effect of a selective proteasomal inhibitor, epoxomicin, on primary cultured mesencephalic neurons. Exposing rat cultured mesencephalic neurons to epoxomicin for 24 h resulted in neurotoxicity in a dose-dependent manner. Epoxomicin caused mitochondrial dysfunction, reduction in reduced glutathione (GSH), and increased generation of free radicals. Neuronal damage was significantly blocked by antioxidative/GSH-augmenting agents. Epoxomicin also increased the expression of Bax and decreased that of Bcl-2, which may cause mitochondrial dysfunction and release of free radicals. Dopaminergic neurons were preferentially resistant to the toxicity of epoxomicin. Inhibiting the synthesis of tetrahydrobiopterin (BH(4)), which has been reported to have antioxidative function, increased the susceptibility of dopaminergic neurons, whereas increasing BH(4) levels protected non-dopaminergic neurons. These findings suggest that BH(4) is at least in part a contributing factor to grand the resistance to dopaminergic neurons against epoxomicin neurotoxicity. Our results suggest that proteasome inhibition causes the neurotoxicity in mesencephalic neurons, but that is not sufficient to reproduce the selective damage to dopaminergic neurons, such as that seen in PD.

Animals↗
PubMed2003

Brefeldin A-induced neurotoxicity in cultured spinal cord neurons.

Brefeldin A (BFA) is a fungus metabolite that is known to cause the disassembly of the Golgi complex and apoptosis in exposed cells, both of which have been suggested as playing roles in the pathogenesis of neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS). This study showed that BFA caused neurotoxicity and apoptotic nuclear changes in cultured spinal neurons of rat spinal cord in a dose- and time-dependent manner. The spinal motor neurons were more vulnerable to this neurotoxicity. The cultured spinal neurons showed irreversible disassembly of the Golgi apparatus as early as 1 hr after exposure to BFA. BFA induced the expression and activation of caspase-12 beginning 8 hr after exposure. The level of the cleaved form of caspase-3 had increased 12 hr after the addition of BFA. Free radical generation and loss of mitochondrial membrane potential were observed in the later stages of neurotoxicity caused by BFA. Collectively, our data suggests that BFA is an excellent agent for reproducing the pathophysiological features of ALS. This in vitro model may be useful in attempts to study the mechanisms of this neurodegenerative disease and to examine therapeutic potentials.

Animals↗
PubMed2003

C-C chemokine receptor 2 gene polymorphism in Japanese patients with multiple sclerosis.

C-C chemokine receptor 2 (CCR2) is a receptor for chemoattractant protein-1 (MCP-1) and associated with infiltrating lymphocytes in chronic active multiple sclerosis (MS) lesions. To study the role of CCR2 gene in the development of MS, we investigated the CCR2-64I polymorphism in 122 MS patients and 112 healthy controls in a Japanese population. We also analysed the influence of CCR2-64I polymorphism on the clinical course, age at disease onset, and severity. The distribution of the CCR2-64I allele was significantly different between patients and controls (p=0.0187), and the 64I/64I homozygote was significantly less common in MS than in control. Logistic analysis, adjusted for HLA-DRB1*1501-positivity, revealed negative association between the CCR2-64I and MS (p=0.0204). There were no significant associations between CCR2 polymorphism and the clinical features of MS. Our results indicate that the presence of CCR2-64I allele seems to provide protection against the development of MS.

Adolescent↗
PubMed2003

Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients.

Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN are present in brains of patients with multiple sclerosis (MS). The aim of this study was to investigate the role of OPN genes in the pathogenesis of MS. Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C genotype at the 8090th position in exon 6 was more prevalent in MS than in control (p<0.0001), and C allele was more prevalent in MS than in control (p<0.0001, OR=2.57, 95% CI=1.65-4.00). For the 9583rd position polymorphism in exon 7, patients with G/G genotype (age; 32.1+/-12.5 years, mean+/-S.D.) showed a later disease onset than G/A (age; 25.9+/-7.8 years, p=0.01) and A/A (age; 25.2+/-8.9 years, p=0.01) genotypes. There were no significant correlations between OPN gene polymorphisms and disease progression. Our results suggest that the 8090th polymorphism might be associated with susceptibility to MS, while the 9583rd polymorphism might be associated with age of onset of MS.

Adult↗
PubMed2003

Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes.

Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.

Acute Disease↗
PubMed2003

[Susceptibility genes for multiple sclerosis].

Multiple lines of evidence support the role of genetic factors for susceptibility to multiple sclerosis (MS), although unknown environmental factors must play an important role in developing MS. In this paper, we review the reports studied for the possible associations between Japanese MS and candidate genes by using case-control method. As for HLA alleles, HLA-DRB1*1501 and -DPB1*0501 allele have been confirmed to be associated with conventional MS and opticospinal MS, respectively. Some polymorphisms of vitamin D receptor gene, estrogen receptor gene, CTLA-4 gene, and osteopontin gene were reported to be associated with conventional MS. Appropriate case ascertainment and collection as well as proper statistical method are needed to isolate the susceptibility genes for MS.

Alleles↗
PubMed2002

An assessment of the association between IL-2 gene polymorphisms and Japanese patients with multiple sclerosis.

Interleukin-2 (IL-2) is a cytokine intimately involved with both the function and regulation of the immune system. Genetic analysis of experimental autoimmune encephalomyelitis (EAE) provides strong evidence supporting the candidacy of IL-2 as a susceptibility gene. We investigated the association of two single nucleotide polymorphisms (SNPs) at position -384 in the promoter region and +114 in the first exon of the IL-2 gene through a case-control study involving 113 Japanese patients with multiple sclerosis (MS) and 118 healthy controls. Our results showed no significant differences in the distribution of the two polymorphisms between MS patients and controls. Furthermore, no association was observed between IL-2 gene polymorphisms and clinical characteristics, such as clinical course and age at disease onset. Together, our findings suggest that IL-2 gene polymorphisms do not influence the susceptibility to MS or the clinical characteristics of MS in Japanese patients.

Adult↗