Naoya Minami

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.

Five-year follow-up with low-dose tacrolimus in patients with myasthenia gravis

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction, and prednisolone (PSL) and immunosuppressive drugs are available for treatment. Tacrolimus, a macrolide that suppresses the immune system, is used as a second-line treatment for MG. There have been several reports of the effects of tacrolimus over a few years of follow-up. Here, we report data from 9 patients with steroid-dependent generalized MG treated with low-dose tacrolimus (2-3 mg/day) for 5 years. Following treatment with tacrolimus, mean MG-activities of daily living score improved from 4.6 at baseline to 3.3 at 5 years after initiation of treatment. Mean dose of PSL could also be reduced, from 24.0 mg/day at baseline to 10.2 mg/day at 5 years, although there were no cases of total withdrawal of PSL. By contrast, 5 of the 9 patients experienced exacerbation of symptoms and transient increases in PSL dose during the 5-year period. Tacrolimus is an important option for treatment of MG; however, careful management is needed for long-term treatment with this drug.

Hot water epilepsy with pineal cyst and cavum septi pellucidi.

Abstract: A case of reflex epilepsy accompanied by pineal cyst and cavum septi pellucidi induced by hot water bathing is presented. The patient is a 25‐year‐old male who has had six episodes of convulsions during the last three years. The seizures were diagnosed as a complex partial epilepsy followed by generalized tonic seizures. We have succeeded in recording his electroencephalogram (EEG) during convulsions. Moreover, a magnetic resonance imaging (MRI) study revealed a pineal cyst and cavum septi pellucidi. This is quite a rare form of adult hot water epilepsy accompanied by intracranial malformations.

Suppression of IL-10 production by calcitriol in patients with multiple sclerosis

We investigated whether calcitriol (1,25-dihydroxyvitamin D) differentially modulates cytokine production by peripheral blood mononuclear cells from multiple sclerosis (MS) patients compared with that from healthy controls. In response to phytohemagglutinin (PHA) or lipopolysaccharide (LPS), cytokine level in a calcitriol-added sample was normalized to that in a calcitriol-absent sample, and this relative unit was compared. The relative unit of IL-12/23(p40) in LPS-stimulation was higher in MS patients. Moreover, the relative unit of IL-10 in PHA-stimulation was lower in MS patients, and negatively correlated with the Expanded Disability Status Scale. The anti-inflammatory response to vitamin D may be reduced in MS.

Association of serum vitamin D levels in Japanese patients with multiple sclerosis

Vitamin D levels are one of the most likely environmental factors related to the development of multiple sclerosis (MS). As vitamin D levels differ between ethnicities, the associated risk of MS also differs. We aimed to determine the associations of serum vitamin D levels in Japanese patients with MS.

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

CD5-positive B cell subsets in secondary progressive multiple sclerosis

Previous studies have demonstrated that CD5(+) B cells produce more interleukin (IL)-10 than CD5(-) B cells and that CD5(+) B cells confer significant protection against experimental autoimmune encephalomyelitis (EAE). The objective of the present study was to determine whether CD5-positive B cell populations are associated with secondary progressive multiple sclerosis (SPMS) and to explore which subsets on CD5(+) B cells are associated with SPMS. A total of 26 patients with SPMS, of whom 11 were treated with IFNβ (IFN-SPMS) and 15 were not treated (non-IFN-SPMS), and 19 healthy control (HC) subjects were included in the study. Expression levels of CD11a, CD23, CD25, CD38, CD49d, CD80, CD86, CD138, CCR5, and CXCR5 on CD5(+) B cells in blood samples were examined by flow cytometry. The percentage of CD5(+) B cells in the SPMS group was significantly lower than in the HC group. Within the subsets of CD5(+) B cells, the expression of CD11a in the non-IFN-SPMS group was significantly decreased compared to the HC subjects. Patients with SPMS showed lower CCR5, CD25, and CD138 positivity on CD5(+) B cells than HC subjects. Our results indicate that CD5(+) B cell subsets might be associated with pathogenesis of SPMS.

Fingolimod suppresses bone resorption in female patients with multiple sclerosis

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

B cell-activating factor of the TNF family expands circulating transitional B cells in multiple sclerosis patients treated with fingolimod

Y.M. received funding for travel and/or speaker honoraria from Biogen, Mitsubishi Tanabe Pharma, and Ono Pharmaceu.cal Company. M.N. received funding for travel and/or speaker honoraria from Biogen, Mitsubishi Tanabe Pharma, and Takeda Pharmaceu.cal Company; is part of a scien.fic advisory board for Biogen and Chugai Pharmaceu.cal Company. The other authors have no relevant conflicts of interest to declare. � Yusei Miyazaki1,2, Masaaki Niino1, Eri Takahashi1, Toshiyuki Fukazawa3, Seiji Kikuchi2� Departments of 1Clinical Research and 2Neurology, Hokkaido Medical Center, Sapporo, Japan; 3Sapporo Neurology Clinic, Sapporo, Japan �

Sirtuin-1 is involved in lipopolysaccharide- and interferon beta-mediated interleukin-10 regulation in human monocytes

associated with a decreased basal secretion of IL-6 and TNF-a by B cells of RR-MS, and of IL-1a and IL-1b by monocytes of SP and PP-MS patients. Upon stimulation, there is a rescue of the level of these cytokines, which reach similar levels in all conditions tested. These data clearly suggest that there is a dysregulated innate immune response in MS, but with different profiles depending on the stage of the disease.