Hiroshi Kuroda

STAM, Signal Transducing Adaptor Molecule, Is Associated with Janus Kinases and Involved in Signaling for Cell Growth and c-myc Induction

We previously identified a putative signal transducing adaptor molecule, named STAM, that contains an Src homology 3 (SH3) domain and immunoreceptor tyrosine-based activation motif (ITAM). In this report, we demonstrate the functional significance of STAM in cytokine-mediated signal transduction. STAM is associated with Jak3 and Jak2 tyrosine kinases via its ITAM region and phosphorylated by Jak3 and Jak2 upon stimulation with IL-2 and GM-CSF, respectively. An SH3 deletion mutant of STAM confers a dominant-negative effect on DNA synthesis mediated by IL-2 and GM-CSF. Furthermore, the wild-type STAM, but not STAM mutants deleted of SH3 and ITAM, significantly enhances c-myc induction mediated by IL-2 and GM-CSF. These results strongly implicate STAM in the signaling pathways for cell growth and c-myc induction immediately downstream of the Jaks associated with the cytokine receptors.

Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders

Objectives: To analyze aquaporin-4 (AQP4) antibody–positive patients who do not fulfill the current diagnostic criteria of neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD). Methods: We used a cell-based assay (CBA) with AQP4-transfected cells to detect AQP4 antibody in 298 consecutive patients with inflammatory CNS disorders seen at Tohoku University Hospital from 2007 to 2012. The patients were diagnosed as NMO, NMOSD, multiple sclerosis, or others using the respective current diagnostic criteria. The seropositive samples by CBA were also tested using a commercial ELISA. Results: Seventy-two patients were AQP4 antibody positive. Among them, 18.1% (13/72) did not meet the NMO or NMOSD criteria (7 with monophasic optic neuritis, 2 with attacks restricted to the brainstem, and 4 with myelitis with less than 3 vertebral segments) and 84.6% (11/13) of these had only a single attack. The ELISA results were negative in 38.4% (5/13) of those patients, and they had lower antibody titers by CBA than patients with NMO/NMOSD. Although these patients had a shorter follow-up and few attacks, they shared some clinical features with NMO/NMOSD patients such as onset age, female predominance, presence of other autoantibodies, severe optic neuritis attacks, centrally located spinal cord lesions, persisting hiccups, and nausea or vomiting episodes. Conclusions: AQP4 antibody–positive patients with single or recurrent attacks of optic neuritis, myelitis, or brain/brainstem disease not fulfilling the current criteria of NMO or NMOSD may not be uncommon, and they should also be included in the NMO spectrum.

Induction of histidine decarboxylase in skeletal muscle in mice by electrical stimulation, prolonged walking and interleukin-1

1 In normal non‐exercised skeletal muscles in mice, the activity of histidine decarboxylase (HDC), the enzyme which forms histamine, was very low. 2 HDC activity in the quadriceps femoris muscle was markedly elevated following contractions evoked by even a few minutes of direct electrical stimulation, peaking at 8‐12 h following contraction lasting 10 min, and gradually decreasing during the 24 h following contraction. The elevation in HDC activity depended on the duration and strength of stimulation. 3 Direct electrical stimulation induced a quantitatively similar elevation of HDC activity in the muscles of mast‐cell‐deficient mice (W/Wv mice). 4 Prolonged walking at a speed of 6 m min−1 for up to 6 h with a 30 min rest period at 3 h also elevated muscle HDC activity, the magnitude of the elevation being related to the duration of the walking. Repeated exercise (training) for several days diminished the elevation of muscle HDC activity induced by walking. In contrast, starvation augmented the elevation of muscle HDC activity induced by walking. 5 Intraperitoneal injection of interleukin‐1β (IL‐1β) also elevated muscle HDC activity in a dose‐dependent manner, as little as 1 μg kg−1 of IL‐1 producing a significant elevation of muscle HDC activity. 6 IL‐1β was immunohistochemically detected in normal non‐exercised quadriceps femoris muscle. We could not detect a significant increase in IL‐1β after exercise in the muscle or in serum: it may be below the level of detection. 7 On the basis of these results, together with those reported previously and the known actions of histamine, we propose that an elevation of HDC activity and generation of histamine occur in skeletal muscle following muscle contraction possibly as a result of induction by IL‐1β and that the histamine may be involved in fatigue in skeletal muscle as part of a defence mechanism preventing damage to the muscle.

Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and transverse myelitis. The relationship of NMO to multiple sclerosis (MS) has long been debated, but NMO has been classified as a demyelinating disease. Since the discovery of an NMO‐specific autoantibody to aquaporin 4 (AQP4), a dominant water channel in the central nervous system densely expressed on end‐feet of astrocytes, the clinical, magnetic resonance imaging and laboratory findings to distinguish NMO from MS have been clarified. Furthermore, pathological studies showed an extensive loss of immunoreactivities to astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), and perivascular deposition of immunoglobulins and activated complements with a relative preservation of the staining of myelin basic protein (MBP) in acute NMO lesions, but not in MS. In support of these pathological findings, the GFAP levels in the cerebrospinal fluid (CSF) during acute exacerbation of NMO are remarkably elevated compared with MBP and neurofilament, whereas the CSF‐GFAP in MS is not different from those in controls. Additionally, recent experimental studies have convincingly shown that AQP4 antibody is pathogenic in causing astorocytic destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that damage of astrocytes is far more severe than those of myelin and neurons, and that autoimmune astrocytopathy is the primary pathology in NMO. Based on these accumulated data, we propose that NMO should be classified as an astrocytopathic disease rather than a demyelinating disease.

Severe demyelination but no astrocytopathy in clinically definite neuromyelitis optica with anti-myelin-oligodendrocyte glycoprotein antibody

We report a patient with neuromyelitis optica (NMO) presenting anti-myelin-oligodendrocyte glycoprotein (MOG)-seropositive, in whom biomarkers of demyelination and astrocyte damage were measured during an acute attack. A 31-year-old man developed right optic neuritis followed by longitudinally extensive transverse myelitis, fulfilling the criteria for definite NMO. He was anti-MOG-seropositive and anti-aquaporin-4 seronegative. The myelin basic protein level was markedly elevated whereas glial fibrillary acidic protein was not detectable in cerebrospinal fluid during an acute attack. His symptoms quickly improved after high-dose methylprednisolone therapy. This case suggests that NMO patients with anti-MOG may have severe demyelination in the absence of astrocyte injury.

Familial neuromyelitis optica (Devic’s syndrome) with late onset in Japan

Neuromyelitis optica (NMO), or Devic’s syndrome, is characterized by the selective involvement of the optic nerves and spinal cord with normal brain MRI, in distinction to typical MS. The majority of NMO cases are sporadic, and the disease usually affects young adults: familial NMO has never previously been reported in Japan, where the nonfamilial form of NMO is relatively common, and none of the 71 cases of NMO seen at the Mayo Clinic was familial, although four patients reported a family history of MS.1 Only two familial NMO cases have been reported in the literature, and the ages at onset in those cases were 2 and 3 years in one family and 24 and 26 years in the other.2,3 We herein report NMO in two elderly Japanese sisters in whom the onset of disease occurred at age 59 and age 62 years. Patient 1. Patient 1 was a 67-year-old woman. When she was 62, right-sided blindness developed over 4 days, but the vision was restored in a year. At age 65, she became quadriplegic and felt numb below the neck. After 3 months of rehabilitation, she could walk using a cane. At age 67, she developed bilateral blurred vision, paraplegia, and dysuria subacutely, …

MRI and retinal abnormalities in isolated optic neuritis with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies: a comparative study

Acute optic neuritis (ON) typically presents with ocular pain and low visual acuity (VA), and there is a risk of permanent vision loss if ON is not managed properly.1 ON may be the first symptom of inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD). Recently, we reported some distinct characteristics between seropositive anti-aquaporin-4 (anti-AQP4) patients and seropositive antimyelin oligodendrocyte glycoprotein (anti-MOG) patients with NMOSD, using our in-house cell-based assays (CBA). However, patients with a single attack of unilateral ON were not included in our previous study. None of the previous studies of anti-MOG+ patients performed orbital MRI or optical coherence tomography (OCT) segmentation analyses, which may have diagnostic and prognostic implications. To address these issues, we evaluated the diagnostic utility of the anti-MOG assay and compared the MRI and OCT findings of anti-MOG+ and anti-AQP4+ patients with isolated ON. ### Patients We investigated 28 affected ON eyes from 21 consecutive anti-AQP4 seronegative patients aged 12 years or older who presented with isolated ON (4 cases with simultaneous bilateral ON, 3 cases with relapsing unilateral ON, and 14 cases with a single attack of unilateral ON) and were admitted to Tohoku University Hospital between 2011 and 2013. We excluded patients with ON already associated with brain and/or spinal cord MRI lesions. We compared anti-MOG+ ON eyes with nine affected ON eyes from eight anti-AQP4+ patients with isolated ON (one simultaneous bilateral ON). Severe VA loss was set at 0.1 in the decimal Japanese chart (equivalent to 20/200).2 ### Orbital MRI All patients performed orbital imaging using a 1.5 T MRI. We measured the short τ inversion recovery (STIR) and/or T2-weighted image hyperintense lesions …

MOG antibody–positive, benign, unilateral, cerebral cortical encephalitis with epilepsy

Objective: To describe the features of adult patients with benign, unilateral cerebral cortical encephalitis positive for the myelin oligodendrocyte glycoprotein (MOG) antibody. Methods: In this retrospective, cross-sectional study, after we encountered an index case of MOG antibody–positive unilateral cortical encephalitis with epileptic seizure, we tested for MOG antibody using our in-house, cell-based assay in a cohort of 24 consecutive adult patients with steroid-responsive encephalitis of unknown etiology seen at Tohoku University Hospital (2008–2014). We then analyzed the findings in MOG antibody–positive cases. Results: Three more patients, as well as the index case, were MOG antibody–positive, and all were adult men (median age 37 years, range 23–39 years). The main symptom was generalized epileptic seizure with or without abnormal behavior or consciousness disturbance. Two patients also developed unilateral benign optic neuritis (before or after seizure). In all patients, brain MRI demonstrated unilateral cerebral cortical fluid-attenuated inversion recovery hyperintense lesions, which were swollen and corresponded to hyperperfusion on SPECT. CSF studies showed moderate mononuclear pleocytosis with some polymorphonuclear cells and mildly elevated total protein levels, but myelin basic protein was not elevated. A screening of encephalitis-associated autoantibodies, including aquaporin-4, glutamate receptor, and voltage-gated potassium channel antibodies, was negative. All patients received antiepilepsy drugs and fully recovered after high-dose methylprednisolone, and the unilateral cortical MRI lesions subsequently disappeared. No patient experienced relapse. Conclusions: These MOG antibody–positive cases represent unique benign unilateral cortical encephalitis with epileptic seizure. The pathology may be autoimmune, although the findings differ from MOG antibody–associated demyelination and Rasmussen and other known immune-mediated encephalitides.

Pregnancy outcomes in aquaporin-4–positive neuromyelitis optica spectrum disorder

Objective: To investigate the association between neuromyelitis optica spectrum disorder (NMOSD) and pregnancy outcome. Methods: An international cohort of women with aquaporin-4 antibody–positive NMOSD and ≥1 pregnancy was studied retrospectively. Multivariate logistic regression was used to investigate whether pregnancy after NMOSD onset was associated with an increased risk of miscarriage (cohort of 40 women) or preeclampsia (cohort of 57 women). Results: Miscarriage rate was higher in pregnancies after NMOSD onset (42.9% [95% confidence interval 17.7%–71.1%] vs 7.04% [2.33%–15.7%]). Pregnancies conceived after, or up to 3 years before, NMOSD onset had an increased odds ratio of miscarriage (7.28 [1.03–51.6] and 11.6 [1.05–128], respectively), independent of maternal age or history of miscarriage. Pregnancies after, or up to 1 year before, NMOSD onset ending in miscarriage were associated with increased disease activity from 9 months before conception to the end of pregnancy, compared to viable pregnancies (mean annualized relapse rate 0.707 vs 0.100). The preeclampsia rate (11.5% [6.27%–18.9%]) was significantly higher than reported in population studies. The odds of preeclampsia were greater in women with multiple other autoimmune disorders or miscarriage in the most recent previous pregnancy, but NMOSD onset was not a risk factor. Conclusions: Pregnancy after NMOSD onset is an independent risk factor for miscarriage, and pregnancies conceived at times of high disease activity may be at increased risk of miscarriage. Women who develop NMOSD and have multiple other autoimmune disorders have greater odds of preeclampsia, independent of NMOSD onset timing.

Changes in Th17 and regulatory T cells after fingolimod initiation to treat multiple sclerosis

Fingolimod has demonstrated efficacy in patients with multiple sclerosis (MS), and patients become gradually lymphopenic after a few days of treatment, with selective reductions in CD4+ subsets. We observed an increase in the frequencies of circulating regulatory T cells after fingolimod administration. However, we also found that half of patients had increased proportion of circulating Th17 cells in CD4+ T cells after treatment (including a patient with MS relapses), whereas the others showed lower frequencies of Th17 cells, indicating some variability among patients. Further studies may confirm if slower reduction of circulating Th17 cells following fingolimod initiation predisposes to relapses.