Autoimmune autonomic ganglionopathy (AAG) is a rare acquired channelopathy that is characterized by pandysautonomia, in which autoantibodies to ganglionic nicotinic acetylcholine receptors (gAChR) may play a central role. Radioimmunoprecipitation (RIP) assays have been used for the sensitive detection of autoantibodies to gAChR in the serum of patients with AAG. Here, we developed luciferase immunoprecipitation systems (LIPS) to diagnose AAG based on IgGs to both the α3 and β4 gAChR subunits in patient serum. We reviewed the serological and clinical data of 50 Japanese patients who were diagnosed with AAG. With the LIPS testing, we detected anti-α3 and -β4 gAChR antibodies in 48% (24/50) of the patients. A gradual mode of onset was more common in the seropositive group than in the seronegative group. Patients with AAG frequently have orthostatic hypotension and upper and lower gastrointestinal tract symptoms, with or without anti-gAChR. The occurrence of autonomic symptoms was not significantly different between the seropositive and seronegative group, with the exception of achalasia in three patients from the seropositive group. In addition, we found a significant overrepresentation of autoimmune diseases in the seropositive group and endocrinological abnormalities as an occasional complication of AAG. Our results demonstrated that the LIPS assay was a useful novel tool for detecting autoantibodies against gAChR in patients with AAG.

The aim of this study was to evaluate the association between postural orthostatic tachycardia syndrome (POTS) and circulating antiganglionic acetylcholine receptor (gAChR) antibodies. We reviewed clinical assessments of Japanese patients with POTS, and determined the presence of gAChR antibodies in serum samples from those patients. Luciferase immunoprecipitation systems detected anti‐gAChRα3 and β4 antibodies in the sera from POTS (29%). Antecedent infections were frequently reported in patients in POTS patients. Moreover, autoimmune markers and comorbid autoimmune diseases were also frequent in seropositive POTS patients. Anti‐gAChR antibodies were detectable in significant number of patients with POTS, and POTS entailed the element of autoimmune basis.

Cognitive 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. The 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. In 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. Cognitive 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.

The therapeutic potency of M2000 (beta-D-mannuronic acid), a novel designed nonsteroidal anti-inflammatory drug with immunosuppressive property in T-cell-mediated autoimmune disease, was tested. The influence of M2000 on myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, was assessed. M2000 at two doses, 40 and 80 mg/kg/day, was administered intraperitoneally (i.p.) to prevention and treatment groups, respectively. Onset of i.p. injections of M2000 to prophylactic and therapeutic groups was day-1 and day-7 postimmunization. The WEHI-164 cell line was used for assaying the tolerability against M2000. The results of this experiment showed that the treatment of EAE with M2000 could significantly suppress disease development both prophylactically and therapeutically; the onset and symptoms of EAE in Lewis rats could be suppressed following the administration of M2000. Clinical improvement was accompanied by a marked decrease in mean numbers of vessels with perivascular cellular infiltration in M2000-treated rats compared with nontreated control. Disease suppression was associated with a marked suppression of MBP-specific T-cell reactivity in vitro, without any evidence for a generalized impairment of T-cell activity. Moreover, M2000 also showed a very high tolerability compared with certain steroidal and nonsteroidal anti-inflammatory drugs. Collectively, our data suggest that M2000 may provide a novel therapeutic option for T-cell-mediated autoimmune diseases in animal models and possibly in humans.

The purposes of the present study were to identify anti-striational antibodies in myasthenia gravis (MG) patients with myositis and/or myocarditis using a combination of cell-based assays and flow cytometry (cytometric cell-based assays) and to describe the main clinical implications. Among 2,609 stored samples collected from all over Japan between 2003 and 2016, we had serum samples from 30 MG patients with myositis and/or myocarditis. Cytometric cell-based assays with titin, ryanodine receptor, and voltage-gated Kv1.4 were performed. Autoantibodies were determined by differences in phycoerythin fluorescence between the 293F cells and titin-transfected cells. MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies. In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies. Thirty MG patients with myositis and/or myocarditis showed a severe generalized form, and 21 of them had thymoma. Anti-titin and anti-Kv1.4 antibodies were found in 28 (93%) and 15 (50%) patients, respectively, and all patients had at least one of these antibodies. Cytometric cell-based assays thus demonstrated that anti-striational antibodies are biomarkers of MG with myositis and/or myocarditis.

Since there has been no conclusive evidence regarding the treatment of ocular myasthenia, treatment guidelines were recently issued by the European Federation of Neurological Societies/European Neurological Society (EFNS/ENS). However, the therapeutic outcomes concerning the quality-of-life (QOL) of patients with ocular myasthenia are not yet fully understood. We investigated the therapeutic outcomes of patients with purely ocular myasthenia in a multicenter cross-sectional survey in Japan. To evaluate the severity of ocular symptoms, we used the ocular-quantitative MG (QMG) score advocated by Myasthenia Gravis Foundation of America. We used the Japanese translated version of the MG-QOL15, a self-appraised scoring system. Of 607 myasthenia gravis (MG) patients with an observation-duration of illness ≥ 2 years, the cases of 123 patients (20%) were limited to ocular muscles (purely ocular myasthenia). During the entire clinical course, 81 patients experienced both ptosis and diplopia, 36 had ptosis alone, and six had diplopia alone. Acetyl-cholinesterase inhibitors and prednisolone were used in 98 and 52 patients, respectively. Treatment improved ocular symptoms, with the mean reduction in ocular-QMG score of 2.3 ± 1.8 points. However, 47 patients (38%) failed to gain minimal manifestation or a better status. Patients with unfavorable outcomes also self-reported severe QOL impairment. Multivariate analyses showed that the pretreatment ocular-QMG score was associated with unfavorable outcomes, but not associated with the patient’s QOL. A treatment strategy designed in accord with a patient's ocular presentation must be considered in order to improve ocular symptoms and the patient's QOL.