Search

Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer’s disease, as well as other neurodegenerative disorders. TREM2 is glycosylated in vitro and in vivo, but the significance of the modification is unknown. We previously established a sensitive and specific reporter cell model involving cultured Jurkat cells stably expressing a luciferase reporter gene and a gene encoding a TREM2DAP12 fusion protein to monitor TREM2-dependent signalling. In the present study, we prepared modified reporter cells to investigate the role of the N-glycans at N20 and N79. We show that the N-glycans at N79 have a requisite role in translocation of TREM2 to the cell surface, while the N-glycans at both N20 and N79 have a critical role in intracellular signal transduction. Our results indicate that structural changes to the TREM2 N-glycans may cause microglial dysfunction that contributes to the pathogenesis of neurodegenerative disorders and that maintaining the integrity of TREM2 N-glycosylation and the responsible glycosyltransferases may be a novel therapeutic strategy to treat these disorders.

The purpose of this study was to identify the clinical characteristics and predictors of serious infections (SIs) in the RemIT-JAV, a nationwide, prospective, inception cohort study for Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).We analyzed SIs within six months of remission induction therapy in 156 AAV patients. Hazard ratios with 95% confidence intervals (CIs) for SIs were calculated using the COX proportional hazard model.Sixty-three SIs in 42 patients were identified. The incidence rate (IR) of SIs was 87.59/100 patient-years. The median length of time to the onset of first SIs was 54 days. Hazard ratios (95%CI) for SIs were 1.97 (0.99-3.95) for age65 years, 0.47 (0.25-0.89) for female sex, 2.11 (1.05-4.27) for the severe form of AAV, and 2.88 (1.49-5.88) for initial PSL0.8 mg/kg/day in the first model, and 2.64 (1.39-5.01) for smoking and 3.27 (1.66-6.45) for initial PSL0.8 mg/kg/day in the second model.Lowering the IR of SIs in Japanese AAV patients is mandatory to improve the vital prognosis of these patients. For remission induction therapy of AAV patients with these risk factors, risk management of immunosuppressive treatment should be carefully considered.

Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP.A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model.A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age ≥ 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates.Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD-IP is indispensable for improving the short-term vital prognosis of these patients.

Acrylamide may affect the sex hormone system in the prepubertal period. This study examined the cross-sectional associations between dietary acrylamide intake and sex hormone levels among preschool-age Japanese children. The study was conducted in 2006 among 230 boys and 198 girls aged 3-6 years in Aichi, Japan. Acrylamide intake was assessed using 3-day diet records. Urinary concentrations of estrone, estradiol, testosterone, and androst-5-ene-3β, 17β diol (hereafter referred to as androstenediol) were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry. Sex hormone levels were adjusted for urinary creatinine levels. The estimated acrylamide intake was 1.00 μg/kg of body weight per day. After controlling for age and other covariates, acrylamide intake was significantly positively associated with urinary levels of testosterone and androstenediol in boys. On average, boys in the highest quartile of acrylamide intake had 96.9% higher testosterone (95% confidence interval: -1.8, 295; P for trend = 0.048) and 34.5% higher androstenediol levels (95% confidence interval: -5.9, 92.3; P for trend = 0.04) than boys in the lowest quartile. In girls, there were no significant associations between acrylamide intake and the hormones measured. Acrylamide intake may alter androgen metabolism in preschool-age boys. Because this is a first observation, our findings require confirmation in additional studies.

Objective. To compare the incidence and risk factors of serious adverse events (SAEs) in rheumatoid arthritis (RA) patients treated with etanercept (ETN) or adalimumab (ADA) between Korean and Japanese registries. Methods. We recruited 416 RA patients [505.2 patient-years (PYs)] who started ETN or ADA from Korean registry and 537 RA patients (762.0 PY) from Japanese registry. The patient background, incidence rate (IR) of SAE in 2 years, and risk factors for SAEs were compared. Results. Korean patients were younger and used more nonbiologic DMARDs, higher doses of methotrexate, and lower doses of prednisolone (PSL). The IR of SAEs (/100 PY) was higher in the Japanese registry compared to the Korean [13.65 vs. 6.73]. In both registries, infection was the most frequently reported SAE. The only significant risk factor for SAEs in Korean registry was age by decade [1.45]. In Japanese registry, age by decade [1.54], previous use of nonbiologic DMARDs ≥ 4 [1.93], and concomitant use of oral PSL ≥ 5 mg/day [2.20] were identified as risk factors for SAEs. Conclusions. The IR of SAE in Japan, especially infection, was higher than that of Korea, which was attributed to the difference of demographic and clinical characteristics of RA patients and treatment profiles.

A 44-year old woman with eosinophilic granulomatosis with polyangiitis (EGPA) developed sequential paralysis of different cranial nerves despite treatments including methylpredonisolone pulse therapy, intravenous immunoglobulins (IVIG), and cyclophosphamide. Infusions of rituximab ameliorated her neurological symptoms and serological inflammatory findings. Rituximab, a specific B cell-targeting therapy, might offer an alternative for refractory EGPA with possible advantages of cost and ease of use compared to IVIG, which also targets (at least in part) B lymphocytes and immunoglobulin production.