Abstract
Systemic lupus erythematosus (SLE) is mediated by a chronic and dysregulated inflammatory response. Interleukin (IL)-17, a proinflammatory cytokine, and T helper (Th)17 cells are associated ...with chronic autoimmune diseases. We hypothesized that inhibition of IL-17 would decrease the numbers of T cell subsets that function as B-cell helpers, as well as B-cell differentiation into plasma cells and autoantibody expression. The IL-17 level was increased markedly in Roquin
san/san
mice. Loss of IL-17 in Roquin
san/san
mice improved nephritis by downregulating immunoglobulin (Ig)G, IgG1, and IgG2a production. Formation of germinal centers (GCs), and follicular B- and T-cell differentiation was reduced, whereas the number of regulatory T (Treg) cells and immature B cells was increased, by IL-17 deficiency in Roquin
san/san
mice. These results suggest that IL-17 inhibition can ameliorate SLE by inhibiting B-cell differentiation into GCs. Therefore, IL-17–producing Th17 cells show promise as a target for development of novel therapeutics for SLE.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
An outbreak of lung injury among South Korean adults was examined in a hospital-based case-control study, and the suspected cause was exposure to humidifier disinfectant (HD). However, a case-control ...study with community-dwelling controls was needed to validate the previous study's findings, and to confirm the exposure-response relationship between HD and lung injury.
Each case of lung injury was matched with four community-dwelling controls, according to age (±3 years), sex, residence, and history of childbirth since 2006 (for women). Environmental risk factors, which included type and use of humidifier and HD, were investigated using a structured questionnaire during August 2011. The exposure to HD was calculated for both cases and controls, and the corresponding risks of lung injury were compared.
Among 28 eligible cases, 16 patients agreed to participate, and 60 matched controls were considered eligible for this study. The cases were more likely to have been exposed to HD (odds ratio: 116.1, 95% confidence interval: 6.5-2,063.7). All cases were exposed to HDs containing polyhexamethyleneguanidine phosphate, and the risk of lung injury increased with the cumulative exposure, duration of exposure, and exposure per day.
This study revealed a statistically significant exposure-response relationship between HD and lung injury. Therefore, continuous monitoring and stricter evaluation of environmental chemicals' safety should be conducted.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dysfunction of T helper 17 (Th17) cells leads to chronic inflammatory disorders. Signal transducer and activator of transcription 3 (STAT3) orchestrates the expression of proinflammatory cytokines ...and pathogenic cell differentiation from interleukin (IL)-17-producing Th17 cells. However, the pathways mediated by STAT3 signaling are not fully understood. Here, we observed that Fos-related antigen 1 (FRA1) and JUNB are directly involved in STAT3 binding to sites in the promoters of
and
. Promoter binding increased expression of IL-17 and the development of Th17 cells. Overexpression of
and
in mice resulted in susceptibility to collagen-induced arthritis and an increase in Th17 cell numbers and inflammatory cytokine production. In patients with rheumatoid arthritis, FRA1 and JUNB were colocalized with STAT3 in the inflamed synovium. These observations suggest that FRA1 and JUNB are associated closely with STAT3 activation, and that this activation leads to Th17 cell differentiation in autoimmune diseases and inflammation.
OBJECTIVE––Moyamoya disease (MMD) is a common cause of childhood stroke, in which the abnormal function of the endothelial colony–forming cell (ECFC) plays a key role in the pathogenesis of the ...disease. This study was designed to identify genes involved in MMD pathogenesis using gene expression profiling and to understand the defective function of MMD ECFCs.
APPROACH AND RESULTS––We compared gene expression profiles of ECFCs isolated from patients with MMD and normal controls. Among the differentially expressed genes, we selected a gene with the most downregulated expression, retinaldehyde dehydrogenase 2 (RALDH2). The activity of RALDH2 in MMD ECFCs was assessed by in vitro tube formation assay and in vivo Matrigel plug assay in the presence of all-trans retinoic acid. The transcriptional control of RALDH2 was tested using ChIP assays on acetyl-histone H3. In the results, MMD ECFCs inefficiently formed capillary tubes in vitro and capillaries in vivo, a defect restored by all-trans retinoic acid treatment. Knockdown of RALDH2 mRNA in normal ECFCs also induced decreased activity of capillary formation in vitro. The decreased level of RALDH2 mRNA in MMD ECFCs was attributed to defective acetyl-histone H3 binding to the promoter region.
CONCLUSIONS––From these results, we conclude that the expression of RALDH2 was epigenetically suppressed in ECFCs from patients with MMD, which may play a key role in their functional impairment.
Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 ...participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined.
Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells.
Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21 expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5.
Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.
IL-6-mediated STAT3 signaling is essential for Th17 differentiation and plays a central role in the pathogenesis of rheumatoid arthritis. To investigate the molecular mechanism underlying the ...antirheumatic effects and T cell regulatory effects of STAT3 inhibition, we studied the effects of the JAK 2 inhibitor AG490 on Th17 cell/regulatory T cell (Treg) balance and osteoclastogenesis. AG490 was administered to mice with collagen-induced arthritis (CIA) via i.p. injection, and its in vivo effects were determined. Differential expression of proinflammatory cytokines, including IL-17A, IL-1β, and IL-6, was analyzed by immunohistochemistry. Levels of phosphorylated STAT3 and STAT5 and differentiation of Th17 cells and Tregs after AG490 treatment in our CIA model were analyzed by immunostaining. In vitro development of Th17 cells and Tregs was analyzed by flow cytometry and real-time PCR. AG490 ameliorated the arthritic phenotype in CIA and increased the proportion of Foxp3(+) Tregs. In contrast, the proportion of IL-17A-producing T cells and levels of inflammatory markers were reduced in AG490-treated mice. Numbers of p-STAT3(+) CD4(+) T cells and p-STAT5(+) CD4(+) T cells were reduced and elevated, respectively, after treatment with AG490. Furthermore, AG490 markedly increased the expression of molecules associated with Treg development (ICOS, programmed cell death protein 1, ICAM-1, and CD103). The development and function of osteoclasts were suppressed by AG490 treatment. Our results suggest that AG490, specifically regulating the JAK2/STAT3 pathway, may be a promising treatment for rheumatoid arthritis.
Mercury speciation and removal were investigated for a newly developed hybrid filter (HF) originally designed to remove fine particulates and retrofitted to the exhaust cleaning system in a ...coal-fired power plant. The test plant used a blend of anthracite and semi-anthracite coals for combustion. At the boiler outlet, Hg0 was the dominant mercury species in the flue gas at 89% of total Hg. After passing through the electrostatic precipitator (ESP) and HF, Hg2+ became the dominant species owing to oxidation of Hg at the lower temperature and interaction with other air pollutants in the flue gas. The Hg2+ subsequently accumulated as Hgp by bonding with fly ash. Due to higher oxidation of Hg in the HF than in the ESP, more Hg2+ could be removed by the flue gas desulfurization (FGD) system through dissolution of Hg2+ when an HF was included. By installing hybrid filters alongside the existing devices, removal efficiencies of 86.7% and 99.3% for Hg and fine particulates, respectively, could be achieved, as opposed to 62.4% and 95.2% without the installation. Applying HFs in the existing air pollution control device (APCD) configuration was therefore recommended as the best simultaneous control technology for Hg and fine particulate matter (PM) at the test plant.
•The prediction for the speciation behavior of gas phase mercury•Mercury speciation changes with flue-gas composition.•Elemental mercury oxidation and removal by Hybrid filter•The suggestion of the configuration of Air Pollution Control Device for Hg removal
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
BACKGROUND: The bacteria Orientia tsutsugamushi is the causative agent of scrub typhus, mite-borne disease, which causes an acute febrile illness in patients. An epidemiologic study was conducted to ...understand the characteristics of scrub typhus in South Korea. FINDINGS: Reporting of tsutsugamushi disease is mandatory in South Korea since 1994. To investigate the prevalence of tsutsugamushi disease from 2001 to 2013, medical records from the Korea Center for Disease Control and Prevention were reviewed. In total, 70,914 cases were reported during 2001–2013. Of these, 37.16% (26,349) were male and 62.84% (44,565) were female. The highest number of cases was in the 60–69-year-old age group (19,484; 27.48%), and 72.22% (51,212) were in the 50–79-year-old age group. There were 65,100 cases (91.80%) reported during October (24,964; 35.20%) and November (40,136; 56.60%). An almost four-fold increase in the number of patients was observed in 2013 (10,485 cases) compared to 2001 (2,637 cases). The highest number of patients was reported in the Jeonbuk (9,425; 13.29%) and lowest in the Jeju (362; 0.51%). CONCLUSIONS: A rapid increase in the incidence of patients with tsutsugamushi disease was observed in most areas from 2001 to 2013, with the majority of cases reported in the western and southern coast.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The hybrid filter (HF) was newly designed and operated with powder activated carbon (PAC) injection to capture mercury and fine particulate matter in the coal power plant. With PAC injection in HF ...operation, the capture efficiency of elemental mercury was clearly enhanced. When the injection rate of PAC increased from 0 to 20 mg/m3, the speciation fraction of elemental mercury significantly decreased from 85.19% to 3.76% at the inlet of the hybrid filter. The speciation fraction of oxidized mercury did not vary greatly, whereas the particulate mercury increased from 1.31% to 94.04%. It was clearly observed that the HF played a role in the capture of mercury and fine PM by leading the conversion of elemental mercury as particulate mercury and the growth of PM via electrode discharge in the HF operation with PAC injection.
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•Surface change of captured PM by hybrid filter operation.•Fine PM capture by charged PAC during hybrid filter operation.•Speciation changes of Hg as particulate Hg in hybrid filter with PAC injection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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