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121.
Pacheco FJ Servin J Dang D Kim J Molinaro C Daniels T Brown-Bryan TA Imoto-Egami M Casiano CA 《Arthritis and rheumatism》2005,52(7):2133-2145
OBJECTIVE: Autoantibodies to DNA topoisomerase I (topo I) are associated with diffuse systemic sclerosis (SSc), appear to be antigen driven, and may be triggered by cryptic epitopes exposed during in vivo topo I fragmentation. These autoantibodies recognize topo I and fragments of this autoantigen generated during apoptosis and necrosis. We undertook this study to determine whether lysosomal cathepsins are involved in topo I fragmentation during necrosis. METHODS: Topo I cleavage during necrosis was assessed by immunoblotting of lysates from L929 fibroblasts exposed to tumor necrosis factor alpha (TNFalpha) and the broad caspase inhibitor Z-VAD-FMK, and by immunoblotting of lysates from endothelial cells treated with HgCl2. Purified topo I and L929 nuclei were incubated with cathepsins B, D, G, H, and L, and topo I cleavage was detected by immunoblotting. The intracellular localization of cathepsin L activity and topo I in necrotic cells was examined using fluorescence microscopy. RESULTS: Treatment of L929 cells with TNFalpha and Z-VAD-FMK induced caspase-independent cell death with necrotic morphology. This cell death involved topo I cleavage into fragments of approximately 70 kd and 45 kd. This cleavage profile was reproduced in vitro by cathepsins L and H and was inhibited by the cathepsin L inhibitor Z-FY-CHO. During necrosis, cathepsin L activity diffused from lysosomes into the cytoplasm and nucleus, whereas topo I partially relocalized to the cytoplasm. Z-FY-CHO delayed necrosis and partially blocked topo I cleavage. The topo I cleavage fragments were also detected in necrotic endothelial cells and recognized by SSc sera containing anti-topo I antibodies. CONCLUSION: These results implicate cathepsins, particularly cathepsin L, in the cleavage of topo I during necrosis. This cleavage may generate potentially immunogenic fragments that could trigger anti-topo I immune responses in SSc. 相似文献
122.
King EM Kim HT Dang NT Michael E Drake L Needham C Haque R Bundy DA Webster JP 《Parasite immunology》2005,27(3):89-96
The role of the humoral immune system in human infection with Ascaris lumbricoides remains unclear. This study documents an epidemiological investigation in a highly endemic community in Vietnam, whereby serum antibody levels were assessed before treatment and after a 6-month reinfection period. These data were examined by correlation with infection status using an age-structured approach in an attempt to help shed light on the role of the humoral immune response. The first part of this study characterized levels of all serum antibody isotypes from the community in response to antigens of both adult and larval A. lumbricoides. Data were assessed in terms of their relation to host age and infection intensity with the aim to provide a broadly detailed account of immune responses to the parasite. In the second part, antibody responses to both life-stages of A. lumbricoides in serum samples collected before anthelmintic chemotherapy were analysed in relation to intensity of re-infection with the parasite 6 months following treatment. The results suggest that antibody responses may not confer protection from current infection or re-infection with A. lumbricoides and may not serve as reliable indicators of future infection intensity. Our results thereby lend support to the theory that immunity to A. lumbricoides may not be based on the humoral immune system. 相似文献
123.
124.
Abbi L. Engel Guan-Cheng Sun Ekram Gad Lauren R. Rastetter Katie Strobe Yi Yang Yushe Dang Mary L. Disis Hailing Lu 《Immunobiology》2013
Protein-bound polysaccharide-K (PSK) is a hot water extract from Trametes versicolor mushroom. It has been used traditionally in Asian countries for its immune stimulating and anti-cancer effects. We have recently found that PSK can activate Toll-like receptor 2 (TLR2). TLR2 is highly expressed on dendritic cells (DC), so the current study was undertaken to evaluate the effect of PSK on DC activation and the potential of using PSK as a vaccine adjuvant. In vitro experiments using mouse bone marrow-derived DC (BMDC) demonstrated that PSK induces DC maturation as shown by dose-dependent increase in the expression of CD80, CD86, MHCII, and CD40. PSK also induces the production of multiple inflammatory cytokines by DC, including IL-12, TNF-α, and IL-6, at both mRNA and protein levels. In vivo experiments using PSK as an adjuvant to OVAp323–339 vaccine showed that PSK as adjuvant leads to enlarged draining lymph nodes with higher number of activated DC. PSK also stimulates proliferation of OVA-specific T cells, and induces T cells that produce multiple cytokines, IFN-γ, IL-2, and TNF-α. Altogether, these results demonstrate the ability of PSK to activate DC in vitro and in vivo and the potential of using PSK as a novel vaccine adjuvant. 相似文献
125.
Satyan S. Kalkunte Stefan Neubeck Wendy E. Norris Shi-Bin Cheng Stefan Kostadinov Dang Vu Hoang Aftab Ahmed Ferdinand von Eggeling Zahir Shaikh James Padbury Goran Berg Anders Olofsson Udo R. Markert Surendra Sharma 《The American journal of pathology》2013,183(5):1425-1436
Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinol, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.Preeclampsia occurs in 5% to 8% of pregnancies worldwide and is a major cause of fetal and maternal morbidity and mortality.1–3 It is a heterogeneous disease with varied presentations from mild self-limited hypertension and proteinuria to severe forms with significant end-organ dysfunction and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets).3 Although the cause of preeclampsia and its appropriate treatment remain elusive, this syndrome has been proposed to reflect at least two stages of complications during pregnancy. These begin with preclinical manifestations at the maternal-fetal interface, followed by systemic clinical symptoms.1,2 Hypertension, proteinuria, and edema, with a variable degree of fetal growth restriction, are the cardinal features of preeclampsia.3 Because the placenta is the nutritional and immunological gateway to normal fetal development and pregnancy outcome, placenta-related events are believed to be central to the pathogenesis of this disease. Evidence exists for the release of disease-initiating molecules into maternal circulation that triggers the clinical symptoms.1,4 Placental and systemic anomalies reflected by circulating placental debris, inflammation, impaired remodeling of spiral arteries, placental hypoxia/ischemia, excess production of anti-angiogenic factors [soluble fms-like tyrosine kinase-1 (sFlt-1)], and soluble endoglin (sEng), and angiotensin receptor autoantibodies have all emerged as contributors to the pathophysiological characteristics of preeclampsia.2,4–14Preeclampsia has remained enigmatic because of lack of well-defined etiology and animal models. Although normal mice do not develop preeclampsia spontaneously, mouse models have been judged to be particularly useful to uterine diseases and pregnancy complications because many similarities in female reproduction and placentation have been identified between the two species.15 Moreover, their tractable genetics provide an effective way to probe mechanisms more deeply than many other species.15–17 We recently showed that sera from preeclamptic women could function as a source of novel causative factors that induced hypertension, proteinuria, and kidney pathological characteristics, as well as intrauterine growth restriction (IUGR), in IL-10−/− mice in a pregnancy-specific manner.18 IL-10 functions as a potent vascular and anti-inflammatory cytokine and has been shown to be present at significantly reduced levels in preeclampsia placental tissue.19,20 Preeclampsia serum (PES) was found to disrupt endovascular cross talk between trophoblasts and endothelial cells and to induce placental hypoxia and excess production of sFlt-1 and sEng,18 soluble factors known to precipitate maternal symptoms.21,22 These results from our serum-based humanized mouse model suggest that the pathophysiological characteristics of preeclampsia are more complex than previously thought and are likely to involve interactions and dysregulation of multiple factors. By using serum proteomic screening by surface-enhanced laser-desorption ionization-time-of-flight (SELDI-TOF), our results suggest that PES contains a reduced abundance of transthyretin, a plasma transport protein for the thyroid hormone, thyroxine, and retinol-binding protein.23 More important, transthyretin has been widely studied for its role in amyloid diseases associated with protein misfolding and aggregation, resulting in deposits of toxic, fibrillar aggregates in specific organs.24–26 Dysregulated or reduced transthyretin has also been implicated in Alzheimer disease, and overexpression of a wild-type human transthyretin transgene has been shown to ameliorate the disease in the transgenic murine model of human Alzheimer disease.27,28 Transthyretin in its native form assumes a homotetrameric quaternary configuration (approximately 14 kDa per monomer). Post-translational modifications of the monomer result in detection of several isoforms.29 Circulating transthyretin is also a validated marker of malnutrition and has a putative role in oocyte maturation and inflammation.30–32 Although the presence of transthyretin during implantation in mice and in the placenta and trophoblasts in humans has been reported,33,34 its functional role in normal pregnancy or adverse pregnancy outcomes has not been recognized. We hypothesize that transthyretin in preeclampsia is structurally and functionally dysregulated and contributes to the onset of this serious pregnancy complication. Herein, we present complementary in vitro and in vivo approaches, which show that endogenously altered transthyretin is a preeclampsia-causing agent and that native transthyretin has the ability to block the onset of preeclampsia-like features. 相似文献
126.
Nobuhiro Takemae Tung Nguyen Long Thanh Ngo Yasuaki Hiromoto Yuko Uchida Vu Phong Pham Tsutomu Kageyama Shizuko Kasuo Shinichi Shimada Yasutaka Yamashita Kaoru Goto Hideyuki Kubo Vu Tri Le Hung Van Vo Hoa Thi Do Dang Hoang Nguyen Tsuyoshi Hayashi Aya Matsuu Takehiko Saito 《Archives of virology》2013,158(4):859-876
The antigenicity of the influenza A virus hemagglutinin is responsible for vaccine efficacy in protecting pigs against swine influenza virus (SIV) infection. However, the antigenicity of SIV strains currently circulating in Japan and Vietnam has not been well characterized. We examined the antigenicity of classical H1 SIVs, pandemic A(H1N1)2009 (A(H1N1)pdm09) viruses, and seasonal human-lineage SIVs isolated in Japan and Vietnam. A hemagglutination inhibition (HI) assay was used to determine antigenic differences that differentiate the recent Japanese H1N2 and H3N2 SIVs from the H1N1 and H3N2 domestic vaccine strains. Minor antigenic variation between pig A(H1N1)pdm09 viruses was evident by HI assay using 13 mAbs raised against homologous virus. A Vietnamese H1N2 SIV, whose H1 gene originated from a human strain in the mid-2000s, reacted poorly with post-infection ferret serum against human vaccine strains from 2000-2010. These results provide useful information for selection of optimal strains for SIV vaccine production. 相似文献
127.
Li Zhou Xuemin He Peihong Cai Ting Li Rongdong Peng Junlong Dang Yue Li Haicheng Li Feng Huang Guojun Shi Chichu Xie Yan Lu Yanming Chen 《Cellular & molecular immunology》2021,18(3):698
Type 1 diabetes mellitus (T1D) is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells. In addition to well-established pathogenic effector T cells, regulatory T cells (Tregs) have also been shown to be defective in T1D. Thus, an increasing number of therapeutic approaches are being developed to target Tregs. However, the role and mechanisms of TGF-β-induced Tregs (iTregs) in T1D remain poorly understood. Here, using a streptozotocin (STZ)-induced preclinical T1D mouse model, we found that iTregs could ameliorate the development of T1D and preserve β cell function. The preventive effect was associated with the inhibition of type 1 cytotoxic T (Tc1) cell function and rebalancing the Treg/Tc1 cell ratio in recipients. Furthermore, we showed that the underlying mechanisms were due to the TGF-β-mediated combinatorial actions of mTOR and TCF1. In addition to the preventive role, the therapeutic effects of iTregs on the established STZ-T1D and nonobese diabetic (NOD) mouse models were tested, which revealed improved β cell function. Our findings therefore provide key new insights into the basic mechanisms involved in the therapeutic role of iTregs in T1D. 相似文献
128.
129.
Temperature-dependent variations in toxicity of diamide insecticides against three lepidopteran insects 总被引:1,自引:0,他引:1
Yaofa Li Yanan Dou Jingjie An Xuewei Tu Haiying Lv Wenliang Pan Zhihong Dang Zhanlin Gao 《Ecotoxicology (London, England)》2020,29(5):607-612
The effect of temperature on the toxicities of four diamide insecticides (chlorantraniliprole, cyantraniliprole, flubendiamide, tetraniliprole) against three lepidopteran insects (Helicoverpa armigera, Plutella xylostella, Athetis lepigone) were determined from 15 to 35 °C by exposing third-instar larvae to dip-treated cabbage leaf. The results indicated that increase in temperature led to an increase significantly and regularly in the toxicities of the four diamide insecticides against P. xylostella and H. armigera, but not for A. lepigone. The temperature coefficients (TCs) of the four diamide insecticides increased from 15 to 35 °C. Tetraniliprole for H. armigera (+825.83), chlorantraniliprole for P. xylostella (+315.65) and cyantraniliprole for H. armigera (+225.77) exhibited high positive TCs. For A. lepigone, temperature had a positively weak or no effect on the toxicities of most of the diamide insecticides from 20 to 30 °C, but a higher effect from 30 to 35 °C. In addition, the toxicities of chlorantraniliprole, cyantraniliprole and tetraniliprole all decreased from 15 to 20 °C. This study can guide pest managers in choosing suitable ambient field temperature when spraying diamide insecticides against lepidopteran insects. 相似文献
130.