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Lis N Velásquez, M Ayelén Milillo, M Victoria Delpino, Aldana Trotta, Pablo Fernández, Roberto G Pozner, Roland Lang, Luciana Balboa, Guillermo H Giambartolomei, Paula Barrionuevo
Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4(+) T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B...
October 20, 2016: Journal of Leukocyte Biology
T Huibertus van Essen, Sake I van Pelt, Inge H G Bronkhorst, Mieke Versluis, Fariba Némati, Cécile Laurent, Gregorius P M Luyten, Thorbald van Hall, Peter J van den Elsen, Pieter A van der Velden, Didier Decaudin, Martine J Jager
INTRODUCTION: Uveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors should be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors...
2016: PloS One
Sheng Zeng, Yuyu Yang, Xian Cheng, Bisheng Zhou, Ping Li, Yuhao Zhao, Xiaocen Kong, Yong Xu
Differentiation of B lymphocytes into isotope-specific plasma cells represents a hallmark event in adaptive immunity. During B cell maturation, expression of the class II transactivator (CIITA) gene is down-regulated although the underlying epigenetic mechanism is not completely defined. Here we report that hypermethylated in cancer 1 (HIC1) was up-regulated in differentiating B lymphocytes paralleling CIITA repression. Over-expression of HIC1 directly repressed endogenous CIITA transcription in B cells. Reporter assay and chromatin immunoprecipitation (ChIP) assay confirmed that HIC1 bound to the proximal CIITA type III promoter (-545/-113); mutation of a conserved HIC1 site within this region abrogated CIITA trans-repression...
October 6, 2016: Biochimica et Biophysica Acta
Kouji Okada, Shuko Hakata, Jun Terashima, Toshie Gamou, Wataru Habano, Shogo Ozawa
Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 µM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7...
October 2016: Oncology Reports
Hui Yu, Victor Wei Zhang, Asbjørg Stray-Pedersen, Imelda Celine Hanson, Lisa R Forbes, M Teresa de la Morena, Ivan K Chinn, Elizabeth Gorman, Nancy J Mendelsohn, Tamara Pozos, Wojciech Wiszniewski, Sarah K Nicholas, Anne B Yates, Lindsey E Moore, Knut Erik Berge, Hanne Sorte, Diana K Bayer, Daifulah ALZahrani, Raif S Geha, Yanming Feng, Guoli Wang, Jordan S Orange, James R Lupski, Jing Wang, Lee-Jun Wong
BACKGROUND: Primary immunodeficiency diseases (PIDDs) are inherited disorders of the immune system. The most severe form, severe combined immunodeficiency (SCID), presents with profound deficiencies of T cells, B cells, or both at birth. If not treated promptly, affected patients usually do not live beyond infancy because of infections. Genetic heterogeneity of SCID frequently delays the diagnosis; a specific diagnosis is crucial for life-saving treatment and optimal management. OBJECTIVE: We developed a next-generation sequencing (NGS)-based multigene-targeted panel for SCID and other severe PIDDs requiring rapid therapeutic actions in a clinical laboratory setting...
October 2016: Journal of Allergy and Clinical Immunology
Qian Cui, Qi-Sheng Feng, Hao-Yuan Mo, Jian Sun, Yun-Fei Xia, Hongxing Zhang, Jia Nee Foo, Yun-Miao Guo, Li-Zhen Chen, Ming Li, Wen-Sheng Liu, Miao Xu, Gangqiao Zhou, Fuchu He, Xueqing Yu, Wei-Hua Jia, Jianjun Liu, Yi-Xin Zeng, Jin-Xin Bei
To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese...
July 19, 2016: Human Molecular Genetics
Jiahe Liu, Xu Liu, Yong Liu, Shimin Deng, Hongbin Huang, Qicong Chen, Weidong Liu, Zunnan Huang
PURPOSE: Multiple sclerosis (MS) is a major demyelinating disease of the central nervous system with a strong genetic component. Previous studies have reported that the association of EVI5 rs11808092, CD58 rs2300747, and CIITA rs3087456 polymorphisms with the susceptibility to MS. However, the results were inconsistent. Thus, we conducted this meta-analysis to provide a more accurate estimation of the association between any of these polymorphisms and MS risk. METHODS: The PubMed, Embase, Chinese National Knowledge Infrastructure, Wan Fang databases and MSGene were used to search all potentially relevant studies...
September 2016: Meta Gene
Xi-Ping Huang, Ana Ludke, Sanjiv Dhingra, Jian Guo, Zhuo Sun, Li Zhang, Richard D Weisel, Ren-Ke Li
This study was performed to investigate how to overcome immunorejection associated with allogeneic stem cell therapy in the infarcted heart. Allogeneic bone marrow mesenchymal stem cell (MSC) differentiation increases major histocompatibility complex II (MHC II) expression, inducing transition from immunoprivileged to immunogenic phenotype. MHC II expression is regulated by the class II transactivator (CIITA). We isolated and characterized mouse and human MSCs and knocked down CIITA expression. Wild-type (WT) or CIITA-knockout (CIITA(-)) mouse MSCs were implanted into infarcted mouse myocardia, and recipient allo-antibody formation, cell survival, and cardiac function were measured...
September 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Alberto Falorni, Annalisa Brozzetti, Roberto Perniola
Autoimmune Addison's disease (AAD) is a complex disease that results from the interaction of a predisposing genetic background with still unknown environmental factors. Pathogenic variants in the autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrine syndrome type 1, of which AAD is a major disease component. Among the genetic factors for isolated AAD and autoimmune polyendocrine syndrome type 2, a key role is played by HLA class II genes: HLA-DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 are positively, and DRB1*0403 is negatively, associated with genetic risk for AAD...
2016: Frontiers of Hormone Research
Song-Yang Zhang, Ying Lv, Heng Zhang, Song Gao, Ting Wang, Juan Feng, Yuhui Wang, George Liu, Ming-Jiang Xu, Xian Wang, Changtao Jiang
MHC class II (MHCII) antigen presentation in adipocytes was reported to trigger early adipose inflammation and insulin resistance. However, the benefits of MHCII inhibition in adipocytes remain largely unknown. Here, we showed that human plasma polypeptide adrenomedullin 2 (ADM2) levels were negatively correlated with HOMA of insulin resistance in obese human. Adipose-specific human ADM2 transgenic (aADM2-tg) mice were generated. The aADM2-tg mice displayed improvements in high-fat diet-induced early adipose insulin resistance...
August 2016: Diabetes
Karin Luttropp, Malgorzata Debowska, Tomasz Lukaszuk, Leon Bobrowski, Juan Jesus Carrero, Abdul Rashid Qureshi, Peter Stenvinkel, Bengt Lindholm, Jacek Waniewski, Louise Nordfors
BACKGROUND: In complex diseases such as chronic kidney disease (CKD), the risk of clinical complications is determined by interactions between phenotypic and genotypic factors. However, clinical epidemiological studies rarely attempt to analyse the combined effect of large numbers of phenotype and genotype features. We have recently shown that the relaxed linear separability (RLS) model of feature selection can address such complex issues. Here, it is applied to identify risk factors for inflammation in CKD...
April 19, 2016: Nephrology, Dialysis, Transplantation
Sara Cajander, Elisabet Tina, Anders Bäckman, Anders Magnuson, Kristoffer Strålin, Bo Söderquist, Jan Källman
INTRODUCTION: A decrease in the expression of monocyte surface protein HLA-DR (mHLA-DR), measured by flow cytometry (FCM), has been suggested as a marker of immunosuppression and negative outcome in severe sepsis. However, FCM is not always available due to sample preparation that limits its use to laboratory operational hours. In this prospective study we evaluated dynamic changes in mHLA-DR expression during sepsis in relation to changes in HLA-DRA gene expression and Class II transactivator (CIITA), measured by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)...
2016: PloS One
Ryosuke Miura, Kazumi Kasakura, Nobuhiro Nakano, Mutsuko Hara, Keiko Maeda, Ko Okumura, Hideoki Ogawa, Takuya Yashiro, Chiharu Nishiyama
The cofactor CIITA is a master regulator of MHC class II expression and several transcription factors regulating the cell type-specific expression of CIITA have been identified. Although the MHC class II expression in plasmacytoid dendritic cells (pDCs) is also mediated by CIITA, the transcription factors involved in the CIITA expression in pDCs are largely unknown. In the present study, we analyzed the role of a hematopoietic lineage-specific transcription factor, PU.1, in CIITA transcription in pDCs. The introduction of PU...
2016: PloS One
Byung Hyun Kang, Hyo Jin Park, Hi Jung Park, Jae-Ii Lee, Seong Hoe Park, Kyeong Cheon Jung
PLZF-expressing invariant natural killer T cells and CD4 T cells are unique subsets of innate T cells. Both are selected via thymocyte-thymocyte interaction, and they contribute to the generation of activated/memory-like CD4 and CD8 T cells in the thymus via the production of IL-4. Here, we investigated whether PLZF(+) innate T cells also affect the development and function of Foxp3(+) regulatory CD4 T cells. Flow cytometry analysis of the thymus and spleen from both CIITA transgenic C57BL/6 and wild-type BALB/c mice, which have abundant PLZF(+) CD4 T cells and invariant natural killer T cells, respectively, revealed that Foxp3(+) T cells in these mice exhibited a CD103(+) activated/memory-like phenotype...
June 30, 2016: Molecules and Cells
Greta Forlani, Filippo Turrini, Silvia Ghezzi, Alessandra Tedeschi, Guido Poli, Roberto S Accolla, Giovanna Tosi
BACKGROUND: We previously demonstrated that the HLA class II transactivator CIITA inhibits HIV-1 replication in T cells by competing with the viral transactivator Tat for the binding to Cyclin T1 subunit of the P-TEFb complex. Here, we analyzed the anti-viral function of CIITA in myeloid cells, another relevant HIV-1 target cell type. We sinvestigated clones of the U937 promonocytic cell line, either permissive (Plus) or non-permissive (Minus) to HIV-1 replication. This different phenotype has been associated with the expression of TRIM22 in U937 Minus but not in Plus cells...
2016: Journal of Translational Medicine
Isaac Downs, Saptha Vijayan, Tabasum Sidiq, Koichi S Kobayashi
Major histocompatibility complex (MHC) class I and class II molecules play essential roles in the development and activation of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator) has been recognized as a master regulator of MHC class II gene expression, albeit knowledge about the regulatory mechanism of MHC class I gene expression had been limited. Recently identified MHC class I transactivator (CITA), or NLRC5, also belongs to the NLR protein family and constitutes a critical regulator for the transcriptional activation of MHC class I genes...
July 8, 2016: BioFactors
Susan C Pitt, Roland A Hernandez, Matthew A Nehs, Atul A Gawande, Francis D Moore, Daniel T Ruan, Nancy L Cho
BACKGROUND: Thyroid cancer patients frequently have favorable outcomes. However, a small subset develops aggressive disease refractory to traditional treatments. Therefore, we sought to characterize oncogenic mutations in thyroid cancers to identify novel therapeutic targets that may benefit patients with advanced, refractory disease. STUDY DESIGN: Data on 239 thyroid cancer specimens collected between January 2009 and September 2014 were obtained from the Dana Farber/Brigham and Women's Cancer Center...
June 2016: Journal of the American College of Surgeons
Ryo Maekawa, Lifa Lee, Maki Okada, Hiromi Asada, Masahiro Shinagawa, Isao Tamura, Shun Sato, Hiroshi Tamura, Norihiro Sugino
BACKGROUND: The ovulatory LH surge rapidly alters the expression of steroidogenesis-related genes such as steroidogenic acute regulatory protein (StAR) in granulosa cells (GCs) undergoing luteinization. We recently reported that histone modifications contribute to these changes. Histone modifications are regulated by a variety of histone modification enzymes. This study investigated the changes in gene expression of histone modification enzymes in rat GCs undergoing luteinization after the induction of ovulation...
2016: Journal of Ovarian Research
Zhiwen Fan, Xiaocen Kong, Jun Xia, Xiaoyan Wu, He Li, Huihui Xu, Mingming Fang, Yong Xu
Class II major histocompatibility complex (MHC II) dependent antigen presentation serves as a key step in mammalian adaptive immunity and host defense. In antigen presenting cells (e.g., macrophages), MHC II transcription can be activated by interferon gamma (IFN-γ) and mediated by class II transactivator (CIITA). The underlying epigenetic mechanism, however, is not completely understood. Here we report that following IFN-γ stimulation, symmetrically dimethylated histone H3 arginine 2 (H3R2Me2s) accumulated on the MHC II promoter along with CIITA...
May 2016: Biochimica et Biophysica Acta
Yves B Beaulieu, Jorge A Leon Machado, Sylvain Ethier, Luc Gaudreau, Viktor Steimle
Multiple relationships between ubiquitin-proteasome mediated protein turnover and transcriptional activation have been well documented, but the underlying mechanisms are still poorly understood. One way to induce degradation is via ubiquitination of the N-terminal α-amino group of proteins. The major histocompatibility complex (MHC) class II transactivator CIITA is the master regulator of MHC class II gene expression and we found earlier that CIITA is a short-lived protein. Using stable and transient transfections of different CIITA constructs into HEK-293 and HeLa cell lines, we show here that the extreme N-terminal end of CIITA isoform III induces both rapid degradation and transactivation...
2016: PloS One
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