The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Wenbin Zhan - One of the best experts on this subject based on the ideXlab platform.
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polymeric immunoglobulin receptor mediates immune excretion of mucosal igm antigen complexes across Intestinal Epithelium in flounder paralichthys olivaceus
Frontiers in Immunology, 2018Co-Authors: Xiuzhen Sheng, Xiaoyu Qian, Xiaoqian Tang, Jing Xing, Wenbin ZhanAbstract:Polymeric immunoglobulin receptor (pIgR) is one important player of mucosal defenses, but very little is known on pIgR-mediated immune excretion of the antigens that penetrate mucosal surface in fish. Previously we cloned the pIgR of flounder (Paralichthys olivaceus) and developed anti-pIgR antibody. In this study, the flounders were immunized intraperitoneally with the chicken ovalbumin (OVA) and the control protein bovine serum albumin (BSA) to elicit mucosal IgM antibody and pIgR response, and then challenged with OVA via caudal vein injection after the immunized OVA was absent from fish body at the fourth week post immunization. After OVA challenge, strong OVA-positive fluorescence signals were observed in submucosa, lamina propria and epithelial cells of the hindgut at 30 min, increased proceeding towards the distal portion of Intestinal folds, reached a peak at 2-3 h and then weakened and disappeared at 12 h, indicating that the OVA rapidly diffused from bloodstream into submucosa and lamina propria and excreted across Intestinal Epithelium. Whereas in BSA-immunized and OVA-challenged control fish, the OVA was detected in lamina propria but not in Intestinal Epithelium due to the lack of OVA-specific antibody. Accordingly, in Intestinal Epithelium, the transepithelial transport of OVA was confirmed by immunogold electron microscopy, and co-localization of OVA, IgM and pIgR were illuminated by multiple-label immunofluorescence confocal microscopy. Furthermore, in gut mucus but not in serum, a ~800kDa protein showed IgM-positive, OVA-positive and pIgR-positive simultaneously, and the OVA, together with IgM and secretory component (SC) of pIgR, could be immunoprecipitated by anti-OVA antibody, demonstrating the existence of SC-polymeric IgM-OVA complexes. All these results collectively revealed that the pIgR could transport mucosal IgM-OVA complexes from lamina propria across Intestinal Epithelium into gut mucus via the transcytosis in flounder. These new findings provided direct evidences for pIgR-mediated immune excretion of IgM-antigen complexes, and better understanding the role of pIgR in mucosal immunity in teleost fish.
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Polymeric Immunoglobulin Receptor Mediates Immune Excretion of Mucosal IgM–Antigen Complexes Across Intestinal Epithelium in Flounder (Paralichthys olivaceus)
Frontiers Media S.A., 2018Co-Authors: Xiuzhen Sheng, Xiaoyu Qian, Xiaoqian Tang, Jing Xing, Wenbin ZhanAbstract:Polymeric immunoglobulin receptor (pIgR) is one important player of mucosal defenses, but very little is known on pIgR-mediated immune excretion of the antigens that penetrate mucosal surface in fish. Previously, we cloned the pIgR of flounder (Paralichthys olivaceus) and developed anti-pIgR antibody. In this study, the flounders were immunized intraperitoneally with the chicken ovalbumin (OVA) and the control protein bovine serum albumin (BSA) to elicit mucosal IgM antibody and pIgR response, and then challenged with OVA via caudal vein injection after the immunized OVA was absent from fish body at the fourth week after immunization. After OVA challenge, strong OVA-positive fluorescence signals were observed in lamina propria (LP) submucosa and epithelial cells of the hindgut at 30 min, increased proceeding toward the distal portion of Intestinal folds, reached a peak at 2–3 h, and then weakened and disappeared at 12 h, indicating that the OVA rapidly diffused from bloodstream into LP submucosa and excreted across Intestinal Epithelium. Whereas in BSA-immunized and OVA-challenged control fish, the OVA was detected in LP submucosa but not in Intestinal Epithelium due to the lack of OVA-specific antibody. Accordingly, in Intestinal Epithelium, the transepithelial transport of OVA was confirmed by immunogold electron microscopy, and co-localization of OVA, IgM, and pIgR was illuminated by multiple-label immunofluorescence confocal microscopy and analyzed using Image J software. Furthermore, in gut mucus but not in serum, an ~800-kDa protein band showed IgM-positive, OVA-positive, and pIgR-positive simultaneously, and the OVA, together with IgM and secretory component (SC) of pIgR, could be immunoprecipitated by anti-OVA antibody, demonstrating the existence of SC–polymeric IgM–OVA complexes. All these results collectively revealed that the pIgR could transport mucosal IgM–OVA complexes from LP across Intestinal Epithelium into gut mucus via the transcytosis in flounder. These new findings provided direct evidences for pIgR-mediated immune excretion of IgM–antigen complexes, and better understanding the role of pIgR in mucosal immunity in teleost fish
Hans Clevers - One of the best experts on this subject based on the ideXlab platform.
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many inflammatory bowel disease risk loci include regions that regulate gene expression in immune cells and the Intestinal Epithelium
Gastroenterology, 2014Co-Authors: Michal Mokry, Hans Clevers, Sabine Middendorp, Caroline L Wiegerinck, Merlijn Witte, Hans Teunissen, Claartje A Meddens, Edwin Cuppen, Edward E S NieuwenhuisAbstract:Background & Aims The contribution of genetic factors to the pathogenesis of inflammatory bowel disease (IBD) has been established by twin, targeted-sequencing, and genome-wide association studies. These studies identified many risk loci, and research is underway to identify causal variants. These studies have focused mainly on protein-coding genes. We investigated other functional elements in the human genome, such as regulatory regions. Methods Using acetylated histone 3 lysine 27 chromatin immunoprecipitation and sequencing, we identified tens of thousands of potential regulatory regions that are active in Intestinal Epithelium (primary Intestinal crypts and cultured organoids) isolated from resected material and from biopsies collected during ileo-colonoscopies and immune cells (monocytes, macrophages, CD34 + , CD4 + , and CD8 + ). We correlated these regions with susceptibility loci for IBD. Results We have generated acetylated histone 3 lysine 27 profiles from primary Intestinal Epithelium and cultured organoids, which we have made publically available. We found that 45 of 163 single nucleotide polymorphisms (SNPs) associated with IBD overlap specifically with active regulatory elements. In addition, by taking strong linkage disequilibrium into account, another 47 IBD-associated SNPs colocalized with active regulatory elements through other SNPs in their vicinity. Altogether, 92 of 163 IBD-associated SNPs correlated with distinct active regulatory elements—a frequency 2.5- to 3.5-fold greater than that expected from random sampling. The variations in these SNPs often create or disrupt known binding motifs; they might affect the binding of transcriptional regulators to alter expression of regulated genes. Conclusions In addition to variants in protein coding genes, variants in noncoding DNA regulatory regions that are active in Intestinal Epithelium and immune cells are potentially involved in the pathogenesis of IBD.
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retromer dependent recycling of the wnt secretion factor wls is dispensable for stem cell maintenance in the mammalian Intestinal Epithelium
PLOS ONE, 2013Co-Authors: Reinoud E A De Groot, Hans Clevers, Henner F Farin, Marie Macůrkova, Hendrik C KorswagenAbstract:In C. elegans and Drosophila, retromer mediated retrograde transport of Wntless (Wls) from endosomes to the trans-Golgi network (TGN) is required for Wnt secretion. When this retrograde transport pathway is blocked, Wls is missorted to lysosomes and degraded, resulting in reduced Wnt secretion and various Wnt related phenotypes. In the mammalian intestine, Wnt signaling is essential to maintain stem cells. This prompted us to ask if retromer mediated Wls recycling is also important for Wnt signaling and stem cell maintenance in this system. To answer this question, we generated a conditional Vps35fl allele. As Vps35 is an essential subunit of the retromer complex, this genetic tool allowed us to inducibly interfere with retromer function in the Intestinal Epithelium. Using a pan-Intestinal epithelial Cre line (Villin-CreERT2), we did not observe defects in crypt or villus morphology after deletion of Vps35 from the Intestinal Epithelium. Wnt secreted from the mesenchyme of the intestine may compensate for a reduction in epithelial Wnt secretion. To exclude the effect of the mesenchyme, we generated Intestinal organoid cultures. Loss of Vps35 in Intestinal organoids did not affect the overall morphology of the organoids. We were able to culture Vps35∆/∆ organoids for many passages without Wnt supplementation in the growth medium. However, Wls protein levels were reduced and we observed a subtle growth defect in the Vps35∆/∆ organoids. These results confirm the role of retromer in the retrograde trafficking of Wls in the intestine, but show that retromer mediated Wls recycling is not essential to maintain Wnt signaling or stem cell proliferation in the Intestinal Epithelium.
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wnt control of stem cells and differentiation in the Intestinal Epithelium
Experimental Cell Research, 2005Co-Authors: Daniel Pinto, Hans CleversAbstract:The Intestinal Epithelium represents a very attractive experimental model for the study of integrated key cellular processes such as proliferation and differentiation. The tissue is subjected to a rapid and perpetual self-renewal along the crypt-villus axis. Renewal requires division of multipotent stem cells, still to be morphologically identified and isolated, followed by transit amplification, and differentiation of daughter cells into specialized absorptive and secretory cells. Our understanding of the crucial role played by the Wnt/beta-catenin signaling pathway in controlling the fine balance between cell proliferation and differentiation in the gut has been significantly enhanced in recent years. Mutations in some of its components irreversibly lead to carcinogenesis in humans and in mice. Here, we discuss recent advances related to the Wnt/beta-catenin signaling pathway in regulating Intestinal stem cells, homeostasis, and cancer. We emphasize how Wnt signaling is able to maintain a stem cell/progenitor phenotype in normal Intestinal crypts, and to impose a very similar phenotype onto colorectal adenomas.
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wnt signaling in the Intestinal Epithelium from endoderm to cancer
Genes & Development, 2005Co-Authors: Alex Gregorieff, Hans CleversAbstract:The Wnt pathway controls cell fate during embryonic development. It also persists as a key regulator of homeostasis in adult self-renewing tissues. In these tissues, mutational deregulation of the Wnt cascade is closely associated with malignant transformation. The Intestinal Epithelium represents the best-understood example for the closely linked roles of Wnt signaling in homeostatic self-renewal and malignant transformation. In this review, we outline current understanding of the physiological role of Wnt signaling in Intestinal biology. From this perspective, we then describe how mutational subversion of the Wnt cascade leads to colorectal cancer.
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live and let die in the Intestinal Epithelium
Current Opinion in Cell Biology, 2003Co-Authors: Elena Sancho, Eduard Batlle, Hans CleversAbstract:The Intestinal Epithelium is a relatively simple developmental system and a prime example of tissue renewal from a source of multipotent stem cells. Throughout adulthood, Intestinal epithelial proliferation, cell-fate specification and differentiation are coupled to migration in discrete units known as crypts of Lieberkuhn. Physically guided by Eph receptors and their ligands, the ephrins, stem cell progeny transit through the proliferation/differentiation switch, and Notch diversifies their subsequent fates. Wnt signalling appears to control most of these events.
B M Evers - One of the best experts on this subject based on the ideXlab platform.
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tsc2 mtorc1 signaling controls paneth and goblet cell differentiation in the Intestinal Epithelium
Cell Death and Disease, 2015Co-Authors: Yuning Zhou, Piotr G Rychahou, Qingding Wang, Heidi L Weiss, B M EversAbstract:The Intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of Intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in Intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the Intestinal Epithelium, with a marked decrease in the goblet and Paneth cell lineages. Conversely, treatment of mice with either Notch inhibitor dibenzazepine (DBZ) or mTORC1 inhibitor rapamycin significantly attenuated the reduction of goblet and Paneth cells. Accordingly, knockdown of TSC2 activated, whereas knockdown of mTOR or treatment with rapamycin decreased, the activity of Notch signaling in the Intestinal cell line LS174T. Importantly, our findings demonstrate that TSC2/mTORC1 signaling contributes to the maintenance of Intestinal Epithelium homeostasis by regulating Notch activity.
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TSC2/mTORC1 signaling controls Paneth and goblet cell differentiation in the Intestinal Epithelium
Cell Death & Disease, 2015Co-Authors: Yuning Zhou, Piotr G Rychahou, Qingding Wang, Heidi L Weiss, B M EversAbstract:The Intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Notch signaling is critical for the control of Intestinal stem cell maintenance and differentiation. However, the precise mechanisms involved in the regulation of differentiation are not fully understood. Previously, we have shown that tuberous sclerosis 2 (TSC2) positively regulates the expression of the goblet cell differentiation marker, MUC2, in Intestinal cells. Using transgenic mice constitutively expressing a dominant negative TSC2 allele, we observed that TSC2 inactivation increased mTORC1 and Notch activities, and altered differentiation throughout the Intestinal Epithelium, with a marked decrease in the goblet and Paneth cell lineages. Conversely, treatment of mice with either Notch inhibitor dibenzazepine (DBZ) or mTORC1 inhibitor rapamycin significantly attenuated the reduction of goblet and Paneth cells. Accordingly, knockdown of TSC2 activated, whereas knockdown of mTOR or treatment with rapamycin decreased, the activity of Notch signaling in the Intestinal cell line LS174T. Importantly, our findings demonstrate that TSC2/mTORC1 signaling contributes to the maintenance of Intestinal Epithelium homeostasis by regulating Notch activity.
Xiuzhen Sheng - One of the best experts on this subject based on the ideXlab platform.
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polymeric immunoglobulin receptor mediates immune excretion of mucosal igm antigen complexes across Intestinal Epithelium in flounder paralichthys olivaceus
Frontiers in Immunology, 2018Co-Authors: Xiuzhen Sheng, Xiaoyu Qian, Xiaoqian Tang, Jing Xing, Wenbin ZhanAbstract:Polymeric immunoglobulin receptor (pIgR) is one important player of mucosal defenses, but very little is known on pIgR-mediated immune excretion of the antigens that penetrate mucosal surface in fish. Previously we cloned the pIgR of flounder (Paralichthys olivaceus) and developed anti-pIgR antibody. In this study, the flounders were immunized intraperitoneally with the chicken ovalbumin (OVA) and the control protein bovine serum albumin (BSA) to elicit mucosal IgM antibody and pIgR response, and then challenged with OVA via caudal vein injection after the immunized OVA was absent from fish body at the fourth week post immunization. After OVA challenge, strong OVA-positive fluorescence signals were observed in submucosa, lamina propria and epithelial cells of the hindgut at 30 min, increased proceeding towards the distal portion of Intestinal folds, reached a peak at 2-3 h and then weakened and disappeared at 12 h, indicating that the OVA rapidly diffused from bloodstream into submucosa and lamina propria and excreted across Intestinal Epithelium. Whereas in BSA-immunized and OVA-challenged control fish, the OVA was detected in lamina propria but not in Intestinal Epithelium due to the lack of OVA-specific antibody. Accordingly, in Intestinal Epithelium, the transepithelial transport of OVA was confirmed by immunogold electron microscopy, and co-localization of OVA, IgM and pIgR were illuminated by multiple-label immunofluorescence confocal microscopy. Furthermore, in gut mucus but not in serum, a ~800kDa protein showed IgM-positive, OVA-positive and pIgR-positive simultaneously, and the OVA, together with IgM and secretory component (SC) of pIgR, could be immunoprecipitated by anti-OVA antibody, demonstrating the existence of SC-polymeric IgM-OVA complexes. All these results collectively revealed that the pIgR could transport mucosal IgM-OVA complexes from lamina propria across Intestinal Epithelium into gut mucus via the transcytosis in flounder. These new findings provided direct evidences for pIgR-mediated immune excretion of IgM-antigen complexes, and better understanding the role of pIgR in mucosal immunity in teleost fish.
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Polymeric Immunoglobulin Receptor Mediates Immune Excretion of Mucosal IgM–Antigen Complexes Across Intestinal Epithelium in Flounder (Paralichthys olivaceus)
Frontiers Media S.A., 2018Co-Authors: Xiuzhen Sheng, Xiaoyu Qian, Xiaoqian Tang, Jing Xing, Wenbin ZhanAbstract:Polymeric immunoglobulin receptor (pIgR) is one important player of mucosal defenses, but very little is known on pIgR-mediated immune excretion of the antigens that penetrate mucosal surface in fish. Previously, we cloned the pIgR of flounder (Paralichthys olivaceus) and developed anti-pIgR antibody. In this study, the flounders were immunized intraperitoneally with the chicken ovalbumin (OVA) and the control protein bovine serum albumin (BSA) to elicit mucosal IgM antibody and pIgR response, and then challenged with OVA via caudal vein injection after the immunized OVA was absent from fish body at the fourth week after immunization. After OVA challenge, strong OVA-positive fluorescence signals were observed in lamina propria (LP) submucosa and epithelial cells of the hindgut at 30 min, increased proceeding toward the distal portion of Intestinal folds, reached a peak at 2–3 h, and then weakened and disappeared at 12 h, indicating that the OVA rapidly diffused from bloodstream into LP submucosa and excreted across Intestinal Epithelium. Whereas in BSA-immunized and OVA-challenged control fish, the OVA was detected in LP submucosa but not in Intestinal Epithelium due to the lack of OVA-specific antibody. Accordingly, in Intestinal Epithelium, the transepithelial transport of OVA was confirmed by immunogold electron microscopy, and co-localization of OVA, IgM, and pIgR was illuminated by multiple-label immunofluorescence confocal microscopy and analyzed using Image J software. Furthermore, in gut mucus but not in serum, an ~800-kDa protein band showed IgM-positive, OVA-positive, and pIgR-positive simultaneously, and the OVA, together with IgM and secretory component (SC) of pIgR, could be immunoprecipitated by anti-OVA antibody, demonstrating the existence of SC–polymeric IgM–OVA complexes. All these results collectively revealed that the pIgR could transport mucosal IgM–OVA complexes from LP across Intestinal Epithelium into gut mucus via the transcytosis in flounder. These new findings provided direct evidences for pIgR-mediated immune excretion of IgM–antigen complexes, and better understanding the role of pIgR in mucosal immunity in teleost fish
Eric R Houpt - One of the best experts on this subject based on the ideXlab platform.
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leptin signaling in Intestinal Epithelium mediates resistance to enteric infection by entamoeba histolytica
Mucosal Immunology, 2011Co-Authors: Margo R Roberts, Stephen M Becker, Bradley S Podd, Eric R Houpt, Streamson C. Chua, Priya Duggal, Yiying Zhang, Martin G. Myers, William A PetriAbstract:Leptin signaling in Intestinal Epithelium mediates resistance to enteric infection by Entamoeba histolytica
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leptin signaling in Intestinal Epithelium mediates resistance to enteric infection by entamoeba histolytica
Mucosal Immunology, 2011Co-Authors: Margo R Roberts, Stephen M Becker, Bradley S Podd, Streamson C. Chua, Priya Duggal, Yiying Zhang, Martin G. Myers, Xiaoti Guo, Eric R HouptAbstract:Leptin is an adipocytokine that links nutrition to immunity. Previous observation that a genetic polymorphism in the leptin receptor affected susceptibility to Entamoeba histolytica infection led to the hypothesis that leptin signaling has a protective role during Intestinal amebic infection. In this study we show that mice lacking the functional leptin receptor developed devastating mucosal destruction after E. histolytica infection. Bone marrow chimera experiments demonstrated that leptin receptor expressed on hematopoietic cells was not sufficient to confer resistance. Similarly, peripheral knockout of the leptin receptor rendered animals susceptible, indicating that central expression of the leptin receptor was not sufficient to confer protection. The site of leptin action was localized to the gut via an Intestinal Epithelium-specific deletion of the leptin receptor, which rendered mice susceptible to infection and mucosal destruction by the parasite. Mutation of tyrosine 985 or 1138 in the intracellular domain of the leptin receptor, which mediates signaling through the SH2-containing tyrosine phosphatase/extracellular signal-regulated kinase (SHP2/ERK) and signal transducer and activator of transcription 3 (STAT3) pathways, respectively, demonstrated that both were important for mucosal protection. We conclude that leptin-mediated resistance to amebiasis is via its actions on Intestinal Epithelium rather than hematopoietic cells or the brain, and requires leptin receptor signaling through both the STAT3 and SHP2/ERK pathways.
