Skip to main content
Top
Published in:

Open Access 03-01-2024 | Chronic Inflammatory Bowel Disease | Review

Glycoprotein 2 as a gut gate keeper for mucosal equilibrium between inflammation and immunity

Authors: Zhongwei Zhang, Izumi Tanaka, Rika Nakahashi-Ouchida, Peter B. Ernst, Hiroshi Kiyono, Yosuke Kurashima

Published in: Seminars in Immunopathology | Issue 4-6/2024

Login to get access

Abstract

Glycoprotein 2 (GP2) is a widely distributed protein in the digestive tract, contributing to mucosal barrier maintenance, immune homeostasis, and antigen-specific immune response, while also being linked to inflammatory bowel disease (IBD) pathogenesis. This review sheds light on the extensive distribution of GP2 within the gastrointestinal tract and its intricate interplay with the immune system. Furthermore, the significance of GP2 autoantibodies in diagnosing and categorizing IBD is underscored, alongside the promising therapeutic avenues for modulating GP2 to regulate immunity and maintain mucosal balance.
Literature
1.
go back to reference Okumura R, Kurakawa T, Nakano T, Kayama H, Kinoshita M, Motooka D, Gotoh K, Kimura T, Kamiyama N, Kusu T, Ueda Y, Wu H, Iijima H, Barman S, Osawa H, Matsuno H, Nishimura J, Ohba Y, Nakamura S et al (2016) Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia. Nature 532:117–121PubMedCrossRef Okumura R, Kurakawa T, Nakano T, Kayama H, Kinoshita M, Motooka D, Gotoh K, Kimura T, Kamiyama N, Kusu T, Ueda Y, Wu H, Iijima H, Barman S, Osawa H, Matsuno H, Nishimura J, Ohba Y, Nakamura S et al (2016) Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia. Nature 532:117–121PubMedCrossRef
3.
go back to reference Kurashima Y, Kiyono H (2017) Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing. Annu Rev Immunol 35:119–147PubMedCrossRef Kurashima Y, Kiyono H (2017) Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing. Annu Rev Immunol 35:119–147PubMedCrossRef
4.
go back to reference Kamioka M, Goto Y, Nakamura K, Yokoi Y, Sugimoto R, Ohira S, Kurashima Y, Umemoto S, Sato S, Kunisawa J, Takahashi Y, Domino SE, Renauld JC, Nakae S, Iwakura Y, Ernst PB, Ayabe T, Kiyono H (2022) Intestinal commensal microbiota and cytokines regulate Fut2(+) Paneth cells for gut defense. Proc Natl Acad Sci USA 119(3):e2115230119 Kamioka M, Goto Y, Nakamura K, Yokoi Y, Sugimoto R, Ohira S, Kurashima Y, Umemoto S, Sato S, Kunisawa J, Takahashi Y, Domino SE, Renauld JC, Nakae S, Iwakura Y, Ernst PB, Ayabe T, Kiyono H (2022) Intestinal commensal microbiota and cytokines regulate Fut2(+) Paneth cells for gut defense. Proc Natl Acad Sci USA 119(3):e2115230119
5.
go back to reference Yeh TC, Wilson AC, Irwin DM (1993) Evolution of rodent lysozymes: isolation and sequence of the rat lysozyme genes. Mol Phylogenet Evol 2:65–75PubMedCrossRef Yeh TC, Wilson AC, Irwin DM (1993) Evolution of rodent lysozymes: isolation and sequence of the rat lysozyme genes. Mol Phylogenet Evol 2:65–75PubMedCrossRef
6.
go back to reference Russell AB, LeRoux M, Hathazi K, Agnello DM, Ishikawa T, Wiggins PA, Wai SN, Mougous JD (2013) Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors. Nature 496:508–512PubMedPubMedCentralCrossRef Russell AB, LeRoux M, Hathazi K, Agnello DM, Ishikawa T, Wiggins PA, Wai SN, Mougous JD (2013) Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors. Nature 496:508–512PubMedPubMedCentralCrossRef
7.
go back to reference Mukherjee S, Zheng H, Derebe MG, Callenberg KM, Partch CL, Rollins D, Propheter DC, Rizo J, Grabe M, Jiang Q-X, Hooper LV (2014) Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505:103–107PubMedCrossRef Mukherjee S, Zheng H, Derebe MG, Callenberg KM, Partch CL, Rollins D, Propheter DC, Rizo J, Grabe M, Jiang Q-X, Hooper LV (2014) Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505:103–107PubMedCrossRef
8.
go back to reference Hand TW, Reboldi A (2021) Production and function of immunoglobulin A. Ann Rev Immunol 39:695–718CrossRef Hand TW, Reboldi A (2021) Production and function of immunoglobulin A. Ann Rev Immunol 39:695–718CrossRef
9.
go back to reference Zhang Z, Tanaka I, Pan Z, Ernst PB, Kiyono H, Kurashima Y (2022) Intestinal homeostasis and inflammation: gut microbiota at the crossroads of pancreas-intestinal barrier axis. Eur J Immunol 52:1035–1046PubMedPubMedCentralCrossRef Zhang Z, Tanaka I, Pan Z, Ernst PB, Kiyono H, Kurashima Y (2022) Intestinal homeostasis and inflammation: gut microbiota at the crossroads of pancreas-intestinal barrier axis. Eur J Immunol 52:1035–1046PubMedPubMedCentralCrossRef
10.
go back to reference Jia W, Xie G, Jia W (2018) Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol 15:111–128PubMedCrossRef Jia W, Xie G, Jia W (2018) Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol 15:111–128PubMedCrossRef
11.
go back to reference Konturek SJ, Zabielski R, Konturek JW, Czarnecki J (2003) Neuroendocrinology of the pancreas; role of brain-gut axis in pancreatic secretion. Eur J Pharmacol 481:1–14PubMedCrossRef Konturek SJ, Zabielski R, Konturek JW, Czarnecki J (2003) Neuroendocrinology of the pancreas; role of brain-gut axis in pancreatic secretion. Eur J Pharmacol 481:1–14PubMedCrossRef
12.
go back to reference Kurashima Y, Kigoshi T, Murasaki S, Arai F, Shimada K, Seki N, Kim YG, Hase K, Ohno H, Kawano K, Ashida H, Suzuki T, Morimoto M, Saito Y, Sasou A, Goda Y, Yuki Y, Inagaki Y, Iijima H et al (2021) Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation. Nat Commun 12:1067PubMedPubMedCentralCrossRef Kurashima Y, Kigoshi T, Murasaki S, Arai F, Shimada K, Seki N, Kim YG, Hase K, Ohno H, Kawano K, Ashida H, Suzuki T, Morimoto M, Saito Y, Sasou A, Goda Y, Yuki Y, Inagaki Y, Iijima H et al (2021) Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation. Nat Commun 12:1067PubMedPubMedCentralCrossRef
13.
go back to reference Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Shibata S, Miyamoto K, Ishigame H, Chu PS, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H et al (2020) The liver-brain-gut neural arc maintains the T(reg) cell niche in the gut. Nature 585:591–596PubMedCrossRef Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Shibata S, Miyamoto K, Ishigame H, Chu PS, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H et al (2020) The liver-brain-gut neural arc maintains the T(reg) cell niche in the gut. Nature 585:591–596PubMedCrossRef
14.
go back to reference Cai J, Sun L, Gonzalez FJ (2022) Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host & Microbe 30:289–300CrossRef Cai J, Sun L, Gonzalez FJ (2022) Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host & Microbe 30:289–300CrossRef
15.
go back to reference Doyle CJ, Yancey K, Pitt HA, Wang M, Bemis K, Yip-Schneider MT, Sherman ST, Lillemoe KD, Goggins MD, Schmidt CM (2012) The proteome of normal pancreatic juice. Pancreas 41:186–194PubMedPubMedCentralCrossRef Doyle CJ, Yancey K, Pitt HA, Wang M, Bemis K, Yip-Schneider MT, Sherman ST, Lillemoe KD, Goggins MD, Schmidt CM (2012) The proteome of normal pancreatic juice. Pancreas 41:186–194PubMedPubMedCentralCrossRef
16.
go back to reference Ishimoto Y, Yamada K, Yamamoto S, Ono T, Notoya M, Hanasaki K (2003) Group V and X secretory phospholipase A(2)s-induced modification of high-density lipoprotein linked to the reduction of its antiatherogenic functions. Biochim Biophys Acta 1642:129–138PubMedCrossRef Ishimoto Y, Yamada K, Yamamoto S, Ono T, Notoya M, Hanasaki K (2003) Group V and X secretory phospholipase A(2)s-induced modification of high-density lipoprotein linked to the reduction of its antiatherogenic functions. Biochim Biophys Acta 1642:129–138PubMedCrossRef
18.
go back to reference Chairatana P, Chu H, Castillo PA, Shen B, Bevins CL, Nolan EM (2016) Proteolysis triggers self-assembly and unmasks innate immune function of a human alpha-defensin peptide. Chem Sci 7:1738–1752PubMedCrossRef Chairatana P, Chu H, Castillo PA, Shen B, Bevins CL, Nolan EM (2016) Proteolysis triggers self-assembly and unmasks innate immune function of a human alpha-defensin peptide. Chem Sci 7:1738–1752PubMedCrossRef
19.
go back to reference Nishiyama H, Nagai T, Kudo M, Okazaki Y, Azuma Y, Watanabe T, Goto S, Ogata H, Sakurai T (2018) Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice. Biochem Biophys Res Commun 495:273–279PubMedCrossRef Nishiyama H, Nagai T, Kudo M, Okazaki Y, Azuma Y, Watanabe T, Goto S, Ogata H, Sakurai T (2018) Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice. Biochem Biophys Res Commun 495:273–279PubMedCrossRef
20.
go back to reference Mukherjee S, Partch CL, Lehotzky RE, Whitham CV, Chu H, Bevins CL, Gardner KH, Hooper LV (2009) Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. J Biol Chem 284:4881–4888PubMedPubMedCentralCrossRef Mukherjee S, Partch CL, Lehotzky RE, Whitham CV, Chu H, Bevins CL, Gardner KH, Hooper LV (2009) Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. J Biol Chem 284:4881–4888PubMedPubMedCentralCrossRef
21.
go back to reference MacDonald RJ, Ronzio RA (1972) Comparative analysis of zymogen granule membrane polypeptides. Biochem Biophys Res Commun 49:377–382PubMedCrossRef MacDonald RJ, Ronzio RA (1972) Comparative analysis of zymogen granule membrane polypeptides. Biochem Biophys Res Commun 49:377–382PubMedCrossRef
22.
go back to reference Hoops TC, Ivanov I, Cui Z, Colomer-Gould V, Rindler MJ (1993) Incorporation of the pancreatic membrane protein GP-2 into secretory granules in exocrine but not endocrine cells. J Biol Chem 268:25694–25705PubMedCrossRef Hoops TC, Ivanov I, Cui Z, Colomer-Gould V, Rindler MJ (1993) Incorporation of the pancreatic membrane protein GP-2 into secretory granules in exocrine but not endocrine cells. J Biol Chem 268:25694–25705PubMedCrossRef
23.
go back to reference Merz S, Breunig M, Melzer MK, Heller S, Wiedenmann S, Seufferlein T, Meier M, Kruger J, Mulaw MA, Hohwieler M, Kleger A (2023) Single-cell profiling of GP2-enriched pancreatic progenitors to simultaneously create acinar, ductal, and endocrine organoids. Theranostics 13:1949–1973PubMedPubMedCentralCrossRef Merz S, Breunig M, Melzer MK, Heller S, Wiedenmann S, Seufferlein T, Meier M, Kruger J, Mulaw MA, Hohwieler M, Kleger A (2023) Single-cell profiling of GP2-enriched pancreatic progenitors to simultaneously create acinar, ductal, and endocrine organoids. Theranostics 13:1949–1973PubMedPubMedCentralCrossRef
24.
go back to reference Ronzio RA, Kronquist KE, Lewis DS, MacDonald RJ, Mohrlok SH, O’Donnell JJ Jr (1978) Glycoprotein synthesis in the adult rat pancreas. IV. Subcellular distribution of membrane glycoproteins. Biochim Biophys Acta 508:65–84PubMedCrossRef Ronzio RA, Kronquist KE, Lewis DS, MacDonald RJ, Mohrlok SH, O’Donnell JJ Jr (1978) Glycoprotein synthesis in the adult rat pancreas. IV. Subcellular distribution of membrane glycoproteins. Biochim Biophys Acta 508:65–84PubMedCrossRef
25.
go back to reference Fukuoka S (1994) Analysis of ZAPs, zymogen granule membrane associated proteins, in the regulated exocytosis of the pancreas. Biosci Biotechnol Biochem 58:1282–1285PubMedCrossRef Fukuoka S (1994) Analysis of ZAPs, zymogen granule membrane associated proteins, in the regulated exocytosis of the pancreas. Biosci Biotechnol Biochem 58:1282–1285PubMedCrossRef
26.
go back to reference Terahara K, Yoshida M, Igarashi O, Nochi T, Pontes GS, Hase K, Ohno H, Kurokawa S, Mejima M, Takayama N, Yuki Y, Lowe AW, Kiyono H (2008) Comprehensive gene expression profiling of Peyer’s patch M cells, villous M-like cells, and intestinal epithelial cells. J Immunol 180:7840–7846PubMedCrossRef Terahara K, Yoshida M, Igarashi O, Nochi T, Pontes GS, Hase K, Ohno H, Kurokawa S, Mejima M, Takayama N, Yuki Y, Lowe AW, Kiyono H (2008) Comprehensive gene expression profiling of Peyer’s patch M cells, villous M-like cells, and intestinal epithelial cells. J Immunol 180:7840–7846PubMedCrossRef
27.
go back to reference Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, Kadokura K, Tobe T, Fujimura Y, Kawano S, Yabashi A, Waguri S, Nakato G, Kimura S, Murakami T, Iimura M, Hamura K, Fukuoka S, Lowe AW et al (2009) Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 462:226–230PubMedCrossRef Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, Kadokura K, Tobe T, Fujimura Y, Kawano S, Yabashi A, Waguri S, Nakato G, Kimura S, Murakami T, Iimura M, Hamura K, Fukuoka S, Lowe AW et al (2009) Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 462:226–230PubMedCrossRef
28.
go back to reference Roggenbuck D, Goihl A, Sowa M, Lopens S, Rodiger S, Schierack P, Conrad K, Sommer U, Johrens K, Grutzmann R, Reinhold D, Laass MW (2023) Human glycoprotein-2 expressed in Brunner glands — a putative autoimmune target and link between Crohn’s and coeliac disease. Clin Immunol 247:109214PubMedCrossRef Roggenbuck D, Goihl A, Sowa M, Lopens S, Rodiger S, Schierack P, Conrad K, Sommer U, Johrens K, Grutzmann R, Reinhold D, Laass MW (2023) Human glycoprotein-2 expressed in Brunner glands — a putative autoimmune target and link between Crohn’s and coeliac disease. Clin Immunol 247:109214PubMedCrossRef
29.
go back to reference Derer S, Brethack AK, Pietsch C, Jendrek ST, Nitzsche T, Bokemeyer A, Hov JR, Schaffler H, Bettenworth D, Grassl GA, Sina C (2020) Inflammatory bowel disease-associated GP2 autoantibodies inhibit mucosal immune response to adherent-invasive bacteria. Inflamm Bowel Dis 26:1856–1868PubMedCrossRef Derer S, Brethack AK, Pietsch C, Jendrek ST, Nitzsche T, Bokemeyer A, Hov JR, Schaffler H, Bettenworth D, Grassl GA, Sina C (2020) Inflammatory bowel disease-associated GP2 autoantibodies inhibit mucosal immune response to adherent-invasive bacteria. Inflamm Bowel Dis 26:1856–1868PubMedCrossRef
30.
go back to reference Fukuoka S (2000) Molecular cloning and sequences of cDNAs encoding alpha (large) and beta (small) isoforms of human pancreatic zymogen granule membrane-associated protein GP2. Biochim Biophys Acta 1491:376–380PubMedCrossRef Fukuoka S (2000) Molecular cloning and sequences of cDNAs encoding alpha (large) and beta (small) isoforms of human pancreatic zymogen granule membrane-associated protein GP2. Biochim Biophys Acta 1491:376–380PubMedCrossRef
31.
go back to reference Rober N, Noss L, Goihl A, Reinhold D, Jahn J, de Laffolie J, Johannes W, Flemming GM, Roggenbuck D, Conrad K, Laass MW (2017) Autoantibodies against glycoprotein 2 isoforms in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 23:1624–1636PubMedCrossRef Rober N, Noss L, Goihl A, Reinhold D, Jahn J, de Laffolie J, Johannes W, Flemming GM, Roggenbuck D, Conrad K, Laass MW (2017) Autoantibodies against glycoprotein 2 isoforms in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 23:1624–1636PubMedCrossRef
32.
go back to reference Bork P, Sander C (1992) A large domain common to sperm receptors (Zp2 and Zp3) and TGF-beta type III receptor. FEBS Lett 300:237–240PubMedCrossRef Bork P, Sander C (1992) A large domain common to sperm receptors (Zp2 and Zp3) and TGF-beta type III receptor. FEBS Lett 300:237–240PubMedCrossRef
33.
go back to reference Li KJ, Siao SC, Wu CH, Shen CY, Wu TH, Tsai CY, Hsieh SC, Yu CL (2014) EGF receptor-dependent mechanism may be involved in the Tamm-Horsfall glycoprotein-enhanced PMN phagocytosis via activating Rho family and MAPK signaling pathway. Molecules 19:1328–1343PubMedPubMedCentralCrossRef Li KJ, Siao SC, Wu CH, Shen CY, Wu TH, Tsai CY, Hsieh SC, Yu CL (2014) EGF receptor-dependent mechanism may be involved in the Tamm-Horsfall glycoprotein-enhanced PMN phagocytosis via activating Rho family and MAPK signaling pathway. Molecules 19:1328–1343PubMedPubMedCentralCrossRef
34.
go back to reference Kolenda R, Burdukiewicz M, Schiebel J, Rodiger S, Sauer L, Szabo I, Orlowska A, Weinreich J, Nitschke J, Bohm A, Gerber U, Roggenbuck D, Schierack P (2018) Adhesion of Salmonella to pancreatic secretory granule membrane major glycoprotein GP2 of human and porcine origin depends on FimH sequence variation. Front Microbiol 9:1905PubMedPubMedCentralCrossRef Kolenda R, Burdukiewicz M, Schiebel J, Rodiger S, Sauer L, Szabo I, Orlowska A, Weinreich J, Nitschke J, Bohm A, Gerber U, Roggenbuck D, Schierack P (2018) Adhesion of Salmonella to pancreatic secretory granule membrane major glycoprotein GP2 of human and porcine origin depends on FimH sequence variation. Front Microbiol 9:1905PubMedPubMedCentralCrossRef
35.
go back to reference Lewis DS, MacDonald RJ, Kronquist KE, Ronzio RA (1977) Purification and partial characterization of an integral membrane glycoprotein from zymogen granules of dog pancreas. FEBS Lett 76:115–120PubMedCrossRef Lewis DS, MacDonald RJ, Kronquist KE, Ronzio RA (1977) Purification and partial characterization of an integral membrane glycoprotein from zymogen granules of dog pancreas. FEBS Lett 76:115–120PubMedCrossRef
36.
go back to reference Havinga JR, Strous GJ, Poort C (1983) Biosynthesis of the major glycoprotein associated with zymogen-granule membranes in the pancreas. Eur J Biochem 133:449–454PubMedCrossRef Havinga JR, Strous GJ, Poort C (1983) Biosynthesis of the major glycoprotein associated with zymogen-granule membranes in the pancreas. Eur J Biochem 133:449–454PubMedCrossRef
37.
go back to reference Paquette J, Leblond FA, Beattie M, LeBel D (1986) Reducing conditions induce a total degradation of the major zymogen granule membrane protein in both its membranous and its soluble form. Immunochemical quantitation of the two forms. Biochem Cell Biol 64:456–462PubMedCrossRef Paquette J, Leblond FA, Beattie M, LeBel D (1986) Reducing conditions induce a total degradation of the major zymogen granule membrane protein in both its membranous and its soluble form. Immunochemical quantitation of the two forms. Biochem Cell Biol 64:456–462PubMedCrossRef
38.
go back to reference Reggio HA, Palade GE (1978) Sulfated compounds in the zymogen granules of the guinea pig pancreas. J Cell Biol 77:288–314PubMedCrossRef Reggio HA, Palade GE (1978) Sulfated compounds in the zymogen granules of the guinea pig pancreas. J Cell Biol 77:288–314PubMedCrossRef
39.
go back to reference Tartakoff AM, Jamieson JD, Scheele GA, Palade GE (1975) Studies on the pancreas of the guinea pig. Parallel processing and discharge of exocrine proteins. J Biol Chem 250:2671–2677PubMedCrossRef Tartakoff AM, Jamieson JD, Scheele GA, Palade GE (1975) Studies on the pancreas of the guinea pig. Parallel processing and discharge of exocrine proteins. J Biol Chem 250:2671–2677PubMedCrossRef
40.
go back to reference Scheele GA, Fukuoka S, Freedman SD (1994) Role of the GP2/THP family of GPI-anchored proteins in membrane trafficking during regulated exocrine secretion. Pancreas 9:139–149PubMedCrossRef Scheele GA, Fukuoka S, Freedman SD (1994) Role of the GP2/THP family of GPI-anchored proteins in membrane trafficking during regulated exocrine secretion. Pancreas 9:139–149PubMedCrossRef
41.
go back to reference Fritz BA, Lowe AW (1996) Polarized GP2 secretion in MDCK cells via GPI targeting and apical membrane-restricted proteolysis. Am J Physiol 270:G176–G183PubMed Fritz BA, Lowe AW (1996) Polarized GP2 secretion in MDCK cells via GPI targeting and apical membrane-restricted proteolysis. Am J Physiol 270:G176–G183PubMed
42.
go back to reference Colomer V, Lal K, Hoops TC, Rindler MJ (1994) Exocrine granule specific packaging signals are present in the polypeptide moiety of the pancreatic granule membrane protein GP2 and in amylase: implications for protein targeting to secretory granules. EMBO J 13:3711–3719PubMedPubMedCentralCrossRef Colomer V, Lal K, Hoops TC, Rindler MJ (1994) Exocrine granule specific packaging signals are present in the polypeptide moiety of the pancreatic granule membrane protein GP2 and in amylase: implications for protein targeting to secretory granules. EMBO J 13:3711–3719PubMedPubMedCentralCrossRef
43.
go back to reference Fritz BA, Poppel CS, Fei MW, Lowe AW (2002) Processing of the major pancreatic zymogen granule membrane protein, GP2. Pancreas 24:336–343PubMedCrossRef Fritz BA, Poppel CS, Fei MW, Lowe AW (2002) Processing of the major pancreatic zymogen granule membrane protein, GP2. Pancreas 24:336–343PubMedCrossRef
44.
go back to reference Maxwell SE, Ramalingam S, Gerber LD, Udenfriend S (1995) Cleavage without anchor addition accompanies the processing of a nascent protein to its glycosylphosphatidylinositol-anchored form. Proc Natl Acad Sci USA 92:1550–1554PubMedPubMedCentralCrossRef Maxwell SE, Ramalingam S, Gerber LD, Udenfriend S (1995) Cleavage without anchor addition accompanies the processing of a nascent protein to its glycosylphosphatidylinositol-anchored form. Proc Natl Acad Sci USA 92:1550–1554PubMedPubMedCentralCrossRef
45.
go back to reference Scheffer RC, Poort C, Slot JW (1980) Fate of the major zymogen granule membrane-associated glycoproteins from rat pancreas. A biochemical and immunocytochemical study. Eur J Cell Biol 23:122–128PubMed Scheffer RC, Poort C, Slot JW (1980) Fate of the major zymogen granule membrane-associated glycoproteins from rat pancreas. A biochemical and immunocytochemical study. Eur J Cell Biol 23:122–128PubMed
46.
go back to reference Geuze HJ, Slot JW, van der Ley PA, Scheffer RC (1981) Use of colloidal gold particles in double-labeling immunoelectron microscopy of ultrathin frozen tissue sections. J Cell Biol 89:653–665PubMedCrossRef Geuze HJ, Slot JW, van der Ley PA, Scheffer RC (1981) Use of colloidal gold particles in double-labeling immunoelectron microscopy of ultrathin frozen tissue sections. J Cell Biol 89:653–665PubMedCrossRef
47.
go back to reference Lisanti MP, Sargiacomo M, Graeve L, Saltiel AR, Rodriguez-Boulan E (1988) Polarized apical distribution of glycosyl-phosphatidylinositol-anchored proteins in a renal epithelial cell line. Proc Natl Acad Sci USA 85:9557–9561PubMedPubMedCentralCrossRef Lisanti MP, Sargiacomo M, Graeve L, Saltiel AR, Rodriguez-Boulan E (1988) Polarized apical distribution of glycosyl-phosphatidylinositol-anchored proteins in a renal epithelial cell line. Proc Natl Acad Sci USA 85:9557–9561PubMedPubMedCentralCrossRef
48.
go back to reference Brown DA, Crise B, Rose JK (1989) Mechanism of membrane anchoring affects polarized expression of two proteins in MDCK cells. Science 245:1499–1501PubMedCrossRef Brown DA, Crise B, Rose JK (1989) Mechanism of membrane anchoring affects polarized expression of two proteins in MDCK cells. Science 245:1499–1501PubMedCrossRef
49.
go back to reference Freedman SD, Scheele GA (1993) Reversible pH-induced homophilic binding of GP2, a glycosyl-phosphatidylinositol-anchored protein in pancreatic zymogen granule membranes. Eur J Cell Biol 61:229–238PubMed Freedman SD, Scheele GA (1993) Reversible pH-induced homophilic binding of GP2, a glycosyl-phosphatidylinositol-anchored protein in pancreatic zymogen granule membranes. Eur J Cell Biol 61:229–238PubMed
50.
go back to reference Freedman SD, Scheele GA (1993) Regulated secretory proteins in the exocrine pancreas aggregate under conditions that mimic the trans-Golgi network. Biochem Biophys Res Commun 197:992–999PubMedCrossRef Freedman SD, Scheele GA (1993) Regulated secretory proteins in the exocrine pancreas aggregate under conditions that mimic the trans-Golgi network. Biochem Biophys Res Commun 197:992–999PubMedCrossRef
51.
go back to reference Fukuoka S, Freedman SD, Scheele GA (1991) A single gene encodes membrane-bound and free forms of GP-2, the major glycoprotein in pancreatic secretory (zymogen) granule membranes. Proc Natl Acad Sci USA 88:2898–2902PubMedPubMedCentralCrossRef Fukuoka S, Freedman SD, Scheele GA (1991) A single gene encodes membrane-bound and free forms of GP-2, the major glycoprotein in pancreatic secretory (zymogen) granule membranes. Proc Natl Acad Sci USA 88:2898–2902PubMedPubMedCentralCrossRef
52.
go back to reference Rindler MJ, Hoops TC (1990) The pancreatic membrane protein GP-2 localizes specifically to secretory granules and is shed into the pancreatic juice as a protein aggregate. Eur J Cell Biol 53:154–163PubMed Rindler MJ, Hoops TC (1990) The pancreatic membrane protein GP-2 localizes specifically to secretory granules and is shed into the pancreatic juice as a protein aggregate. Eur J Cell Biol 53:154–163PubMed
53.
go back to reference Fukuoka S, Freedman SD, Yu H, Sukhatme VP, Scheele GA (1992) GP-2/THP gene family encodes self-binding glycosylphosphatidylinositol-anchored proteins in apical secretory compartments of pancreas and kidney. Proc Natl Acad Sci USA 89:1189–1193PubMedPubMedCentralCrossRef Fukuoka S, Freedman SD, Yu H, Sukhatme VP, Scheele GA (1992) GP-2/THP gene family encodes self-binding glycosylphosphatidylinositol-anchored proteins in apical secretory compartments of pancreas and kidney. Proc Natl Acad Sci USA 89:1189–1193PubMedPubMedCentralCrossRef
54.
go back to reference Freedman SD, Kern HF, Scheele GA (1998) Acinar lumen pH regulates endocytosis, but not exocytosis, at the apical plasma membrane of pancreatic acinar cells. Eur J Cell Biol 75:153–162PubMedCrossRef Freedman SD, Kern HF, Scheele GA (1998) Acinar lumen pH regulates endocytosis, but not exocytosis, at the apical plasma membrane of pancreatic acinar cells. Eur J Cell Biol 75:153–162PubMedCrossRef
55.
go back to reference Freedman SD, Kern HF, Scheele GA (1998) Cleavage of GPI-anchored proteins from the plasma membrane activates apical endocytosis in pancreatic acinar cells. Eur J Cell Biol 75:163–173PubMedCrossRef Freedman SD, Kern HF, Scheele GA (1998) Cleavage of GPI-anchored proteins from the plasma membrane activates apical endocytosis in pancreatic acinar cells. Eur J Cell Biol 75:163–173PubMedCrossRef
56.
go back to reference Schmidt K, Dartsch H, Linder D, Kern HF, Kleene R (2000) A submembranous matrix of proteoglycans on zymogen granule membranes is involved in granule formation in rat pancreatic acinar cells. J Cell Sci 113(Pt 12):2233–2242PubMedCrossRef Schmidt K, Dartsch H, Linder D, Kern HF, Kleene R (2000) A submembranous matrix of proteoglycans on zymogen granule membranes is involved in granule formation in rat pancreatic acinar cells. J Cell Sci 113(Pt 12):2233–2242PubMedCrossRef
57.
go back to reference Kalus I, Hodel A, Koch A, Kleene R, Edwardson JM, Schrader M (2002) Interaction of syncollin with GP-2, the major membrane protein of pancreatic zymogen granules, and association with lipid microdomains. Biochem J 362:433–442PubMedPubMedCentralCrossRef Kalus I, Hodel A, Koch A, Kleene R, Edwardson JM, Schrader M (2002) Interaction of syncollin with GP-2, the major membrane protein of pancreatic zymogen granules, and association with lipid microdomains. Biochem J 362:433–442PubMedPubMedCentralCrossRef
58.
go back to reference Jacob M, Laine J, LeBel D (1992) Specific interactions of pancreatic amylase at acidic pH. Amylase and the major protein of the zymogen granule membrane (GP-2) bind to immobilized or polymerized amylase. Biochem Cell Biol 70:1105–1114PubMedCrossRef Jacob M, Laine J, LeBel D (1992) Specific interactions of pancreatic amylase at acidic pH. Amylase and the major protein of the zymogen granule membrane (GP-2) bind to immobilized or polymerized amylase. Biochem Cell Biol 70:1105–1114PubMedCrossRef
59.
go back to reference Parker EM, Zaman MM, Freedman SD (2000) GP2, a GPI-anchored protein in the apical plasma membrane of the pancreatic acinar cell, co-immunoprecipitates with src kinases and caveolin. Pancreas 21:219–225PubMedCrossRef Parker EM, Zaman MM, Freedman SD (2000) GP2, a GPI-anchored protein in the apical plasma membrane of the pancreatic acinar cell, co-immunoprecipitates with src kinases and caveolin. Pancreas 21:219–225PubMedCrossRef
60.
go back to reference Yu S, Michie SA, Lowe AW (2004) Absence of the major zymogen granule membrane protein, GP2, does not affect pancreatic morphology or secretion. J Biol Chem 279:50274–50279PubMedCrossRef Yu S, Michie SA, Lowe AW (2004) Absence of the major zymogen granule membrane protein, GP2, does not affect pancreatic morphology or secretion. J Biol Chem 279:50274–50279PubMedCrossRef
61.
go back to reference Dittie A, Kern HF (1992) The major zymogen granule membrane protein GP-2 in the rat pancreas is not involved in granule formation. Eur J Cell Biol 58:243–258PubMed Dittie A, Kern HF (1992) The major zymogen granule membrane protein GP-2 in the rat pancreas is not involved in granule formation. Eur J Cell Biol 58:243–258PubMed
62.
go back to reference Hansen LJ, Reddy MK, Reddy JK (1983) Comparison of secretory protein and membrane composition of secretory granules isolated from normal and neoplastic pancreatic acinar cells of rats. Proc Natl Acad Sci USA 80:4379–4383PubMedPubMedCentralCrossRef Hansen LJ, Reddy MK, Reddy JK (1983) Comparison of secretory protein and membrane composition of secretory granules isolated from normal and neoplastic pancreatic acinar cells of rats. Proc Natl Acad Sci USA 80:4379–4383PubMedPubMedCentralCrossRef
63.
go back to reference Lin Y, Nakatochi M, Hosono Y, Ito H, Kamatani Y, Inoko A, Sakamoto H, Kinoshita F, Kobayashi Y, Ishii H, Ozaka M, Sasaki T, Matsuyama M, Sasahira N, Morimoto M, Kobayashi S, Fukushima T, Ueno M, Ohkawa S et al (2020) Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. Nat Commun 11:3175PubMedPubMedCentralCrossRef Lin Y, Nakatochi M, Hosono Y, Ito H, Kamatani Y, Inoko A, Sakamoto H, Kinoshita F, Kobayashi Y, Ishii H, Ozaka M, Sasaki T, Matsuyama M, Sasahira N, Morimoto M, Kobayashi S, Fukushima T, Ueno M, Ohkawa S et al (2020) Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer. Nat Commun 11:3175PubMedPubMedCentralCrossRef
64.
go back to reference Hoops TC, Rindler MJ (1991) Isolation of the cDNA encoding glycoprotein-2 (GP-2), the major zymogen granule membrane protein. Homology to uromodulin/Tamm-Horsfall protein. J Biol Chem 266:4257–4263PubMedCrossRef Hoops TC, Rindler MJ (1991) Isolation of the cDNA encoding glycoprotein-2 (GP-2), the major zymogen granule membrane protein. Homology to uromodulin/Tamm-Horsfall protein. J Biol Chem 266:4257–4263PubMedCrossRef
65.
go back to reference Rindler MJ, Naik SS, Li N, Hoops TC, Peraldi MN (1990) Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein. J Biol Chem 265:20784–20789PubMedCrossRef Rindler MJ, Naik SS, Li N, Hoops TC, Peraldi MN (1990) Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein. J Biol Chem 265:20784–20789PubMedCrossRef
66.
go back to reference Saemann MD, Weichhart T, Zeyda M, Staffler G, Schunn M, Stuhlmeier KM, Sobanov Y, Stulnig TM, Akira S, von Gabain A, von Ahsen U, Horl WH, Zlabinger GJ (2005) Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J Clin Invest 115:468–475PubMedPubMedCentralCrossRef Saemann MD, Weichhart T, Zeyda M, Staffler G, Schunn M, Stuhlmeier KM, Sobanov Y, Stulnig TM, Akira S, von Gabain A, von Ahsen U, Horl WH, Zlabinger GJ (2005) Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J Clin Invest 115:468–475PubMedPubMedCentralCrossRef
67.
go back to reference Wu TH, Hsieh SC, Yu CY, Lee YF, Tsai CY, Yu CL (2008) Intact protein core structure is essential for protein-binding, mononuclear cell proliferating, and neutrophil phagocytosis-enhancing activities of normal human urinary Tamm-Horsfall glycoprotein. Int Immunopharmacol 8:90–99PubMedCrossRef Wu TH, Hsieh SC, Yu CY, Lee YF, Tsai CY, Yu CL (2008) Intact protein core structure is essential for protein-binding, mononuclear cell proliferating, and neutrophil phagocytosis-enhancing activities of normal human urinary Tamm-Horsfall glycoprotein. Int Immunopharmacol 8:90–99PubMedCrossRef
68.
go back to reference Kobayashi K, Yanagihara K, Ishiguro K, Fukuoka S (2004) GP2/THP gene family of self-binding, GPI-anchored proteins forms a cluster at chromosome 7F1 region in mouse genome. Biochem Biophys Res Commun 322:659–664PubMedCrossRef Kobayashi K, Yanagihara K, Ishiguro K, Fukuoka S (2004) GP2/THP gene family of self-binding, GPI-anchored proteins forms a cluster at chromosome 7F1 region in mouse genome. Biochem Biophys Res Commun 322:659–664PubMedCrossRef
69.
go back to reference Dou W, Thompson-Jaeger S, Laulederkind SJ, Becker JW, Montgomery J, Ruiz-Bustos E, Hasty DL, Ballou LR, Eastman PS, Srichai B, Breyer MD, Raghow R (2005) Defective expression of Tamm-Horsfall protein/uromodulin in COX-2-deficient mice increases their susceptibility to urinary tract infections. Am J Physiol Renal Physiol 289:F49–F60PubMedCrossRef Dou W, Thompson-Jaeger S, Laulederkind SJ, Becker JW, Montgomery J, Ruiz-Bustos E, Hasty DL, Ballou LR, Eastman PS, Srichai B, Breyer MD, Raghow R (2005) Defective expression of Tamm-Horsfall protein/uromodulin in COX-2-deficient mice increases their susceptibility to urinary tract infections. Am J Physiol Renal Physiol 289:F49–F60PubMedCrossRef
70.
go back to reference Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L (2022) Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH. Nat Struct Mol Biol 29:190–193PubMedPubMedCentralCrossRef Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L (2022) Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH. Nat Struct Mol Biol 29:190–193PubMedPubMedCentralCrossRef
71.
go back to reference Pak J, Pu Y, Zhang ZT, Hasty DL, Wu XR (2001) Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J Biol Chem 276:9924–9930PubMedCrossRef Pak J, Pu Y, Zhang ZT, Hasty DL, Wu XR (2001) Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J Biol Chem 276:9924–9930PubMedCrossRef
72.
go back to reference Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z, Maeda N, Hultgren SJ, Kumar S (2004) Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 65:791–797PubMedCrossRef Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z, Maeda N, Hultgren SJ, Kumar S (2004) Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 65:791–797PubMedCrossRef
73.
go back to reference Roggenbuck D, Hausdorf G, Martinez-Gamboa L, Reinhold D, Buttner T, Jungblut PR, Porstmann T, Laass MW, Henker J, Buning C, Feist E, Conrad K (2009) Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn’s disease. Gut 58:1620–1628PubMedCrossRef Roggenbuck D, Hausdorf G, Martinez-Gamboa L, Reinhold D, Buttner T, Jungblut PR, Porstmann T, Laass MW, Henker J, Buning C, Feist E, Conrad K (2009) Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn’s disease. Gut 58:1620–1628PubMedCrossRef
74.
go back to reference Roggenbuck D, Reinhold D, Werner L, Schierack P, Bogdanos DP, Conrad K (2013) Glycoprotein 2 antibodies in Crohn’s disease. Adv Clin Chem 60:187–208PubMedCrossRef Roggenbuck D, Reinhold D, Werner L, Schierack P, Bogdanos DP, Conrad K (2013) Glycoprotein 2 antibodies in Crohn’s disease. Adv Clin Chem 60:187–208PubMedCrossRef
75.
go back to reference Juste C, Kreil DP, Beauvallet C, Guillot A, Vaca S, Carapito C, Mondot S, Sykacek P, Sokol H, Blon F, Lepercq P, Levenez F, Valot B, Carre W, Loux V, Pons N, David O, Schaeffer B, Lepage P et al (2014) Bacterial protein signals are associated with Crohn’s disease. Gut 63:1566–1577PubMedCrossRef Juste C, Kreil DP, Beauvallet C, Guillot A, Vaca S, Carapito C, Mondot S, Sykacek P, Sokol H, Blon F, Lepercq P, Levenez F, Valot B, Carre W, Loux V, Pons N, David O, Schaeffer B, Lepage P et al (2014) Bacterial protein signals are associated with Crohn’s disease. Gut 63:1566–1577PubMedCrossRef
76.
go back to reference Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124PubMedPubMedCentralCrossRef Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124PubMedPubMedCentralCrossRef
77.
go back to reference Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, Bringer MA, Swidsinski A, Beaugerie L, Colombel JF (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127:412–421PubMedCrossRef Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, Bringer MA, Swidsinski A, Beaugerie L, Colombel JF (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127:412–421PubMedCrossRef
78.
go back to reference Chassaing B, Rolhion N, de Vallee A, Salim SY, Prorok-Hamon M, Neut C, Campbell BJ, Soderholm JD, Hugot JP, Colombel JF, Darfeuille-Michaud A (2011) Crohn disease-associated adherent-invasive E. coli bacteria target mouse and human Peyer’s patches via long polar fimbriae. J Clin Invest 121:966–975PubMedPubMedCentralCrossRef Chassaing B, Rolhion N, de Vallee A, Salim SY, Prorok-Hamon M, Neut C, Campbell BJ, Soderholm JD, Hugot JP, Colombel JF, Darfeuille-Michaud A (2011) Crohn disease-associated adherent-invasive E. coli bacteria target mouse and human Peyer’s patches via long polar fimbriae. J Clin Invest 121:966–975PubMedPubMedCentralCrossRef
80.
go back to reference Zeiner SA, Dwyer BE, Clegg S (2012) FimA, FimF, and FimH are necessary for assembly of type 1 fimbriae on Salmonella enterica serovar Typhimurium. Infect Immun 80:3289–3296PubMedPubMedCentralCrossRef Zeiner SA, Dwyer BE, Clegg S (2012) FimA, FimF, and FimH are necessary for assembly of type 1 fimbriae on Salmonella enterica serovar Typhimurium. Infect Immun 80:3289–3296PubMedPubMedCentralCrossRef
81.
go back to reference Werner L, Paclik D, Fritz C, Reinhold D, Roggenbuck D, Sturm A (2012) Identification of pancreatic glycoprotein 2 as an endogenous immunomodulator of innate and adaptive immune responses. J Immunol 189:2774–2783PubMedCrossRef Werner L, Paclik D, Fritz C, Reinhold D, Roggenbuck D, Sturm A (2012) Identification of pancreatic glycoprotein 2 as an endogenous immunomodulator of innate and adaptive immune responses. J Immunol 189:2774–2783PubMedCrossRef
82.
go back to reference Yamanaka H, Nakanishi T, Takagi T, Ohsawa M, Kubo N, Yamamoto N, Takemoto T, Ohsawa K (2015) Helicobacter sp. MIT 01-6451 infection during fetal and neonatal life in laboratory mice. Exp Anim 64:375–382PubMedPubMedCentralCrossRef Yamanaka H, Nakanishi T, Takagi T, Ohsawa M, Kubo N, Yamamoto N, Takemoto T, Ohsawa K (2015) Helicobacter sp. MIT 01-6451 infection during fetal and neonatal life in laboratory mice. Exp Anim 64:375–382PubMedPubMedCentralCrossRef
83.
go back to reference Yang JY, Lee YS, Kim Y, Lee SH, Ryu S, Fukuda S, Hase K, Yang CS, Lim HS, Kim MS, Kim HM, Ahn SH, Kwon BE, Ko HJ, Kweon MN (2017) Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. Mucosal Immunol 10:104–116PubMedCrossRef Yang JY, Lee YS, Kim Y, Lee SH, Ryu S, Fukuda S, Hase K, Yang CS, Lim HS, Kim MS, Kim HM, Ahn SH, Kwon BE, Ko HJ, Kweon MN (2017) Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. Mucosal Immunol 10:104–116PubMedCrossRef
84.
go back to reference de Souza HL, de Carvalho VR, Romeiro FG, Sassaki LY, Keller R, Rodrigues J (2012) Mucosa-associated but not luminal Escherichia coli is augmented in Crohn’s disease and ulcerative colitis. Gut Pathog 4:21PubMedPubMedCentralCrossRef de Souza HL, de Carvalho VR, Romeiro FG, Sassaki LY, Keller R, Rodrigues J (2012) Mucosa-associated but not luminal Escherichia coli is augmented in Crohn’s disease and ulcerative colitis. Gut Pathog 4:21PubMedPubMedCentralCrossRef
85.
go back to reference Bartlitz C, Kolenda R, Chilimoniuk J, Grzymajlo K, Rodiger S, Bauerfeind R, Ali A, Tchesnokova V, Roggenbuck D, Schierack P (2022) Adhesion of enteropathogenic, enterotoxigenic, and commensal Escherichia coli to the major zymogen granule membrane glycoprotein 2. Appl Environ Microbiol 88:e0227921PubMedCrossRef Bartlitz C, Kolenda R, Chilimoniuk J, Grzymajlo K, Rodiger S, Bauerfeind R, Ali A, Tchesnokova V, Roggenbuck D, Schierack P (2022) Adhesion of enteropathogenic, enterotoxigenic, and commensal Escherichia coli to the major zymogen granule membrane glycoprotein 2. Appl Environ Microbiol 88:e0227921PubMedCrossRef
86.
go back to reference Matsumura T, Sugawara Y, Yutani M, Amatsu S, Yagita H, Kohda T, Fukuoka S, Nakamura Y, Fukuda S, Hase K, Ohno H, Fujinaga Y (2015) Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity. Nat Commun 6:6255PubMedCrossRef Matsumura T, Sugawara Y, Yutani M, Amatsu S, Yagita H, Kohda T, Fukuoka S, Nakamura Y, Fukuda S, Hase K, Ohno H, Fujinaga Y (2015) Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity. Nat Commun 6:6255PubMedCrossRef
87.
go back to reference Holzl MA, Hofer J, Kovarik JJ, Roggenbuck D, Reinhold D, Goihl A, Gartner M, Steinberger P, Zlabinger GJ (2011) The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I). Cell Immunol 267:88–93PubMedPubMedCentralCrossRef Holzl MA, Hofer J, Kovarik JJ, Roggenbuck D, Reinhold D, Goihl A, Gartner M, Steinberger P, Zlabinger GJ (2011) The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I). Cell Immunol 267:88–93PubMedPubMedCentralCrossRef
88.
go back to reference Baumgart DC, Carding SR (2007) Inflammatory bowel disease: cause and immunobiology. Lancet 369:1627–1640PubMedCrossRef Baumgart DC, Carding SR (2007) Inflammatory bowel disease: cause and immunobiology. Lancet 369:1627–1640PubMedCrossRef
90.
go back to reference Walker JE (1978) Possible diagnostic test for Crohn’s disease by use of buccal mucosa. Lancet 2:759–760PubMedCrossRef Walker JE (1978) Possible diagnostic test for Crohn’s disease by use of buccal mucosa. Lancet 2:759–760PubMedCrossRef
91.
go back to reference Martin-de-Carpi J, Moriczi M, Pujol-Muncunill G, Navas-Lopez VM (2017) Pancreatic involvement in pediatric inflammatory bowel disease. Front Pediatr 5:218PubMedPubMedCentralCrossRef Martin-de-Carpi J, Moriczi M, Pujol-Muncunill G, Navas-Lopez VM (2017) Pancreatic involvement in pediatric inflammatory bowel disease. Front Pediatr 5:218PubMedPubMedCentralCrossRef
92.
go back to reference Goischke EM, Zilly W (1992) Clinical importance of organ-specific antibodies in ulcerative colitis and Crohn disease. Z Gastroenterol 30:319–324PubMed Goischke EM, Zilly W (1992) Clinical importance of organ-specific antibodies in ulcerative colitis and Crohn disease. Z Gastroenterol 30:319–324PubMed
93.
go back to reference Spiess SE, Braun M, Vogelzang RL, Craig RM (1992) Crohn’s disease of the duodenum complicated by pancreatitis and common bile duct obstruction. Am J Gastroenterol 87:1033–1036PubMed Spiess SE, Braun M, Vogelzang RL, Craig RM (1992) Crohn’s disease of the duodenum complicated by pancreatitis and common bile duct obstruction. Am J Gastroenterol 87:1033–1036PubMed
94.
go back to reference Desplat-Jego S, Johanet C, Escande A, Goetz J, Fabien N, Olsson N, Ballot E, Sarles J, Baudon JJ, Grimaud JC, Veyrac M, Chamouard P, Humbel RL (2007) Update on anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: results of a multicenter study. World J Gastroenterol 13:2312–2318PubMedPubMedCentralCrossRef Desplat-Jego S, Johanet C, Escande A, Goetz J, Fabien N, Olsson N, Ballot E, Sarles J, Baudon JJ, Grimaud JC, Veyrac M, Chamouard P, Humbel RL (2007) Update on anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: results of a multicenter study. World J Gastroenterol 13:2312–2318PubMedPubMedCentralCrossRef
95.
go back to reference Seibold F, Mork H, Tanza S, Muller A, Holzhuter C, Weber P, Scheurlen M (1997) Pancreatic autoantibodies in Crohn’s disease: a family study. Gut 40:481–484PubMedPubMedCentralCrossRef Seibold F, Mork H, Tanza S, Muller A, Holzhuter C, Weber P, Scheurlen M (1997) Pancreatic autoantibodies in Crohn’s disease: a family study. Gut 40:481–484PubMedPubMedCentralCrossRef
96.
go back to reference Seibold F, Weber P, Jenss H, Wiedmann KH (1991) Antibodies to a trypsin sensitive pancreatic antigen in chronic inflammatory bowel disease: specific markers for a subgroup of patients with Crohn’s disease. Gut 32:1192–1197PubMedPubMedCentralCrossRef Seibold F, Weber P, Jenss H, Wiedmann KH (1991) Antibodies to a trypsin sensitive pancreatic antigen in chronic inflammatory bowel disease: specific markers for a subgroup of patients with Crohn’s disease. Gut 32:1192–1197PubMedPubMedCentralCrossRef
97.
go back to reference Bogdanos DP, Rigopoulou EI, Smyk DS, Roggenbuck D, Reinhold D, Forbes A, Laass MW, Conrad K (2011) Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn’s disease specific-pancreatic autoantibodies. Autoimmun Rev 11:143–148PubMedCrossRef Bogdanos DP, Rigopoulou EI, Smyk DS, Roggenbuck D, Reinhold D, Forbes A, Laass MW, Conrad K (2011) Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn’s disease specific-pancreatic autoantibodies. Autoimmun Rev 11:143–148PubMedCrossRef
98.
go back to reference Pavlidis P, Forbes A, Bogdanos DP (2011) Antibodies to glycoprotein 2 (GP2) in patients with inflammatory bowel diseases from UK. Clin Chim Acta 412:1163–1164PubMedCrossRef Pavlidis P, Forbes A, Bogdanos DP (2011) Antibodies to glycoprotein 2 (GP2) in patients with inflammatory bowel diseases from UK. Clin Chim Acta 412:1163–1164PubMedCrossRef
99.
go back to reference Bonaci-Nikolic B, Spuran M, Andrejevic S, Nikolic M (2012) Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, in patients with gluten-sensitive enteropathy: a possible serological trap. Clin Chim Acta 413:822–823PubMedCrossRef Bonaci-Nikolic B, Spuran M, Andrejevic S, Nikolic M (2012) Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, in patients with gluten-sensitive enteropathy: a possible serological trap. Clin Chim Acta 413:822–823PubMedCrossRef
100.
101.
go back to reference Bogdanos DP, Roggenbuck D, Reinhold D, Wex T, Pavlidis P, von Arnim U, Malfertheiner P, Forbes A, Conrad K, Laass MW (2012) Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn’s disease. BMC Gastroenterol 12:102PubMedPubMedCentralCrossRef Bogdanos DP, Roggenbuck D, Reinhold D, Wex T, Pavlidis P, von Arnim U, Malfertheiner P, Forbes A, Conrad K, Laass MW (2012) Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn’s disease. BMC Gastroenterol 12:102PubMedPubMedCentralCrossRef
102.
go back to reference Wells AD, McMillan I, Price AB, Ritchie JK, Nicholls RJ (1991) Natural history of indeterminate colitis. Br J Surg 78:179–181PubMedCrossRef Wells AD, McMillan I, Price AB, Ritchie JK, Nicholls RJ (1991) Natural history of indeterminate colitis. Br J Surg 78:179–181PubMedCrossRef
103.
go back to reference Conrad K, Schmechta H, Klafki A, Lobeck G, Uhlig HH, Gerdi S, Henker J (2002) Serological differentiation of inflammatory bowel diseases. Eur J Gastroenterol Hepatol 14:129–135PubMedCrossRef Conrad K, Schmechta H, Klafki A, Lobeck G, Uhlig HH, Gerdi S, Henker J (2002) Serological differentiation of inflammatory bowel diseases. Eur J Gastroenterol Hepatol 14:129–135PubMedCrossRef
104.
go back to reference Michaels MA, Jendrek ST, Korf T, Nitzsche T, Teegen B, Komorowski L, Derer S, Schroder T, Baer F, Lehnert H, Buning J, Fellerman K, Sina C (2015) Pancreatic autoantibodies against CUZD1 and GP2 are associated with distinct clinical phenotypes of Crohn’s disease. Inflamm Bowel Dis 21:2864–2872PubMedCrossRef Michaels MA, Jendrek ST, Korf T, Nitzsche T, Teegen B, Komorowski L, Derer S, Schroder T, Baer F, Lehnert H, Buning J, Fellerman K, Sina C (2015) Pancreatic autoantibodies against CUZD1 and GP2 are associated with distinct clinical phenotypes of Crohn’s disease. Inflamm Bowel Dis 21:2864–2872PubMedCrossRef
105.
go back to reference Laass MW, Rober N, Range U, Noss L, Roggenbuck D, Conrad K (2015) Loss and gain of tolerance to pancreatic glycoprotein 2 in celiac disease. PLoS One 10:e0128104PubMedPubMedCentralCrossRef Laass MW, Rober N, Range U, Noss L, Roggenbuck D, Conrad K (2015) Loss and gain of tolerance to pancreatic glycoprotein 2 in celiac disease. PLoS One 10:e0128104PubMedPubMedCentralCrossRef
106.
go back to reference Gross S, Bakker SF, van Bodegraven AA, van Hoogstraten IM, Gelderman KA, Bouma G, Mulder CJ, von Blomberg BM, Bontkes HJ (2014) Increased IgA glycoprotein-2 specific antibody titres in refractory celiac disease. J Gastrointestin Liver Dis 23:127–133PubMedCrossRef Gross S, Bakker SF, van Bodegraven AA, van Hoogstraten IM, Gelderman KA, Bouma G, Mulder CJ, von Blomberg BM, Bontkes HJ (2014) Increased IgA glycoprotein-2 specific antibody titres in refractory celiac disease. J Gastrointestin Liver Dis 23:127–133PubMedCrossRef
107.
go back to reference Werner L, Sturm A, Roggenbuck D, Yahav L, Zion T, Meirowithz E, Ofer A, Guzner-Gur H, Tulchinsky H, Dotan I (2013) Antibodies against glycoprotein 2 are novel markers of intestinal inflammation in patients with an ileal pouch. J Crohns Colitis 7:e522–e532PubMedCrossRef Werner L, Sturm A, Roggenbuck D, Yahav L, Zion T, Meirowithz E, Ofer A, Guzner-Gur H, Tulchinsky H, Dotan I (2013) Antibodies against glycoprotein 2 are novel markers of intestinal inflammation in patients with an ileal pouch. J Crohns Colitis 7:e522–e532PubMedCrossRef
108.
go back to reference Kovacs G, Sipeki N, Suga B, Tornai T, Fechner K, Norman GL, Shums Z, Antal-Szalmas P, Papp M (2018) Significance of serological markers in the disease course of ulcerative colitis in a prospective clinical cohort of patients. PLoS One 13:e0194166PubMedPubMedCentralCrossRef Kovacs G, Sipeki N, Suga B, Tornai T, Fechner K, Norman GL, Shums Z, Antal-Szalmas P, Papp M (2018) Significance of serological markers in the disease course of ulcerative colitis in a prospective clinical cohort of patients. PLoS One 13:e0194166PubMedPubMedCentralCrossRef
109.
go back to reference Sowa M, Kolenda R, Baumgart DC, Pratschke J, Papp M, Tornai T, Suchanski J, Bogdanos DP, Mytilinaiou MG, Hammermann J, Laass MW, Conrad K, Schramm C, Franke A, Roggenbuck D, Schierack P (2018) Mucosal autoimmunity to cell-bound GP2 isoforms is a sensitive marker in PSC and associated with the clinical phenotype. Front Immunol 9:1959PubMedPubMedCentralCrossRef Sowa M, Kolenda R, Baumgart DC, Pratschke J, Papp M, Tornai T, Suchanski J, Bogdanos DP, Mytilinaiou MG, Hammermann J, Laass MW, Conrad K, Schramm C, Franke A, Roggenbuck D, Schierack P (2018) Mucosal autoimmunity to cell-bound GP2 isoforms is a sensitive marker in PSC and associated with the clinical phenotype. Front Immunol 9:1959PubMedPubMedCentralCrossRef
110.
go back to reference Jendrek ST, Gotthardt D, Nitzsche T, Widmann L, Korf T, Michaels MA, Weiss KH, Liaskou E, Vesterhus M, Karlsen TH, Mindorf S, Schemmer P, Bar F, Teegen B, Schroder T, Ehlers M, Hammers CM, Komorowski L, Lehnert H et al (2017) Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis. Gut 66:137–144PubMedCrossRef Jendrek ST, Gotthardt D, Nitzsche T, Widmann L, Korf T, Michaels MA, Weiss KH, Liaskou E, Vesterhus M, Karlsen TH, Mindorf S, Schemmer P, Bar F, Teegen B, Schroder T, Ehlers M, Hammers CM, Komorowski L, Lehnert H et al (2017) Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis. Gut 66:137–144PubMedCrossRef
111.
go back to reference Somma V, Ababneh H, Ababneh A, Gatti S, Romagnoli V, Bendia E, Conrad K, Bogdanos DP, Roggenbuck D, Ciarrocchi G (2013) The novel Crohn’s disease marker anti-GP2 antibody is associated with ileocolonic location of disease. Gastroenterol Res Pract 2013:683824PubMedPubMedCentralCrossRef Somma V, Ababneh H, Ababneh A, Gatti S, Romagnoli V, Bendia E, Conrad K, Bogdanos DP, Roggenbuck D, Ciarrocchi G (2013) The novel Crohn’s disease marker anti-GP2 antibody is associated with ileocolonic location of disease. Gastroenterol Res Pract 2013:683824PubMedPubMedCentralCrossRef
112.
go back to reference Papp M, Sipeki N, Tornai T, Altorjay I, Norman GL, Shums Z, Roggenbuck D, Fechner K, Stocker W, Antal-Szalmas P, Veres G, Lakatos PL (2015) Rediscovery of the anti-pancreatic antibodies and evaluation of their prognostic value in a prospective clinical cohort of Crohn's patients: the importance of specific target antigens [GP2 and CUZD1]. J Crohns Colitis 9:659–668PubMedCrossRef Papp M, Sipeki N, Tornai T, Altorjay I, Norman GL, Shums Z, Roggenbuck D, Fechner K, Stocker W, Antal-Szalmas P, Veres G, Lakatos PL (2015) Rediscovery of the anti-pancreatic antibodies and evaluation of their prognostic value in a prospective clinical cohort of Crohn's patients: the importance of specific target antigens [GP2 and CUZD1]. J Crohns Colitis 9:659–668PubMedCrossRef
113.
go back to reference Rattay K, Meyer HV, Herrmann C, Brors B, Kyewski B (2016) Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. J Autoimmun 67:65–75PubMedCrossRef Rattay K, Meyer HV, Herrmann C, Brors B, Kyewski B (2016) Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. J Autoimmun 67:65–75PubMedCrossRef
114.
go back to reference Lin Y, Nakatochi M, Sasahira N, Ueno M, Egawa N, Adachi Y, Kikuchi S (2021) Glycoprotein 2 in health and disease: lifting the veil. Genes Environ 43:53PubMedPubMedCentralCrossRef Lin Y, Nakatochi M, Sasahira N, Ueno M, Egawa N, Adachi Y, Kikuchi S (2021) Glycoprotein 2 in health and disease: lifting the veil. Genes Environ 43:53PubMedPubMedCentralCrossRef
115.
go back to reference Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N (2017) Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32(185-203):e13 Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N (2017) Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32(185-203):e13
116.
go back to reference Wen W, Cho YS, Zheng W, Dorajoo R, Kato N, Qi L, Chen CH, Delahanty RJ, Okada Y, Tabara Y, Gu D, Zhu D, Haiman CA, Mo Z, Gao YT, Saw SM, Go MJ, Takeuchi F, Chang LC et al (2012) Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet 44:307–311PubMedPubMedCentralCrossRef Wen W, Cho YS, Zheng W, Dorajoo R, Kato N, Qi L, Chen CH, Delahanty RJ, Okada Y, Tabara Y, Gu D, Zhu D, Haiman CA, Mo Z, Gao YT, Saw SM, Go MJ, Takeuchi F, Chang LC et al (2012) Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet 44:307–311PubMedPubMedCentralCrossRef
117.
go back to reference Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, Julier C, Morahan G, Nerup J, Nierras C, Plagnol V, Pociot F, Schuilenburg H, Smyth DJ, Stevens H, Todd JA, Walker NM, Rich SS, Type 1 Diabetes Genetics C (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707PubMedPubMedCentralCrossRef Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, Julier C, Morahan G, Nerup J, Nierras C, Plagnol V, Pociot F, Schuilenburg H, Smyth DJ, Stevens H, Todd JA, Walker NM, Rich SS, Type 1 Diabetes Genetics C (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707PubMedPubMedCentralCrossRef
118.
go back to reference Suzuki K, Akiyama M, Ishigaki K, Kanai M, Hosoe J, Shojima N, Hozawa A, Kadota A, Kuriki K, Naito M, Tanno K, Ishigaki Y, Hirata M, Matsuda K, Iwata N, Ikeda M, Sawada N, Yamaji T, Iwasaki M et al (2019) Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population. Nat Genet 51:379–386PubMedCrossRef Suzuki K, Akiyama M, Ishigaki K, Kanai M, Hosoe J, Shojima N, Hozawa A, Kadota A, Kuriki K, Naito M, Tanno K, Ishigaki Y, Hirata M, Matsuda K, Iwata N, Ikeda M, Sawada N, Yamaji T, Iwasaki M et al (2019) Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population. Nat Genet 51:379–386PubMedCrossRef
119.
go back to reference Choi H, Jung C, Sohn SK, Kim S, Kim HJ, Kim YK, Kim T, Zhang Z, Shin ES, Lee JE, Moon JH, Kim SH, Kim KH, Mun YC, Kim H, Park J, Kim J, Kim D (2013) Genome-wide genotype-based risk model for survival in acute myeloid leukaemia patients with normal karyotype. Br J Haematol 163:62–71PubMedCrossRef Choi H, Jung C, Sohn SK, Kim S, Kim HJ, Kim YK, Kim T, Zhang Z, Shin ES, Lee JE, Moon JH, Kim SH, Kim KH, Mun YC, Kim H, Park J, Kim J, Kim D (2013) Genome-wide genotype-based risk model for survival in acute myeloid leukaemia patients with normal karyotype. Br J Haematol 163:62–71PubMedCrossRef
120.
go back to reference Jones SE, van Hees VT, Mazzotti DR, Marques-Vidal P, Sabia S, van der Spek A, Dashti HS, Engmann J, Kocevska D, Tyrrell J, Beaumont RN, Hillsdon M, Ruth KS, Tuke MA, Yaghootkar H, Sharp SA, Ji Y, Harrison JW, Freathy RM et al (2019) Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour. Nat Commun 10:1585PubMedPubMedCentralCrossRef Jones SE, van Hees VT, Mazzotti DR, Marques-Vidal P, Sabia S, van der Spek A, Dashti HS, Engmann J, Kocevska D, Tyrrell J, Beaumont RN, Hillsdon M, Ruth KS, Tuke MA, Yaghootkar H, Sharp SA, Ji Y, Harrison JW, Freathy RM et al (2019) Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour. Nat Commun 10:1585PubMedPubMedCentralCrossRef
121.
go back to reference Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y (2018) Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat Genet 50:390–400PubMedCrossRef Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y (2018) Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat Genet 50:390–400PubMedCrossRef
122.
go back to reference Cogger KF, Sinha A, Sarangi F, McGaugh EC, Saunders D, Dorrell C, Mejia-Guerrero S, Aghazadeh Y, Rourke JL, Screaton RA, Grompe M, Streeter PR, Powers AC, Brissova M, Kislinger T, Nostro MC (2017) Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors. Nat Commun 8:331PubMedPubMedCentralCrossRef Cogger KF, Sinha A, Sarangi F, McGaugh EC, Saunders D, Dorrell C, Mejia-Guerrero S, Aghazadeh Y, Rourke JL, Screaton RA, Grompe M, Streeter PR, Powers AC, Brissova M, Kislinger T, Nostro MC (2017) Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors. Nat Commun 8:331PubMedPubMedCentralCrossRef
123.
go back to reference Ameri J, Borup R, Prawiro C, Ramond C, Schachter KA, Scharfmann R, Semb H (2017) Efficient generation of glucose-responsive beta cells from isolated GP2(+) human pancreatic progenitors. Cell Rep 19:36–49PubMedCrossRef Ameri J, Borup R, Prawiro C, Ramond C, Schachter KA, Scharfmann R, Semb H (2017) Efficient generation of glucose-responsive beta cells from isolated GP2(+) human pancreatic progenitors. Cell Rep 19:36–49PubMedCrossRef
Metadata
Title
Glycoprotein 2 as a gut gate keeper for mucosal equilibrium between inflammation and immunity
Authors
Zhongwei Zhang
Izumi Tanaka
Rika Nakahashi-Ouchida
Peter B. Ernst
Hiroshi Kiyono
Yosuke Kurashima
Publication date
03-01-2024
Publisher
Springer Berlin Heidelberg
Published in
Seminars in Immunopathology / Issue 4-6/2024
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-023-00999-z

Keynote series | Spotlight on menopause

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the systemic effects of menopause, so you can help patients in your clinics through the transition.   

Prof. Martha Hickey
Dr. Claudia Barth
Dr. Samar El Khoudary
Developed by: Springer Medicine
Watch now

Keynote webinar | Spotlight on adolescent vaping

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?

Prof. Ann McNeill
Dr. Debbie Robson
Benji Horwell
Developed by: Springer Medicine
Watch now

Keynote webinar | Spotlight on modern management of frailty

Frailty has a significant impact on health and wellbeing, especially in older adults. Our experts explain the factors that contribute to the development of frailty and how you can manage the condition and reduce the risk of disability, dependency, and mortality in your patients.

Prof. Alfonso Cruz-Jentoft
Prof. Barbara C. van Munster
Prof. Mirko Petrovic
Developed by: Springer Medicine
Watch now

A quick guide to ECGs

Improve your ECG interpretation skills with this comprehensive, rapid, interactive course. Expert advice provides detailed feedback as you work through 50 ECGs covering the most common cardiac presentations to ensure your practice stays up to date. 

PD Dr. Carsten W. Israel
Developed by: Springer Medizin
Start the cases

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Read more