Benutzerspezifische Werkzeuge

Zeissig Lab

Zeissig Lab

Research focus

Immunological mechanisms of inflammation and cancer (Group leader: Prof. Sebastian Zeissig, MD)

Research focuses on the immunological mechanisms of inflammation and inflammation-associated tumorigenesis in the intestine and the liver, with particular interest in translational research focusing on monogenic forms of inflammatory bowel disease and basic research aiming towards a better understanding of the role of lipids in immunity.

Lipid antigens in immunity

Chronic inflammation and tissue destruction are the basis for inflammatory bowel diseases and autoimmune as well as viral hepatitis. These diseases are not only associated with debilitating clinical symptoms but are also key risk factors for the development of inflammation-associated malignancy. The development of novel therapeutic strategies that target these diseases is dependent on a detailed understanding of the cellular and molecular mechanisms underlying chronic inflammation. Of particular interest in this regard is the role of natural killer T (NKT) cells, an unconventional subset of T cells that responds to CD1d-restricted presentation of self and foreign lipid antigens and is associated with immediate innate-like effects on NK, T, and B cells thereby shaping and orchestrating immune responses. NKT cells are critical for antimicrobial immunity and genetic defects in lipid antigen presentation are associated with primary immunodeficiency in humans. However, recent studies have revealed that NKT cells are not only contributing to protective immunity but also play central roles in the pathogenesis of chronic inflammatory disorders. Thus, it was shown that ulcerative colitis, an inflammatory bowel disease (IBD), is characterized by NKT cell-dependent intestinal inflammation. Similarly, recent studies have revealed that NKT cells are centrally involved in the pathogenesis of autoimmune and infectious hepatitis.

In our recent work investigating the role of lipid antigens and NKT cells in intestinal and hepatic immunity, we could demonstrate that hepatocytes and intestinal epithelial cells can present lipid antigens via the non-classical MHC class I molecule CD1d to natural killer T cells thus providing the basis for protection from infectious hepatitis as well as intestinal inflammation (Zeissig et al., Nat. Med. 2012; Olszak et al., Nature 2014). Furthermore, this work revealed an essential role of the commensal microbiota and microbiota-derived lipid antigens in the control of homeostasis at mucosal surfaces and demonstrated that primary defects in lipid antigen presentation are associated with immunodeficiency in humans (An et al., Cell 2014; Olszak et al., Science 2012; Zeissig et al., J. Clin. Invest.; Zeissig et al., Nat. Immunol. 2014). Current ERC-funded work in the laboratory (ERC Starting Grant) is focused on the identification of lipid antigens which link metabolism and immunity in the liver and the intestine.

Monogenic forms of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic intestinal and often systemic inflammation. In the vast majority of IBD patients, intestinal inflammation occurs through a complex and incompletely understood interplay of genetic and environmental factors. However, we and others have recently identified forms of mono- or oligogenic forms of IBD, in which one or few genetic defects significantly promote intestinal inflammation (Zeissig Y, Gut 2014; Zeissig S, Gut 2014). Patients with monogenic IBD often presented with early-onset disease manifesting during early childhood and exhibited severe and often treatment-refractory intestinal and systemic inflammation. The identification of a genetic etiology in some of these IBD patients not only provided significant insight into the pathophysiology of IBD, but also forced, in a subset of cases, a reconsideration of approaches for medical treatment. This translational research agenda is pursued in close collaboration with the Department of Pediatrics (Prof. Dr. Berner, Dr. Laaß) and the Institute of Clinical Molecular Biology (IKMB) Kiel (Prof. Dr. Schreiber, Prof. Dr. Franke). Genetic screening is offered to patients with early onset and/or familial IBD.

Team

Group Leader

Zeissig_Mitarbeiterfoto.jpgProf. Dr. med. Sebastian Zeissig, M.D.

Principal Investigator

Sascha Wiemer

Personal assistant

Tel: +49 351 458 82305

Postdocs
Emilie Huc-Claustre
Anne Strigli
Yuting Wang
PhD students
Chiara Ceriotti
Shreya Gopalakrishnan
Giuseppina Luzzi
Kenneth Peuker
Tohid Siddiqui
Technical team
Melanie Jäger
Student assistants
Marie Rytir

Funding

  • 2014-2018
    ERC Starting Grant 2013, “Lipid antigens in intestinal inflammation and tumor development”, 1.5 Mio. Euro
  • 2013-2016
    German Research Foundation ZE-814/6-1, Priority Programme SPP 1656, “X-linked inhibitor of apoptosis protein in intestinal homeostasis and the pathogenesis of inflammatory bowel disease”, 220K Euro
  • 2012-2015
    German Research Foundation ZE-814/5-1, “Calcium-dependent pathways in intestinal inflammation and tumorigenesis“, 228K Euro
  • 2012-2015
    German Research Foundation ZE-814/4-1, “Protective and pathogenic roles of natural killer T cells in inflammatory bowel diseases“, 417K Euro
  • 2010-2014
    Marie Curie International Reintegration Grant, EC, “Regulation of hepatic CD1d-restricted antigen presentation and Natural Killer T cell homeostasis by the microsomal triglyceride transfer protein“, 100K Euro

Publications

Please click on the year of publication below

2015

Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, Andersen V, Andrews JM, Annese V, Brand S, Brant SR, Cho JH, Daly MJ, Dubinsky M, Duerr RH, Ferguson LR, Franke A, Gearry RB, Goyette P, Hakonarson H, Halfvarson J, Hov JR, Huang H, Kennedy NA, Kupcinskas L, Lawrance IC, Lee JC, Satsangi J, Schreiber S, Théâtre E, van der Meulen-de Jong AE, Weersma RK, Wilson DC; International Inflammatory Bowel Disease Genetics Consortium, Parkes M, Vermeire S, Rioux JD, Mansfield J, Silverberg MS, Radford-Smith G, McGovern DP, Barrett JC, Lees CW. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2015 Oct 18. pii: S0140-6736(15)00465-1.

Buch S, Stickel F, Trépo E, Way M, Herrmann A, Nischalke HD, Brosch M, Rosendahl J, Berg T, Ridinger M, Rietschel M, McQuillin A, Frank J, Kiefer F, Schreiber S, Lieb W, Soyka M, Semmo N, Aigner E, Datz C, Schmelz R, Brückner S, Zeissig S, Stephan AM, Wodarz N, Devière J, Clumeck N, Sarrazin C, Lammert F, Gustot T, Deltenre P, Völzke H, Lerch MM, Mayerle J, Eyer F, Schafmayer C, Cichon S, Nöthen MM, Nothnagel M, Ellinghaus D, Huse K, Franke A, Zopf S, Hellerbrand C, Moreno C, Franchimont D, Morgan MY, Hampe J. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015 Oct 19. doi: 10.1038/ng.3417.

Dowds CM, Blumberg RS, Zeissig S. Control of intestinal homeostasis through crosstalk between natural killer T cells and the intestinal microbiota. Clin Immunol. 2015 Aug;159(2):128-33. doi: 10.1016/j.clim.2015.05.008. Epub 2015 May 16.

Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, Melum E. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology. 2015 Oct;62(4):1249-59. doi: 10.1002/hep.27840. Epub 2015 May 20.

Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre E, Dougan SK, Laerdahl JK, Stade B, Forster M, Schreiber S, Weir D, Leichtner AM, Franke A, Blumberg RS. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut. 2015 Dec;64(12):1889-97. doi: 10.1136/gutjnl-2014-308541.

Zeissig Y, Petersen, BS, Milutinovic S, Bosse E, Mayr G, Peuker K, Keller A, Kohl M, Laass M, Billmann-Born S, Brandau H, Feller AC, Röcken C, Schrappe M, Rosenstiel P, Reed JC, Schreiber S, Franke A, Zeissig S. XIAP variants associated with NOD1/2 dysfunction in pediatric-onset Crohn’s disease. Gut 2015 Jan;64(1):66-76.

2014

Heap GA, Weedon MN, Bewshea CM, Singh A, Chen M, Satchwell JB, Vivian JP, So K, Dubois PC, Andrews JM, Annese V, Bampton P, Barnardo M, Bell S, Cole A, Connor SJ, Creed T, Cummings FR, D'Amato M, Daneshmend TK, Fedorak RN, Florin TH, Gaya DR, Greig E, Halfvarson J, Hart A, Irving PM, Jones G, Karban A, Lawrance IC, Lee JC, Lees C, Lev-Tzion R, Lindsay JO, Mansfield J, Mawdsley J, Mazhar Z, Parkes M, Parnell K, Orchard TR, Radford-Smith G, Russell RK, Reffitt D, Satsangi J, Silverberg MS, Sturniolo GC, Tremelling M, Tsianos EV, van Heel DA, Walsh A, Watermeyer G, Weersma RK, Zeissig S, Rossjohn J, Holden AL; International Serious Adverse Events Consortium; IBD Pharmacogenetics Study Group, Ahmad T. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014 Oct;46(10):1131-4. doi: 10.1038/ng.3093. Epub 2014 Sep 14.

Geismann C, Grohmann F, Sebens S, Wirths G, Dreher A, Häsler R, Rosenstiel P, Hauser C, Egberts JH, Trauzold A, Schneider G, Sipos B, Zeissig S, Schreiber S, Schäfer H, Arlt A. c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells. Cell Death Dis. 2014 Oct 9;5:e1455. doi: 10.1038/cddis.2014.417.

Zeissig S, Blumberg RS. Commensal microbial regulation of natural killer T cells at the frontiers of the mucosal immune system. FEBS Lett. 2014 Jun 28.

Olszak T**, Neves JF**, Dowds CM**, Baker K, Glickman J, Davidson NO, Lin CS, Jobin C, Brand S, Sotlar K, Wada K, Katayama K, Nakajima A, Mizuguchi H, Kawasaki K, Nagata K, Müller W, Snapper SB, Schreiber S, Kaser A, Zeissig S*, Blumberg RS*. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature. 2014 May 22;509(7501):497-502. (*equally contributing senior authors, **co-shared first authors)

Zeissig S, Blumberg RS. Life at the beginning: perturbation of the microbiota by antibiotics in early life and its role in health and disease. Nat. Immunol. 2014 Mar 19; 15(4): 307-10.

Zeissig Y, Petersen, BS, Milutinovic S, Bosse E, Mayr G, Peuker K, Keller A, Kohl M, Laass M, Billmann-Born S, Brandau H, Feller AC, Röcken C, Schrappe M, Rosenstiel P, Reed JC, Schreiber S, Franke A, Zeissig S. XIAP variants associated with NOD1/2 dysfunction in pediatric-onset Crohn’s disease.Gut 2014 Feb 26.

An D, Oh SF, Olszak T, Neves JF, Erturk-Hasdemir D, Lu X, Zeissig S, Blumberg RS, Kasper DL. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell. 2014 Jan 16;156(1-2): 123-33.

Dowds CM, Kornell SC, Blumberg RS, Zeissig S. Lipid antigens in immunity. Biol. Chem. 2014 Jan 1;395(1):61-81.

2013

Ellinghaus D*, Zhang H*, Zeissig S*, Lipinski S*, Till A*, Jiang T, Stade B, Bromberg Y, Ellinghaus E, Keller A, Rivas MA, Skieceviciene J, Doncheva NT, Liu X, Liu Q, Jiang F, Forster M, Mayr G, Albrecht M, Häsler R, Boehm BO, Goodall J, Berzuini CR, Lee J, Andersen V, Vogel U, Kupcinskas L, Kayser M, Krawczak M, Nikolaus S, Weersma RK, Ponsioen CY, Sans M, Wijmenga C, Strachan DP, McArdle WL, Vermeire S, Rutgeerts P, Sanderson JD, Mathew CG, Vatn MH, Wang J, Nöthen MM, Duerr RH, Büning C, Brand S, Glas J, Winkelmann J, Illig T, Latiano A, Annese V, Halfvarson J, D'Amato M, Daly MJ, Nothnagel M, Karlsen TH, Subramani S, Rosenstiel P, Schreiber S, Parkes M, Franke A. Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies. Gastroenterology. 2013 Aug;145(2):339-47. *equally contributing first authors.

Zeissig S, Blumberg RS. Commensal microbiota and NKT cells in the control of inflammatory diseases at mucosal surfaces. Curr. Opin. Immunol. 2013 Dec;25(6):690-6.

Hosomi S, Chen Z, Baker K, Chen L, Huang YH, Olszak T, Zeissig S, Wang JH, Mandelboim O, Beauchemin N, Lanier LL, Blumberg RS. CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling. Eur J Immunol. 2013 May 22.

2012

Junker Y, Zeissig S, Kim SJ, Barisani D, Wieser H, Leffler DA, Libermann TA, Dillon S, Freitag TL, Kelly CP, Schuppan D. Wheat fuels inflammation: Amylase-trypsin inhibitors activate intestinal toll like receptor 4. J. Exp. Med. 2012 Dec 17;209(13):2395-408.

Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm P, Sharma Y, Anderson CA, Esser J, Mitjovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan A, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton, PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfied J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC Winkelmann J, Xavier R, Zeissig S, Zhang CK, Zhao H, The International IBD Genetics Consortium, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012. Nov 1;491(7422):119-24.

Zeissig S, Murata M, Sweet L, Publicover J, Hu Z, Kaser A, Bosse E, Iqbal J, Hussain MM, Balschun K, Röcken C, Arlt A, Günther R, Hampe J, Schreiber S, Baron JL, Moody DB, Liang JT, Blumberg RS. Hepatitis B virus-induced alterations in hepatocyte CD1d lipid antigens activate natural killer T cells and contribute to protective immunity. Nat. Med. 2012. Jul;18(7):1060-8.

Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, Brunkhorst R, Busch V, Dengler R, Deutschl G, Fellermann K, Fickenscher H, Goettsche A, Greeve J, Hafer C, Haller H, Herget-Rosenthal S, Hertenstein B, Hofmann C, Kielstein JT, Klostermeier U, Knobloch J, Kuehbacher M, Kunzendorf U, Lehnert H, Manns MP, Menne TF, Münte T, Nuernberger J, Ramazan L, Renders L, Rohr A, Sayk F, Schmidt BMW, Schnatter S, Schoecklmann H, Schreiber S, Steinhoff J, Stracke S, Suerbaum S, Vischedyk M, Weissenborn K, Wellhörner P, Wiesner M, Zeissig S, Büning J, Schiffer M, Kuehbacher T. Retrospective Analysis of 298 Adult Haemolytic Uremic Syndrome Cases from the 2011 E.coli O104:H4 Outbreak and Validation of Therapeutic Strategies. Br Med J. 2012. Jul 19;345:e4565.

Khatun I*, Zeissig S*, Iqbal J, Wang M, Curiel D, Shelness GS, Blumberg RS, Hussain MM. The phospholipid transfer activity of MTP produces apoB-lipoproteins and reduces hepatosteatosis while maintaining low plasma lipids. Hepatology. 2012 May;55(5):1356-68. *equally contributing first authors.

Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, Blumberg RS. Microbial exposure during early life has persistent effects on tissue-associated iNKT cells and their function. Science. 2012 Apr 27;336(6080):489-93.

2011

Chen Z, Chen L, Baker K, Olszak T, Zeissig S, Huang YH, Mandelboim O, Beauchemin N, Lanier LL, Blumberg RS. CEACAM1 dampens anti-tumor immunity by downregulating NKG2D ligand expression on tumor cells. J Exp Med. 2011 Dec 19;208(13):2633-40.

Pahl R, Brunke G, Steubesand N, Schubert S, Böttner M, Wedel T, Jürgensen C, Hampe J, Schäfer H, Zeissig S, Schreiber S, Rosenstiel P, Reiss K, Arlt A. IL-1β and ADAM17 are central regulators of β-defensin expression in Candida esophagitis. Am J Physiol Gastrointest Liver Physiol. 2011 Apr;300(4):G547-53.

2004-2010 (selected publication)

Zeissig S, Dougan SK, Barral D, Junker Y, Chen Z, Kaser A, Ho M, Mandel H, McIntyre A, Kennedy SM, Painter, GF, Veerapen N, Besra GS, Cerundolo V, Yue S, Beladi S, Behar SM, Chen X, Gumpertz JE, Breckpot K, Raper A, Baer A, Exley MA, Hegele RA, Cuchel M, Rader DJ, Davidson NO, Blumberg RS, Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function.J Clin Invest. 2010 Aug 2;120(8):2889-99.

Bergann T, Zeissig S, Fromm A, Richter JF, Fromm M, Schulzke JD. Glucocorticoids and tumor necrosis factor-alpha synergize to induce absorption by the epithelial sodium channel in the colon. Gastroenterology. 2009 Mar;136(3):933-42.

Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008 Sep 5;134(5):743-56.

Zeissig S, Bergann T, Fromm A, Bojarski C, Heller F, Guenther U, Zeitz M, Fromm M, Schulzke JD. Altered ENaC expression leads to impaired sodium absorption in the noninflamed intestine in Crohn's disease. Gastroenterology. 2008 May;134(5):1436-47.

Zeissig S, Fromm A, Mankertz J, Weiske J, Zeitz M, Fromm M, Schulzke JD. Butyrate induces intestinal sodium absorption via Sp3-mediated transcriptional up-regulation of epithelial sodium channels. Gastroenterology 2007;132:236-48.

Zeissig S, Burgel N, Gunzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease. Gut 2007;56:61-72.

Zeissig S, Fromm A, Mankertz J, Zeitz M, Fromm M, Schulzke JD. Restoration of ENaC expression by glucocorticoid receptor transfection in human HT-29/B6 colon cells. Biochem Biophys Res Commun 2006;344:1065-70.

Zeissig S, Bojarski C, Buergel N, Mankertz J, Zeitz M, Fromm M, Schulzke JD. Downregulation of epithelial apoptosis and barrier repair in active Crohn's disease by tumour necrosis factor alpha antibody treatment. Gut 2004;53:1295-302.