Sonderforschungsbereich 415:
"Spezifität und Pathophysiologie von Signaltransduktionswegen"

Projekt C8: »Molekulare Charakterisierung der NOD2 (CARD15) abhängigen Pathophysiologie bei intestinalen Entzündungsreaktionen«

Varianten des NOD2-Genes sind mit einem erhöhten Risiko für die Entwicklung eines Morbus Crohn assoziiert. Es konnte gezeigt werden, daß das NOD2 Genprodukt zu einer Familie von Proteinen gehört, die als intrazelluläre Rezeptoren Bakterienwandbestandteile (pathogen-associated molecular patterns, PAMPs) erkennen können und offenbar eine entscheidende Komponente des angeborenen Immunsystems gegen intrazelluläre Pathogene darstellen.

Das Darmepithel bildet eine wichtige mechanische und immunologische Barriere gegen luminale Pathogene. Bei chronisch entzündlichen Darmerkrankungen ist die Barrierefunktion des intestinalen Epithels strukturell und funktionell gestört. Die Expression von NOD2 sensitiviert intestinale Epithelzellen, Bakterienwandbestandteile zu erkennen und induziert die Expression und Sekretion des chemotaktischen Zytokins IL-8. NOD2-Varianten, die mit einem erhöhten Risiko für die Entwicklung eines M. Crohn assoziiert sind, zeigen eine defekte Sensorfunktion für Bakterienwandbestandteile und eine verminderte IL-8 Induktion und Sekretion. Ziel des Projektes ist es, die molekularen Mechanismen der NOD2-Aktivierung in Darmepithelzellen im Zusammenhang mit akuten und chronischen intestinalen Entzündungsprozessen zu beschreiben. Schwerpunkte bilden hier die Identifikation neuer NOD2-interagierender Proteine, deren Bedeutung für NOD2-induzierte Signaltransduktion und die systematische Beschreibung des mRNA Expressionsprofils, welches durch NOD2-abhängige Signalwege induziert wird.

Projektrelevante eigene Veröffentlichungen

Chalaris A, Adam N, Sina C, Rosenstiel P, Lehmann J, Schirmacher P, Hartmann D, Cichy J, Gavrilova O, Schreiber S, Jostock T, Matthews V, Häsler R, Becker C, Neurath MF, Reiß K, Saftig P, Scheller J, Rose-John S. (2010) Critical Role of the Disintegrin Metalloprotease ADAM17 for Intestinal Inflammation and Regeneration in Mice.

J Exp Med 207:1617-1624

Chalaris A, Adam N, Sina C, Rosenstiel P, Lehmann-Koch J, Schirmacher P, Hartmann D, Cichy J, Gavrilova O, Schreiber S, Jostock T, Matthews V, Häsler R, Becker C, Neurath MF, Reiss K, Saftig P, Scheller J, Rose-John S. (2010) Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice.

J Exp Med 207:1617-1624

Kuenzel S, Till A, Winkler M, Haesler R, Lipinski S, Jung S, Grötzinger J, Fickenscher H, Schreiber S, Rosenstiel P. (2010) The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses.

J Immunol 184:1990-2000

Kuenzel S, Till A, Winkler M, Haesler R, Lipinski S, Jung S, Grotzinger J, Fickenscher H, Schreiber S, Rosenstiel P. (2010) The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses.

J Immunol 184:1990-2000

Kuenzel S, Till A, Winkler M, Haesler R, Lipinski S, Jung S, Grötzinger J, Fickenscher H, Schreiber S, Rosenstiel P. (2010) The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses.

J Immunol 184:1990-2000

Rehman A, Lepage P, Nolte A, Hellmig S, Schreiber S, Ott SJ. (2010) Transcriptional activity of dominant gut mucosal microbiota in chronic inflammatory bowel diseases.

J Med Microbiol 59:1114-22

Sina C, Arlt A, Gavrilova O, Midtling E, Kruse ML, Muerkoster SS, Kumar R, Folsch UR, Schreiber S, Rosenstiel P, Schäfer H. (2010) Ablation of gly96/immediate early gene-X1 (gly96/iex-1) aggravates DSS-induced colitis in mice: role for gly96/iex-1 in the regulation of NF-kappaB.

Inflamm Bowel Dis 16:320-331

Sina C, Arlt A, Gavrilova O, Midtling E, Kruse ML, Müerkoster SS, Kumar R, Folsch UR, Schreiber S, Rosenstiel P, Schafer H. (2010) Ablation of gly96/immediate early gene-X1 (gly96/iex-1) aggravates DSS-induced colitis in mice: role for gly96/iex-1 in the regulation of NF-kappaB.

Inflamm Bowel Dis 16:320-331

Waetzig GH, Chalaris A, Rosenstiel P, Suthaus J, Holland C, Karl, N, Uriarte LN, Till A, Scheller J, Grötzinger J, Schreiber S, Rose-John S, Seegert D. (2010) N-linked glycosylation is essential for the stability, but not the signaling function of the interleukin-6 signal transducer gp130.

J Biol Chem 285:1781-1789

Waetzig HG, Chalaris A, Rosenstiel P, Suthaus J, Holland C, Karl N, Uriarte LV, Till A, Scheller J, Grötzinger J, Schreiber S, Rose-John S, Seegert D. (2010) N-linked glycosylation is essential for the stability, but not the function of the interleukin-6 signal transducer gp130.

J Biol Chem 285:1781-1789

Waetzig GH, Chalaris A, Rosenstiel P, Suthaus J, Holland C, Karl N, Valles Uriarte L, Till A, Scheller J, Grötzinger J, Schreiber S, Rose-John S, Seegert D. (2010) N-linked glycosylation is essential for the stability but not the signaling function of the interleukin-6 signal transducer glycoprotein 130.

J Biol Chem 285:1781-1789

von Kampen O, Lipinski S, Till A, Martin SJ, Nietfeld W, Lehrach H, Schreiber S, Rosenstiel P. (2010) The caspase recruitment domain-containing protein 8 (CARD8) negatively regulates NOD2-mediated signaling.

J Biol Chem 285:19921-6

Haesler R, Begun A, Freitag-Wolf S, Kerick M, Mah N, Zvirbliene A, Spehlmann ME, von Wurmb-Schwark N, Kupcinskas L, Rosenstiel P, Schreiber S. (2009) Genetic control of global gene expression levels in the intestinal mucosa: a human twin study.

Physiol Genomics 38:73-79

Häsler R, Begun A, Freitag-Wolf S, Kerick M, Mah N, Zvirbliene A, Spehlmann ME, von Wurmb-Schwark N, Kupcinskas L, Rosenstiel P, Schreiber S. (2009) Genetic control of global gene expression levels in the intestinal mucosa: a human twin study.

Physiol Genomics 38:73-79

Kabelitz D, Schreiber S. (2009) Autoimmunity. Physiological control mechanisms and pathways to autoimmune disease.

Internist (Berl) 50:267-275

Lipinski S, Till A, Sina C, Arlt A, Grasberger H, Schreiber S, Rosenstiel P. (2009) DUOX2-derived reactive oxygen species are effectors of NOD2-mediated antibacterial responses.

J Cell Sci 122:3522-3530

Mockelmann N, von Schonfels W, Buch S, von Kampen O, Sipos B, Egberts JH, Rosenstiel P, Franke A, Brosch M, Hinz S, Roder C, Kalthoff H, Folsch UR, Krawczak M, Schreiber S, Broring CD, Tepel J, Schafmayer C, Hampe J. (2009) Investigation of innate immunity genes CARD4, CARD8 and CARD15 as germline susceptibility factors for colorectal cancer.

BMC Gastroenterol 9:79

Plagmann I, Chalaris A, Kruglov AA; Nedospasov S, Rosenstiel P, Stefan Rose-John S, Scheller J. (2009) Transglutaminase-catalyzed covalent multimerization of camelidae anti-human TNF single domain antibodies improves neutralizing activity.

J Biotechnol 142:170-178

Plagmann I, Chalaris A, Kruglov AA, Nedospasov S, Rosenstiel P, Rose-John S, Scheller J. (2009) Transglutaminase-catalyzed covalent multimerization of camelidae anti-human TNF single domain antibodies improves neutralizing activity.

J Biotechnol 142:170-178

Rosenstiel P, Schreiber S. (2009) NOD-like receptors--pivotal guardians of the immunological integrity of barrier organs.

Adv Exp Med Biol 653:35-47

Rosenstiel P, Philipp EE, Schreiber S, Bosch TC. (2009) Evolution and function of innate immune receptors--insights from marine invertebrates.

J Innate Immun 1:291-300

Rosenstiel P, Sina C, Franke A, Schreiber S. (2009) Towards a molecular risk map--recent advances on the etiology of inflammatory bowel disease.

Semin Immunol 21:334-345

Sina C, Gavrilova O, Foerster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A, Scheller J, Rehmann A, Franke A, Ott S, Häsler R, Nikolaus S, Folsch UR, Rose-John S, Jiang HP, Li J, Schreiber S, Rosenstiel P. (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation.

J Immunol 183:7514-7522

Sina C, Gavrilova O, Förster M, Till, A, Derer S, Hildebrand F, Rabe B, Scheller J, Chalaris A, Scheller J, Rehmann A, Franke A, Ott S, Häsler R, Nikolaus S, Fölsch UR, Rose-John S, Jiang H-P, Li J, Schreiber S, Rosenstiel P. (2009) G-protein coupled receptor 43 (GPR43) is essential for neutrophil recruitment during intestinal inflammation.

J Immunol 183:7514-7522

Sina C, Gavrilova O, Foerster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A, Scheller J, Rehmann A, Franke A, Ott S, Haesler R, Nikolaus S, Folsch UR, Rose-John S, Jiang HP, Li J, Schreiber S, Rosenstiel P. (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation.

J Immunol 183:7514-7522

Steubesand N, Kiehne K, Brunke G, Pahl R, Reiss K, Herzig KH, Schubert S, Schreiber S, Folsch UR, Rosenstiel P, Arlt A. (2009) The expression of the beta-defensins hBD-2 and hBD-3 is differentially regulated by NF-kappaB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis.

BMC Immunol 10:36

Steubesand N, Kiehne K, Brunke G, Pahl R, Reiss K, Herzig KH, Schubert S, Schreiber S, Folsch UR, Rosenstiel P, Arlt A. (2009) The expression of the beta-defensins hBD-2 and hBD-3 is differentially regulated by NF-kappaB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis.

BMC Immunol 10:36

Ufer M, Häsler R, Jacobs G, Haenisch S, Lächelt S, Faltraco F, Sina C, Rosenstiel P, Nikolaus S, Schreiber S, Cascorbi I. (2009) Decreased sigmoidal ABCB1 (P-glycoprotein) expression in ulcerative colitis is associated with disease activity.

Pharmacogenomics 10:1941-53

Ufer M, Häsler R, Jacobs G, Haenisch S, Lächelt S, Faltraco F, Sina C, Rosenstiel P, Nikolaus S, Schreiber S, Cascorbi I. (2009) Decreased sigmoidal ABCB1 (P-glycoprotein) expression in ulcerative colitis is associated with disease activity.

Pharmacogenomics 10:1941-53

Wilms H, Rosenstiel P,  Romero-Ramos M, Arlt A, Schäfer H, Seegert D, Kahle PJ, Odoy S, Claasen JH, Holzknecht C, Brandenburg LO, Deuschl G, Schreiber S, Kirik D, Lucius R. (2009) Suppression of MAP kinases inhibits microglial activation and attenuate neuronal cell death induced by alpha-synuclein protofibrils.

Int J Immunopathol Pharmacol 22:897-909

Wilms H, Rosenstiel P,  Romero-Ramos M, Arlt A, Schäfer H, Seegert D, Kahle PJ, Odoy S, Claasen JH, Holzknecht C, Brandenburg LO, Deuschl G, Schreiber S, Kirik D, Lucius R. (2009) Suppression of MAP kinases inhibits microglial activation and attenuate neuronal cell death induced by alpha-synuclein protofibrils.

Int J Immunopathol Pharmacol 22:897-909

Arlt A, Rosenstiel P, Kruse ML, Grohmann F, Minkenberg J, Perkins ND, Folsch UR, Schreiber S, Schäfer H. (2008) IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis.

Biochim Biophys Acta 1783:941-952

Arlt A, Rosenstiel P, Kruse ML, Grohmann F, Minkenberg J, Perkins ND, Folsch UR, Schreiber S, Schäfer H. (2008) IEX-1 directly interferes with RelA/p65 dependent transactivation and regulation of apoptosis.

Biochim Biophys Acta 1783:941-952

Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, Schuldt D, Nikolaus S, Rosenstiel P, Krawczak M, Schreiber S. (2008) Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis.

Nat Genet 40: 713-715

Kuehbacher T, Rehman A, Lepage P, Hellmig S, Folsch UR, Schreiber S, Ott SJ. (2008) Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease.

J Med Microbiol 57:1569-1576

Ott SJ, Kuehbacher T, Musfeldt M, Rosenstiel P, Hellmig S, Rehman A, Drews O, Weichert W, Timmis KN, Schreiber S. (2008) Fungi and inflammatory bowel diseases: Alterations of composition and diversity.

Scand J Gastroenterol 43:831-841

Rosenstiel P, Derer S, Till A, Häsler R, Eberstein H, Bewig B, Nikolaus S, Nebel A, Schreiber S. (2008) Systematic expression profiling of innate immune genes defines a complex pattern of immunosenescence in peripheral and intestinal leukocytes.

Genes Immun 9:103-114

Rosenstiel P, Derer S, Till A, Häsler R, Eberstein H, Bewig B, Nikolaus S, Nebel A, Schreiber S. (2008) Systematic expression profiling of innate immune genes defines a complex pattern of immunosenescence in peripheral and intestinal leukocytes.

Genes Immun 9:103-114

Rosenstiel P, Schreiber S. (2008) Expression signatures, barriers and beyond: the role of oxidative stress in murine colitis and human inflammatory bowel disease revisited.

Eur J Gastroenterol Hepatol 20:496-499

Rosenstiel P, Jacobs G, Till A, Schreiber S. (2008) NOD-like receptors: ancient sentinels of the innate immune system.

Cell Mol Life Sci 65:1361-1377

Schulze HA, Häsler R, Mah N, Lu T, Nikolaus S, Costello CM, Schreiber S. (2008) From model cell line to in vivo gene expression: disease-related intestinal gene expression in IBD.

Genes Immun 9: 240-248

Schulze HA, Häsler R, Mah N, Lu T, Nikolaus S, Costello CM, Schreiber S. (2008) From model cell line to in vivo gene expression: disease-related intestinal gene expression in IBD.

Genes Immun 9:240-248

Till A, Rosenstiel P, Brautigam K, Sina C, Jacobs G, Oberg HH, Seegert D, Chakraborty T, Schreiber S. (2008) A role for membrane-bound CD147 in NOD2-mediated recognition of bacterial cytoinvasion.

J Cell Sci 121:487-495

Ufer M, Dilger K, Leschhorn L, Daufresne L, Mosyagin I, Rosenstiel P, Häsler R, Kuehbacher T, Nikolaus S, Schreiber S, Cascorbi I. (2008) Influence of CYP3A4, CYP3A5, and ABCB1 Genotype and Expression on Budesonide Pharmacokinetics: A Possible Role of Intestinal CYP3A4 Expression.

Clin Pharmacol Ther 84:43-6

El Mokhtari NE, Ott SJ, Nebel A, Schaefer A, Rosenstiel P, Forster M, Nothnagel M, Simon R, Schreiber S. (2007) Role of NOD2/CARD15 in coronary heart disease.

BMC Genet 8:76

Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, Gunther S, Prescott NJ, Onnie CM, Haesler R, Sipos B, Folsch UR, Lengauer T, Platzer M, Mathew CG, Krawczak M, Schreiber S. (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.

Nat Genet 39:207-211

Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, Gunther S, Prescott NJ, Onnie CM, Hasler R, Sipos B, Folsch UR, Lengauer T, Platzer M, Mathew CG, Krawczak M, Schreiber S. (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.

Nat Genet 39:207-211

Nikolaus S, Schreiber S. (2007) Diagnostics of inflammatory bowel disease.

Gastroenterology 133:1670-1689

Ott SJ, El Mokhtari NE, Rehman A, Rosenstiel P, Hellmig S, Kuehbacher T, Lins M, Simon R, Schreiber S. (2007) Fungal rDNA signatures in coronary atherosclerotic plaques.

Environ Microbiol 9:3035-3045

Rosenstiel P, Huse K, Franke A, Hampe J, Reichwald K, Platzer C, Roberts RG, Mathew CG, Platzer M, Schreiber S. (2007) Functional characterization of two novel 5' untranslated exons reveals a complex regulation of NOD2 protein expression.

BMC Genomics 8:472

Rosenstiel P, Till A, Schreiber S. (2007) NOD-like receptors and human diseases.

Microbes Infect 9:648-657

Rosenstiel P, Sina C, End C, Renner M, Lyer S, Till A, Hellmig S, Nikolaus S, Folsch UR, Helmke B, Autschbach F, Schirmacher P, Kioschis P, Hafner M, Poustka A, Mollenhauer J, Schreiber S. (2007) Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion.

J Immunol 178:8203-8211

Rosenstiel P, Till A, Schreiber S. (2007) NOD-like receptors and human diseases.

Microbes Infect 9:648-657

Rosenstiel P, Sina C, End C, Renner M, Lyer S, Till A, Hellmig S, Nikolaus S, Fölsch UR, Helmke B, Autschbach F, Schirmacher P, Kioschis P, Hafner M, Poustka A, Mollenhauer J, Schreiber S. (2007) Regulation of DMBT1 via NOD2 and TLR4 in Intestinal Epithelial Cell modulates Bacterial Recognition and Invasion

J Immunol, in press

El Mokhtari NE, Ott SJ, Nebel A, Simon R, Schreiber S. (2006) A functional variant in the CARD4 gene and risk of premature coronary heart disease

Int J Immunogenet 33:307-311

Jenisch S, Hampe J, Elder JT, Nair R, Stuart P, Voorhees JJ, Schreiber S, Kabelitz D, Christophers E, Weichenthal M. (2006) CARD15 mutations in patients with plaque-type psoriasis and psoriatic arthritis: lack of association.

Arch Dermatol Res, 297:409-11

Madisch A, Hellmig S, Schreiber S, Bethke B, Stolte M, Miehlke S. (2006) NOD2/CARD15 gene polymorphisms are not associated with collagenous colitis

Int J Colorectal Dis 2006 June 28

Medici V, Mascheretti S, Croucher PJ, Stoll M, Hampe J, Grebe J, Sturniolo GC, Solberg C, Jahnsen J, Moum B, Schreiber S, Vatn MH. (2006) Extreme heterogeneity in CARD15 and DLG5 Crohn disease-associated polymorphisms between German and Norwegian populations.

Eur J Hum Genet 14:459-468

Ott SJ, Schreiber S. (2006) Reduced microbial diversity in inflammatory bowel diseases

Gut 55:1207

Pearce AV, Fisher SA, Prescott NJ, Onnie CM, Pattni R, Green P, Forbes A, Mansfield J, Sanderson J, Schreiber S, Lewis CM, Mathew CG. (2006) Investigation of association of the DLG5 gene with phenotypes of inflammatory bowel disease in the British population.

Int J Colorectal Dis, May 31; [Epub ahead of print]

Rosenstiel P, Huse K, Till A, Hampe J, Hellmig S, Sina C, Billmann S, von Kampen O, Waetzig GH, Platzer M, Seegert D, Schreiber S. (2006) A short isoform of NOD2/CARD15, NOD2-S, is an endogenous inhibitor of NOD2/receptor-interacting protein kinase 2-induced signaling pathways

Proc Natl Acad Sci 103:3280-3285

Rosenstiel P, Hellmig S, Hampe J, Ott S, Till A, Fischbach W, Sahly H, Lucius R, Fölsch UR, Philpott D, Schreiber S. (2006) Influence of polymorphisms in the NOD1/CARD4 and NOD"/CARD15 genes on the clinical outcome of Helicobacter pylori infection.

Cell Microbiol 8:1188-1198

Schreiber S. (2006) Slipping the barrier: how variants in CARD15 could alter permeability of the intestinal wall and population health

Gut 55: 308-309

Schroeder T, Meier-Stiegen F, Schwanbeck R, Eilken H, Nishikawa S, Häsler R, Schreiber S, Bornkamm GW, Nishikawa SI, Just U. (2006) Activated Notch1 alters differentiation of embryonic stem cells into mesodermal cell lineages at multiple stages of development

Mech Dev 123:570-579

Sebens Müerköster S, Lust E, Arlt A, Witt M, Häsler R, Sebens T, Schreiber S, Fölsch UR, Schäfer H. (2006) Acquired chemoresistance in pancreatic carcinoma cells - Induced secretion of IL1ß and NO lead to inactivation of caspases

Oncogene 25:3973-3981

Zheng W, Rosenstiel P, Huse K, Sina C, Valentonyte R, Mah N, Zeitlmann L, Grosse J, Ruf N, Nurnberg P, Costello CM, Onnie C, Mathew C, Platzer M, Schreiber S, Hampe J. (2006) Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease.

Genes Immun 7:11-18

Costello CM, Mah N, Hasler R, Rosenstiel P, Waetzig GH, Hahn A, Lu T, Gurbuz Y, Nikolaus S, Albrecht M, Hampe J, Lucius R, Kloppel G, Eickhoff H, Lehrach H, Lengauer T, Schreiber S. (2005) Dissection of the inflammatory bowel disease transcriptome using genome-wide cDNA microarrays

PLoS Med 2:e199

Lu T, Costello CM, Croucher PJ, Häsler R, Deuschl G, Schreiber S. (2005) Can Zipf's law be adapted to normalize microarrays

BMC Bioinformatics 6:37

Mascheretti S, Schreiber S. (2005) Genetic testing in crohn disease: utility in individualizing patient management

Am J Pharmacogenomics 5:213-222

Rosenstiel P, Agnholt J, Kelsen J, Medici V, Waetzig GH, Seegert D, Schreiber S. (2005) Differential modulation of p38MAPK and STAT3 signalling by infliximab and etanercept in intestinal T-cells

Gut 54:314-315

Schreiber S. (2005) The complicated path to true causes of disease: role of nuclear factor kappaB in inflammatory bowel disease.

Gut 54:444-445

Schreiber S. (2005) Of mice and men: what to learn about human inflammatory bowel disease from genetic analysis of murine inflammation.

Gastroenterology 129:1782-1784

Till A, Rosenstiel P, Krippner-Heidenreich A, Mascheretti-Croucher S, Croucher PJ, Schafer H, Scheurich P, Seegert D, Schreiber S (2005) The Met-196 -> Arg variation of human tumor necrosis factor receptor 2 (TNFR2) affects TNF-alpha-induced apoptosis by impaired NF-kappaB signaling and target gene expression.

J. Biol. Chem. 280, 5994-6004

Valentonyte R, Hampe J, Huse K, Rosenstiel P, Albrecht M, Stenzel A, Nagy M, Gaede KI, Franke A, Haesler R, Koch A, Lengauer T, Seegert D, Reiling N, Ehlers S, Schwinger E, Platzer M, Krawczak M, Muller-Quernheim J, Schurmann M, Schreiber S. (2005) Sarcoidosis is associated with a truncating splice site mutation in BTNL2

Nat Genet 37:357-364

Waetzig GH, Rosenstiel P, Arlt A, Till A, Bräutigam K, Schäfer H, Rose-John S, Seegert D, Schreiber S. (2005) Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor-beta1.

FASEB J 19: 91-93

Weichart D, Gobom J, Klopfleisch S, Häsler R, Gustavsson N, Billmann S, Lehrach H, Seegert D, Schreiber S, Rosenstiel P. (2005) Analysis of NOD2-mediated proteome response to muramyl-dipeptide in HEK293 cells.

J Biol Chem 28:28

Albrecht M, Domingues FS, Schreiber S, Lengauer T. (2004) Structural localization of disease-associated sequence variations in the NACHT and LRR domains of PYPAF1 and NOD2.

FEBS Lett. 2003 Nov 20;554(3):520-8

Helwig U, Gionchetti P, Rizzello F, Lammers K, Kuhbacher T, Schreiber S, Baggiolini M, Uguccioni M, Campieri M. (2004) CXC and CC chemokine expression in inflamed and noninflamed pelvic ileal pouch tissue.

Int J Colorectal Dis. 19:165-70

Kahlke V, Schafmayer C, Schniewind B, Seegert D, Schreiber S, Schroder J. (2004) Are postoperative complications genetically determined by TNF-beta NcoI gene polymorphism?

Surgery 135: 365-375.

La Ferla K, Seegert D, Schreiber S. (2004) Activation of NF-kappaB in intestinal epithelial cells by E. coli strains isolated from the colonic mucosa of IBD patients.

Int J Colorectal Dis19:334-342

Mascheretti S, Hinrichsen H, Ross S, Buggisch P, Hampe J, Foelsch UR, Schreiber S. (2004) Genetic variants in the CCR gene cluster and spontaneous viral elimination in hepatitis C-infected patients.

Clin Exp Immunol. 2004 May;136:328-33.

Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC,Nicholls RJ, Gionchettti P, Campeiri M, Kamm MA. (2004) Randomised, placebo-controlled, double-blind trial of once daily, high dose probiotic therapy (VSL#3) for maintaining remission in patients with recurrent or refractory pouchitis.

Gut 53: 108-114.

Ott SJ, Musfeldt M, Wenderoth DF, Hampe J, Brant O, Folsch UR, Timmis KN, Schreiber S. (2004) Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease.

Gut. 2004 May;53:685-93.

Pender SLF, Croucher PJP, Mascheretti A, Prothero JD, Fisher SA, MacDonald TT, Schreiber S, Ye S. (2004) Transmission disequilibrium test of stromelysin-1 gene variation in relation to Crohn's disease.

J Med Genet. 2004 Sep;41(9):e112

Rutgeerts P, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Hanauer SB. (2004) Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease

Gastroenterology. 2004 Feb;126:402-13.

Scheller J, Kovaleva M, Eichler J, Kallen KJ, Rose-John S. (2004) Development of a monoclonal-antibody-based enzyme linked immunoabsorbent assay for the IL-6/IL-6R interaction and its competitive inhibition

J.Immunol. Meth. 291:93-100

Stenzel A, Lu T, Koch WA, Hampe J, De La Vega FM, Su X, Dong P, Guenther SM, Krawczak M, Schreiber S. (2004) Extent and distribution of linkage disequilibrium in the HLA region

Hum Genetics 114: 377-385

Stoll M, Corneliussen B, Costello CM, Waetzig GH, Mellgard B, Koch WA, Rosenstiel P, Albrecht M, Croucher PJ, Seegert D, Nikolaus S, Hampe J, Lengauer T, Pierrou S, Foelsch UR, Mathew CG, Lagerstrom-Fermer M, Schreiber S. (2004) Genetic variation in DLG5 is associated with inflammatory bowel disease.

Nat Genet., 36:476-80.

Albrecht M, Lengauer T, Schreiber S. (2003) Disease-associated variants in PYPAF1 and NOD2 result in similar alterations of conserved sequence.

Bioinformatics, 19: 2171-2175

Albrecht M, Domingues FS, Schreiber S, Lengauer T. (2003) Identification of mammalian orthologs associates PYPAF5 with distinct functional roles.

FEBS Lett 538:173-177

Albrecht M, Domingues FS, Schreiber S, Lengauer T. (2003) Structural localization of disease associated variants in the NACHT and LRR domains of PYPAF1 and NOD2.

Febs Letters 554: 520-528.

Croucher PJ, Mascheretti S, Hampe J, Huse K, Frenzel H, Stoll M, Lu T, Nikolaus S, Yang SK, Krawczak M, Kim WH, Schreiber S. (2003) Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations.

Eur J Hum Genet 11:6-16

Croucher PJ, Mascheretti S, Foelsch UR, Hampe J, Schreiber S. (2003) Lack of association between the C3435T MDR1 gene polymorphism and inflammatory bowel disease in two independent Northern European populations.

Gastroenterology. 2003 Dec;125:1919-20; author reply 1920-1.

Fisher SA, Moody A, Mirza MM, Cuthbert AP, Hampe J, MacPherson A, Sanderson J, Forbes A, Mansfield J, Schreiber S, Lewis CM, Mathew CG. (2003) Variation at the Chromosome 16 Cytokine Gene Cluster: Development of a Strategy for Association Studies in Complex Disease

Ann Hum Genetics 67:377-390

Giallourakis C, Stoll M, Miller K, Hampe J, Lander ES, Daly MJ, Schreiber S, Rioux JD. (2003) IBD5 is a General Risk Factor for Inflammatory Bowel Disease: Replication of Association with Crohn Disease and Identification of a Novel Association with Ulcerative Colitis

Am J Hum Gen, 73: 205-211

Hampe J, Schreiber S, Krawczak M. (2003) Entropy-based SNP selection for genetic association studies

Hum Genet 114: 36-43.

Hellmig S, Hampe J, Schreiber S. (2003) Helicobacter pylori infection in Europe: the enigma of host genetics.

Gut, 52: 1799

Herbon N, Werner M, Braig C, Gohlke H, Dutsch G, Illig T, Altmuller J, Hampe J, Lantermann A, Schreiber S, Bonifacio E, Ziegler A, Schwab S, Wildenauer, van den Boom D, Braun A, Knapp M, Reitmeir P, Wjst M. (2003) High-resolution snp scan of chromosome 6p21 in pooled samples from patients with complex diseases

Genomics 81: 510-518.

King K, Moody A, Fisher SA, Mirza MM, Cuthbert AP, Hampe J, Sutherland-Craggs A, Sanderson J, MacPherson AJ, Forbes A, Mansfield J, Schreiber S, Lewis CM, Mathew CG (2003). (2003) Genetic variation in the IGSF6 gene and lack of association with inflammatory bowel disease

Eur J Immunogenetics, 30: 187-90.

Mirza MM, Fisher SA, King K, Cuthbert AP, Hampe J, Sanderson J, Mansfield J, Donaldson P, Macpherson AJ, Forbes A, Schreiber S, Lewis CM, Mathew CG. (2003) Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease.

Am J Hum Genet 72:1018-1022

Rosenstiel P, Fantini M, Brautigam K, Kuhbacher T, Waetzig GH, Seegert D, Schreiber S. (2003) TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells.

Gastroenterology 124:1001-1009

Rutgeerts P, van Deventer SJH, Schreiber S. (2003) The expanding role of biological agents in the treatment of inflammatory bowel disease: focus on selective adhesion molecule (SAM) inhibition.

Aliment Pharmacol Therap, 17: 1-18

Schürmann M, Valentonyte R, Hampe J, Müller-Quernheim J, Schwinger E, Schreiber S. (2003) CARD15 gene mutations in sarcoidosis

Eur Resp J, 22:748-54.

Shaw SH, Hampe J, White R, Mathew CG, Curran ME, Schreiber S. (2003) Stratification by CARD15 variant genotype in a genome-wide search for inflammatory bowel disease susceptibility loci.

Human Gen, 113: 514-521

Waetzig GH, Rosenstiel P, Nikolaus S, Seegert D, Schreiber S. (2003) Differential p38 mitogen-activated protein kinase target phosphorylation in responders and nonresponders to infliximab.

Gastroenterology 125:633-634.

Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Croucher PJ, Mascheretti S, Sanderson J, Forbes A, Mansfield J, Schreiber S, Lewis CM, Mathew CG. (2002) The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.

Gastroenterology, 122: 867-874

Fisher SA, Hampe J, Macpherson AJS, Forbes A, Lennard-Jones JE, Schreiber S, Curran ME, Mathew CG, Lewis CM. (2002) Sex stratification of an inflammatory bowel disease genome search shows male specific linkage to the MHC region of chromosome 6.

Eur J Hum Gen, 10: 259-265

Frenzel H, Hampe J, Huse K, Mascheretti SM, Croucher PJP, Lynch NJ, Siebert R, Platzer M, Schreiber S. (2002) Mutation detection and physical mapping of the CD11 gene cluster in association with inflammatory bowel disease.

Immunogenetics, 53: 835-842

Geschonke K, Klempt M, Lynch N, Schreiber S, Fenselau S, Schrezenmeir J. (2002) Detection of a promoter polymorphism in the gene of intestinal fatty acid binding protein (I-FABP).

Ann NY Acad Sci, 967:548-53

Hampe J, Frenzel H, Mirza MM, Croucher PJP, Cuthbert A, Mascheretti S, Huse K, Platzer M, Bridger S, Meyer B, Nürnberg P, Stokkers P, Krawczak M, Mathew CG, Curran M, Schreiber S. (2002) Evidence for a NOD2 independent susceptibility locus for Inflammatory Bowel Disease on Chromosome 16p.

Proc Nat Acad Sci USA, 99: 321-326

Hampe J, Grebe J, Nikolaus S, Solberg C, Croucher PJP, Mascheretti S, Jahnsen J, Moum B, Klump B, Foelsch UR, Krawczak M, Foelsch UR, Vatn M, Schreiber S. (2002) Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study.

Lancet, 359, 1661-1665

Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P. (2002) Maintenance infliximab for Crohn's disease: the ACCENT I randomized trial.

Lancet, 359: 1541-1549

Herfarth H, Obermeier F, Andus T, Rogler G, Nikolaus S, Kühbacher T, Schreiber S. (2002) Improvement of arthritis and arthralgia after treatment with infliximab (Remicade) in a German prospective, open-label, multicenter trial in refractory Crohn's disease.

Am J Gastroenterol, 97: 2268-2290

Heyne R, Ricke S, Bock P, Schreiber S, Wermke W, Lochs H. (2002) Non-invasive evaluation of activity in inflammatory bowel disease by Power Doppler sonography.

Z Gastroenterol, 40: 171-175

Kahlke V, Dohm C, Mees T, Brotzmann K, Schreiber S, Schroder J. (2002) Early interleukin-10 treatment improves survival and enhances immune function only in males after hemorrhage and subsequent sepsis.

Shock, 18: 24-28

Lantermann A, Hampe J, Kim WH, Winter TA, Kidd M, Nagy M, Fölsch UR, Schreiber S. (2002) Investigation of HLA-DPA1 genotypes as predictors of Inflammatory Bowel Disease in the German, South African and South Korean populations.

Int J Colorectal Dis, 17: 238-44

Mascheretti S, Hampe J, Croucher PJ, Nikolaus S, Andus T, Schubert S, Olson A, Bao W, Folsch UR, Schreiber S. (2002) Response to infliximab treatment in Crohn's disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials.

Pharmacogenetics, 12: 509-515

Mascheretti S, Hampe J, Kühbacher T, Herfarth H, Krawczak M, Fölsch UR, Schreiber S. (2002) Pharmacogenetic Investigation of the TNF/TNF-Receptor System in Patients with Chronic Active Crohn's Disease Treated with Infliximab.

Pharmacogenomics J 2: 127-136.

Mickisch O, Baniewicz W, Lutz-Vorderbrugge A, Schreiber S, Kuppers B. (2002) Long-term management of anemia in chronic inflammatory bowel disease.

Z Gastroenterol, 40:241-8

Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Gionchetti P, Campieri M, Kamm M A. (2002) Four-week open-label trial of metronidazole and ciprofloxacin for the treatment of recurrent or refractory pouchitis.

Aliment Pharmacol Ther, 16: 909-917

Schreiber S, Rosenstiel P, Hampe J, Nikolaus S, Groessner B, Schottelius A, Kühbacher T, Hämling J, Fölsch UR, Seegert D. (2002) Activation of Signal Transducer and Activator of Transcription (STAT) 1 in Human Chronic Inflammatory Bowel Disease.

Gut, 51: 379-385

Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M, Lochs H. (2002) Mucosal flora in inflammatory bowel disease.

Gastroenterology, 122: 44-54

Tilg H, van Montfrans C, van Den Ende A, Kaser A, van Deventer SJ, Schreiber S, Gregor M, Ludwiczek O, Rutgeerts P, Gasche C, Koningsberger JC, Abreu L, Kuhn I, Cohard M, LeBeaut A, Grint P, Weiss G. (2002) Treatment of Crohn's disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon gamma.

Gut, 50: 191-195

Tümer Z, Croucher PJP, Jensen LR, Hampe J, Hansen C, Kalscheuer V, Ropers HH, Tommerup N, Schreiber S. (2002) Genomic structure, chromosome mapping and expression analysis of the human AVIL gene, and its exclusion as a candidate for locus for inflammatory bowel disease at 12q13-14 (IBD2).

Gene, 288: 179-185

Waetzig G, Seegert D, Rosenstiel P, Nikolaus S, Schreiber S. (2002) p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease.

J. Immunol, 168: 5342-5351

Hampe J, Wollstein A, Lu T, Frevel HJ, Will M, Manaster C, Schreiber S. (2001) An integrated system for high throughput TaqMan based SNP genotyping

Bioinformatics17:654-655

Hampe J, Lynch NJ, Daniels S, Bridger S, Macpherson AJ, Stokkers P, Forbes A, Lennard-Jones JE, Mathew CG, Curran ME, Schreiber S. (2001) Fine mapping of the chromosome 3p susceptibility locus in inflammatory bowel disease

Gut 48:191-7

Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG. (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations

Lancet 357(9272):1925-1928

Schreiber S. (2001) Monocytes or T cells in Crohn's disease: does IL-16 allow both to play at that game?

Gut49:747-748

Seegert D, Rosenstiel P, Pfahler H, Pfefferkorn P, Nikolaus S, Schreiber S. (2001) Increased expression of IL-16 in inflammatory bowel disease

Gut 48:326-332

Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, Hanauer SB, Kilian A, Cohard M, LeBeaut A, Feagan B. (2000) Recombinant human interleukin-10 (Tenovil) in the treatment of patients with mild to moderately active Crohn's disease.

Gastroenterology 119:1473-1482

Mascheretti S, Hampe J, Kruis W, Raedler A, Reddig J, Schreiber S. (2000) Evaluation of TNF microsatellites and SNPs in a cohort of chronic active, therapy refractory Crohn's disease patients treated with anti-TNF-alpha.

Gastroenterology 2000;118:A335.

Nikolaus S, Raedler A, Sfikas N, Kühbacher T, Fölsch UR, Schreiber S. (2000) Mechanisms in failure of infliximab for Crohn's disease.

The Lancet 356: 1475-1479.

Nikolaus S, Kühbacher T, Hämling J, Raedler A, Fölsch UR, Schreiber S. (2000) Relapse after Therapy with Infliximab in Crohn's Disease.

The Lancet 356:1475-1479

Schreiber S. (2000) Animal models: Are they useful for the investigation of gastrointestinal disease.

Int J Colorectal Dis 15:126

Schreiber S. (2000) Inflammatory Bowel Disease.

Immunologic Concepts Hepatogastroenterology 47: 15-28.

Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams NC, Nikolaus S, Jacyna M, Lashner BA, Gangl A, Rutgeerts P, Isaacs K, van Deventer SJH, Koningsberger JC, Cohard M, Lebeaut A, Hanauer SB. (2000) Recombinant human interleukin-10 for the treatment of chronic Crohn's disease.

Gastroenterology 119:1461-1472

Hampe J, Schreiber S, Shaw SH, Lau KF, Bridger S, Macpherson AJ, Cardon LR, Sakul H, Harris TJ, Buckler A, Hall J, Stokkers P, van Deventer SJ, Nurnberg P, Mirza MM, Lee JC, Lennard-Jones JE, Mathew CG, Curran ME. (1999) A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort.

Am J Hum Genet 1999;64:808-816.

Hampe J, Shaw SH, Saiz R, Leysens N, Lantermann A, Mascheretti S, Lynch NJ, MacPherson AJ, Bridger S, van Deventer S, Stokkers P, Morin P, Mirza MM, Forbes A, Lennard-Jones JE, Mathew CG, Curran ME, Schreiber S. (1999) Linkage of inflammatory bowel disease to human chromosome 6p.

Am J Hum Genet 1999;65:1647-1655.

Schreiber S, Nikolaus S, Hampe J, Hamling J, Koop I, Groessner B, Lochs H, Raedler A. (1999) Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn's disease.

Lancet 1999;353:459-461.

Herman C, Chernajovsky Y. (1998) Mutation of proline 211 reduces shedding of the human p75 TNF receptor.

J Immunol. 160:2478-2487.

Nikolaus S, Bauditz J, Gionchetti P, Witt C, Lochs H, Schreiber S. (1998) Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin 10 during intestinal inflammation.

Gut 1998;42:470-476.

Schreiber S, Nikolaus S, Hampe J. (1998) Activation of nuclear factor kappa B inflammatory bowel disease.

Gut 1998;42:477-484.

Reviews

Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M. (2005) Genetics of Crohn disease, an archetypal inflammatory barrier disease

Nat Rev Genet 6:376-388

Mascheretti S, Schreiber S. (2004) The role of pharmacogenomics in the prediction of efficacy of anti-TNF therapy in patients with Crohn's disease.

Pharmacogenomics 5:479-486.

Mascheretti S, Croucher PJ, Schreiber S (2004) Pharmacogenetics of inflammatory bowel disease.

Best Pract Res Clin Gastroenterol 18:597-609

Schreiber S, Hanpe J, Nikolaus S, Foelsch UR. (2004) Exploration of the genetic aetiology of inflammatory bowel desease - implications for diagnosis and therapy

Aliment Pharmacol Ther 20 Suppl 4:1-8

Schreiber S. (2004) Genetik der CED; Chronisch entzündliche Darmerkrankungen

Thieme, Stuttgart-New York: 22-28.

Waetzig GH, Schreiber S. (2004) Mechanisms of infliximab: the reverse side of a drug effect.

Inflamm Bowel Dis 10:38-43.

Schreiber S. (2003) Medical Treatment: Overview

Inflammatory Bowel Diseases. Churchill Livingstone/Elsevier, Philadelphia, pp 297-301.

Schreiber S. (2003) Development of novel drugs for inflammatory bowel disease based on molecular targets.

Targets of treatment in chronic inflammatory bowel disease. Kluwer, Dordrecht, Boston, London, pp 33-43.

Waetzig G, Schreiber S. (2003) Mitogen-activated protein kinases in chronic intestinal inflammation: targeting ancient pathways to treat modern diseases.

Aliment Pharmacol Therap 18:17-32

Kroesen AJ, Schreiber S, Buhr HJ. (2002) Pouchitis - pathophysiology and therapy.

Zentralbl Chir, 127: 921-32

Seegert D, Schreiber S. (2002) Interleukin-16 and its role in inflammatory bowel disease.

Curr Opin Investig Drugs, 3: 562-564

Schreiber S, Sternon J. (2001) Anti-TNF alpha in rheumatoid arthritis

Med Brux 22:174-180