Pathophysiologische Mechanismen der chronisch-entzündlichen Darmerkrankungen - ein neues Konzept

Zusammenfassung

Sowohl das bekannte Nord-/Südgefälle als auch epidemiologische Studien in den westlichen Industrieländern belegen die fördernde Rolle der Hygiene bei der Entstehung chronisch-entzündlicher Darmerkrankungen. Vermutlich wird wegen des seltenen Auftretens von Darminfektionen das angeborene Immunsystem nicht ausreichend „trainiert” und durch das spezifische Immunsystem mit deletären Entzündungskaskaden ersetzt. Passend zu einer Störung der angeborenen mukosalen antibakteriellen Barriere finden sich bei entzündlichen Darmerkrankungen häufig mukosal adhärente und teilweise invasive Bakterien. Wichtiger Bestandteil dieser chemischen Barriere des Epithels sind die Defensine als antimikrobielle Peptide mit enormem Wirkungsbereich einschließlich gramnegativen, grampositiven, Mykobakterien, Pilzen (Candida), Viren (Herpes) und Protozoen (Giardia lamblia). Beim Morbus Crohn des Kolon fand sich eine verminderte β-Defensinantwort, welche vermutlich die Mucosabarriere beeinträchtigt und so zu einer vermehrten bakteriellen Invasion in die Darmschleimhaut führt. Beim Morbus Crohn des terminalen Ileum sind die dort wichtigeren α-Defensine in den Panethzellen vermindert exprimiert, insbesondere bei einer Mutation des Transkriptionsfaktors NOD2. Der Defensinmangel kann somit als Trigger für die Entzündungsantwort betrachtet werden. Ob diese verminderte Defensinantwort auch zu einer verminderten antibakteriellen Aktivität der Darmschleimhaut führt, ist noch Gegenstand der Forschung. Dennoch ist ein Defensinmangelsyndrom das derzeit plausibelste Pathogenesekonzept des Morbus Crohn. Die Colitis ulcerosa dagegen zeigt in der Entzündung einen adäquaten Anstieg der bisher bekannten humanen Defensine. Dieses Krankheitsbild ist daher durch obiges Konzept nicht zu erklären, dies schließt aber andere Störungen der angeborenen Abwehr nicht aus.

Abstract

The North-/South Gradient as well as epidemilogical studies in the industrialised countries support a promoting role of good hygiene for chronic inflammatory bowel diseases. Probably innate immunity is not sufficiently trained and adaptive immunity with its deleterious inflammatory cascades has to step in. The finding of mucosal adeherent and invasive bacteria fits with this concept. An important part of this chemical barrier are the defensins with a broad effect against gramnegative and grampositive bacteria, mycobacterias, fungi (candida), viruses (herpes) and protozoa (giardia lamblia). β-defensins are diminshed in Crohn's disease of the colon, which may compromise the mucosal barrier and lead to its bacterial invasion. In terminal ileitis the expression of α-defensins is diminished in the Paneth cells, especially if the transcription factor NOD2 is mutated. The defensin deficiency may therefore trigger the secondary inflammatory events in the mucosa. In contrast to Crohn's disease, ulcerative colitis shows an adequate increase of all known human defensins during inflammation. Hence, other impaired mechanisms of innate defense may be responsible.

Schlüsselwörter

Chronisch entzündliche Darmerkrankungen - Morbus Crohn - Colitis ulcerosa - Pathophysiologie - angeborene Immunität - Defensine

Key words

Inflammatory bowel disease - Crohn's disease - ulcerative colitis - pathophysiology - innate immunity - defensins

Literatur

• 1 Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, van Blankenstein M. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).  Gut. 1996;  39 690-697
• 2 Gent A E, Hellier M D, Grace R H, Swarbrick E T, Coggon D. Inflammatory bowel disease and domestic hygiene in infancy.  Lancet. 1994;  343 766-767
• 3 Gilat T, Hacohen D, Lilos P, Langman M J. Childhood factors in ulcerative colitis and Crohn's disease. An international cooperative study.  Scand J Gastroenterol. 1987;  22 1009-1024
• 4 Persson P G, Leijonmarck C E, Bernell O, Hellers G, Ahlbom A. Risk indicators for inflammatory bowel disease.  Int J Epidemiol. 1993;  22 268-272
• 5 Probert C S, Jayanthi V, Rampton D S, Mayberry J F. Epidemiology of inflammatory bowel disease in different ethnic and religious groups: limitations and aetiological clues.  Int J Colorectal Dis. 1996;  11 25-28
• 6 Calkins B M. A meta-analysis of the role of smoking in inflammarory bowel disease.  Dig Dis Sci. 1989;  34 1841-1854
• 7 Stallmach A, Carstens O. Role of infections in the manifestation or reactivation of inflammatory bowel diseases.  Inflamm Bowel Dis. 2002;  8 213-218
• 8 Moss M T, Sanderson J D, Tizard M L, Hermon-Taylor J, el-Zaatari F A, Markesich D C, Graham D Y. Polymerase chain reaction detection of Mycobacterium paratuberculosis and Mycobacterium avium subsp silvaticum in long term cultures from Crohn's disease and control tissues.  Gut. 1992;  33 1209-1213
• 9 McFadden J J, Butcher P D, Chiodini R, Hermon-Taylor J. Crohn's disease-isolated mycobacteria are identical to Mycobacterium paratuberculosis, as determined by DNA probes that distinguish between mycobacterial species.  J Clin Microbiol. 1987;  25 796-801
• 10 Ryan P, Bennett M W, Aarons S, Lee G, Collins J K, O'Sullivan G C, O'Connell J, Shanahan F. PCR detection of Mycobacterium paratuberculosis in Crohn's disease granulomas isolated by laser capture microdissection.  Gut. 2002;  51 665-670
• 11 Liu Y, van Kruiningen H J, West A B, Cartun R W, Cortot A, Colombel J F. Immunocytochemical evidence of Listeria, Escherichia coli, and Streptococcus antigens in Crohn's disease.  Gastroenterology. 1995;  108 1396-1404
• 12 Darfeuille-Michaud A, Neut C, Barnich N, Lederman E, Di Martino P, Desreumaux P, Gambiez L, Joly B, Cortot A, Colombel J F. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease.  Gastroenterology. 1998;  115 1405-1413
• 13 Wakefield A J, Ekbom A, Dhillon A P, Pittilo R M, Pounder R E. Crohn's disease: pathogenesis and persistent measles virus infection.  Gastroenterology. 1995;  108 911-916
• 14 Neut C, Bulois P, Desreumaux P, Membre J M, Lederman E, Gambiez L, Cortot A, Quandalle P, van Kruiningen H, Colombel J F. Changes in the bacterial flora of the neoterminal ileum after ileocolonic resection for Crohn's disease.  Am J Gastroenterol. 2002;  97 939-946
• 15 D'Haens G R, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum.  Gastroenterology. 1998;  114 262-267
• 16 Janowitz H D, Croen E C, Sachar D B. The role of the fecal stream in Crohn's disease: an historical and analytic review.  Inflamm Bowel Dis. 1998;  4 29-39
• 17 Sellon R K, Tonkonogy S, Schultz M, Dieleman L A, Grenther W, Balish E, Rennick D M, Sartor R B. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice.  Infect Immun. 1998;  66 5224-5231
• 18 Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M, Lochs H. Mucosal flora in inflammatory bowel disease.  Gastroenterology. 2002;  122 44-54
• 19 Heller F, Duchmann R. Intestinal flora and mucosal immune responses.  Int J Med Microbiol. 2003;  293 77-86
• 20 Seksik P, Rigottier-Gois L, Gramet G, Sutren M, Pochart P, Marteau P, Jian R, Dore J. Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon.  Gut. 2003;  52 237-242
• 21 Boman H G. Gene-encoded peptide antibiotics and the concept of innate immunity: an update review.  Scand J Immunol. 1998;  48 15-25
• 22 Cunliffe R N, Mahida Y R. Antimicrobial peptides in innate intestinal host defence.  Gut. 2000;  47 16-17
• 23 Fellermann K, Stange E F. Defensins - innate immunity at the epithelial frontier.  Eur J Gastroenterol Hepatol. 2001;  13 771-776
• 24 Lehrer R I, Ganz T. Defensins of vertebrate animals.  Curr Opin Immunol. 2002;  14 96-102
• 25 Harder J, Siebert R, Zhang Y, Matthiesen P, Christophers E, Schlegelberger B, Schroder J M. Mapping of the gene encoding human beta-defensin-2 (DEFB2) to chromosome region 8p22-p23.1.  Genomics. 1997;  46 472-475
• 26 Liu L, Zhao C, Heng H H, Ganz T. The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry.  Genomics. 1997;  43 316-320
• 27 Liu L, Wang L, Jia H P, Zhao C, Heng H H, Schutte B C, McCray P B, Ganz T. Structure and mapping of the human beta-defensin HBD-2 gene and its expression at sites of inflammation.  Gene. 1998;  222 237-244
• 28 Wilson C L, Ouellette A J, Satchell D P, Ayabe T, Lopez-Boado Y S, Stratman J L, Hultgren S J, Matrisian L M, Parks W C. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense.  Science. 1999;  286 113-117
• 29 Becker M N, Diamond G, Verghese M W, Randell S H. CD14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium.  J Biol Chem. 2000;  275 29 731-29 736
• 30 Diamond G, Kaiser V, Rhodes J, Russell J P, Bevins C L. Transcriptional regulation of beta-defensin gene expression in tracheal epithelial cells.  Infect Immun. 2000;  68 113-119
• 31 Ogura Y, Bonen D K, Inohara N, Nicolae D L, Chen F F, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr R H, Achkar J P, Brant S R, Bayless T M, Kirschner B S, Hanauer S B, Nunez G, Cho J H. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.  Nature. 2001;  411 603-606
• 32 Hugot J P, Chamaillard M, Zouali H, Lesage S, Cezard J P, Belaiche J, Almer S, Tysk C, O'Morain C A, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel J F, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.  Nature. 2001;  411 599-603
• 33 Ogura Y, Inohara N, Benito A, Chen F F, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB.  J Biol Chem. 2001;  276 4812-4818
• 34 Hisamatsu T, Suzuki M, Reinecker H C, Nadeau W J, McCormick B A, Podolsky D K. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.  Gastroenterology. 2003;  124 993-1000
• 35 Porter E M, van Dam E, Valore E V, Ganz T. Broad-spectrum antimicrobial activity of human intestinal defensin 5.  Infect Immun. 1997;  65 2396-2401
• 36 Harder J, Bartels J, Christophers E, Schroder J M. A peptide antibiotic from human skin.  Nature. 1997;  387 861
• 37 Harder J, Bartels J, Christophers E, Schroder J M. Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic.  J Biol Chem. 2001;  276 5707-5713
• 38 Garcia J R, Jaumann F, Schulz S, Krause A, Rodriguez-Jimenez J, Forssmann U, Adermann K, Kluver E, Vogelmeier C, Becker D, Hedrich R, Forssmann W G, Bals R. Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction.  Cell Tissue Res. 2001;  306 257-264
• 39 Fujii G, Selsted M E, Eisenberg D. Defensins promote fusion and lysis of negatively charged membranes.  Protein Sci. 1993;  2 1301-1312
• 40 Wimley W C, Selsted M E, White S H. Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores.  Protein Sci. 1994;  3 1362-1373
• 41 Salzman N H, Ghosh D, Huttner K M, Paterson Y, Bevins C L. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin.  Nature. 2003;  422 522-526
• 42 Salzman N H, Chou M M, de Jong H, Liu L, Porter E M, Paterson Y. Enteric salmonella infection inhibits Paneth cell antimicrobial peptide expression.  Infect Immun. 2003;  71 1109-1115
• 43 Ong P Y, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo R L, Leung D Y. Endogenous antimicrobial peptides and skin infections in atopic dermatitis.  N Engl J Med. 2002;  347 1151-1160
• 44 Smith J J, Travis S M, Greenberg E P, Welsh M J. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.  Cell. 1996;  85 229-236
• 45 Goldman M J, Anderson G M, Stolzenberg E D, Kari U P, Zasloff M, Wilson J M. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis.  Cell. 1997;  88 553-560
• 46 Cunliffe R N, Kamal M, Rose F R, James P D, Mahida Y R. Expression of antimicrobial neutrophil defensins in epithelial cells of active inflammatory bowel disease mucosa.  J Clin Pathol. 2002;  55 298-304
• 47 Wehkamp J, Schwind B, Herrlinger K R, Baxmann S, Schmidt K, Duchrow M, Wohlschlager C, Feller A C, Stange E F, Fellermann K. Innate immunity and colonic inflammation: enhanced expression of epithelial alpha-defensins.  Dig Dis Sci. 2002;  47 1349-1355
• 48 Cunliffe R N, Rose F R, Keyte J, Abberley L, Chan W C, Mahida Y R. Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease.  Gut. 2001;  48 176-185
• 49 Lawrance I C, Fiocchi C, Chakravarti S. Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes.  Hum Mol Genet. 2001;  10 445-456
• 50 Wehkamp J, Harder J, Weichenthal M, Herrlinger K R, Schmid M, Noack F, Schlee M, Nuding S, Hohmann N, Schwab M, Schäffeler E, Stallmach A, Fritz P, Schroeder J M, Fellermann K, Stange E F. Pathomechanism of Crohn's disease NOD2 (CARD 15) mutation: Deficient mucosal antimicrobial peptide (defensin) expression.  Gut. 2003;  52 (Suppl VI) p. A 1
• 51 Lala S, Ogura Y, Osborne C, Hor S Y, Bromfield A, Davies S, Ogunbiyi O, Nunez G, Keshav S. Crohn's disease and the NOD2 gene: a role for paneth cells.  Gastroenterology. 2003;  125 47-57
• 52 O'Neil D A, Porter E M, Elewaut D, Anderson G M, Eckmann L, Ganz T, Kagnoff M F. Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium.  J Immunol. 1999;  163 6718-6724
• 53 Wehkamp J, Fellermann K, Herrlinger K R, Baxmann S, Schmidt K, Schwind B, Duchrow M, Wohlschlager C, Feller A C, Stange E F. Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease.  Eur J Gastroenterol Hepatol. 2002;  14 745-752
• 54 Wehkamp J, Harder J, Weichenthal M, Mueller O, Herrlinger K R, Fellermann K, Schroeder J M, Stange E F. Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis.  Inflamm Bowel Dis. 2003;  9 215-223
• 55 Fahlgren A, Hammarstrom S, Danielsson A, Hammarstrom M L. Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis.  Clin Exp Immunol. 2003;  131 90-101
• 56 Ursing B, Alm T, Barany F, Bergelin I, Ganrot-Norlin K, Hoevels J, Huitfeldt B, Jarnerot G, Krause U, Krook A, Lindstrom B, Nordle O, Rosen A. A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. II. Result.  Gastroenterology. 1982;  83 550-562
• 57 Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, Summers R, Mekhjian H, Greenberger N, Kelly M ,. et al . Double blind, placebo controlled trial of metronidazole in Crohn's disease.  Gut. 1991;  32 1071-1075
• 58 Colombel J F, Lemann M, Cassagnou M, Bouhnik Y, Duclos B, Dupas J L, Notteghem B, Mary J Y. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID).  Am J Gastroenterol. 1999;  94 674-678
• 59 Prantera C, Zannoni F, Scribano M L, Berto E, Andreoli A, Kohn A, Luzi C. An antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin.  Am J Gastroenterol. 1996;  91 328-332
• 60 Arnold G L, Beaves M R, Pryjdun V O, Mook W J. Preliminary study of ciprofloxacin in active Crohn's disease.  Inflamm Bowel Dis. 2002;  8 10-15
• 61 Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection.  Gastroenterology. 1995;  108 1617-1621
• 62 Prantera C, Scribano M L, Falasco G, Andreoli A, Luzi C. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn's disease: a randomised controlled trial with Lactobacillus GG.  Gut. 2002;  51 405-409
• 63 Jakobovits J, Schuster M M. Metronidazole therapy for Crohn's disease and associated fistulae.  Am J Gastroenterol. 1984;  79 533-540
• 64 Brandt L J, Bernstein L H, Boley S J, Frank M S. Metronidazole therapy for perineal Crohn's disease: a follow-up study.  Gastroenterology. 1982;  83 383-387
• 65 Mantzaris G J, Archavlis E, Christoforidis P, Kourtessas D, Amberiadis P, Florakis N, Petraki K, Spiliadi C, Triantafyllou G. A prospective randomized controlled trial of oral ciprofloxacin in acute ulcerative colitis.  Am J Gastroenterol. 1997;  92 454-456
• 66 Mantzaris G J, Petraki K, Archavlis E, Amberiadis P, Kourtessas D, Christidou A, Triantafyllou G. A prospective randomized controlled trial of intravenous ciprofloxacin as an adjunct to corticosteroids in acute, severe ulcerative colitis.  Scand J Gastroenterol. 2001;  36 971-974
• 67 Chapman R W, Selby W S, Jewell D P. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis.  Gut. 1986;  27 1210-1212
• 68 Mantzaris G J, Hatzis A, Kontogiannis P, Triadaphyllou G. Intravenous tobramycin and metronidazole as an adjunct to corticosteroids in acute, severe ulcerative colitis.  Am J Gastroenterol. 1994;  89 43-46
• 69 Turunen U M, Farkkila M A, Hakala K, Seppala K, Sivonen A, Ogren M, Vuoristo M, Valtonen V V, Miettinen T A. Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study.  Gastroenterology. 1998;  115 1072-1078
• 70 Kruis W, Schutz E, Fric P, Fixa B, Judmaier G, Stolte M. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis.  Aliment Pharmacol Ther. 1997;  11 853-858
• 71 Rembacken B J, Snelling A M, Hawkey P M, Chalmers D M, Axon A T. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial.  Lancet. 1999;  354 635-639
• 72 Schlee M, Wehkamp J, Harder J, Wehkamp K, Schroeder J M, Stange E F, Fellermann K. Das Probiotikum E. coli Nissle 1917 induziert humanes beta Defensin-2 in Abhängigkeit von NFkB in intestinalen Epithelzellen.  Z Gastroenterol. 2003;  41 734
• 73 Boirivant M, Pica R, DeMaria R, Testi R, Pallone F, Strober W. Stimulated human lamina propria T cells manifest enhanced Fas-mediated apoptosis.  J Clin Invest. 1996;  98 2616-2622
• 74 Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S, Schutz M, Bartsch B, Holtmann M, Becker C, Strand D, Czaja J, Schlaak J F, Lehr H A, Autschbach F, Schurmann G, Nishimoto N, Yoshizaki K, Ito H, Kishimoto T, Galle P R, Rose-John S, Neurath M F. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.  Nat Med. 2000;  6 583-588
• 75 Fuss I J, Marth T, Neurath M F, Pearlstein G R, Jain A, Strober W. Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice.  Gastroenterology. 1999;  117 1078-1088
• 76 Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis.  Gastroenterology. 1998;  115 182-205
• 77 MacDonald T T, Monteleone G, Pender S L. Recent developments in the immunology of inflammatory bowel disease.  Scand J Immunol. 2000;  51 2-9
• 78 van Denventer S JH. Tumour necrosis factor and Crohn's disease.  Gut. 1997;  40 443-448
• 79 Keates A C, Castagliuolo I, Cruickshank W W, Qiu B, Arseneau K O, Brazer W, Kelly C P. Interleukin 16 is up-regulated in Crohn's disease and participates in TNBS colitis in mice.  Gastroenterology. 2000;  119 972-982
• 80 Fais S, Capobianchi M R, Pallone F, Di Marco P, Boirivant M, Dianzani F, Torsoli A. Spontaneous release of interferon gamma by intestinal lamina propria lymphocytes in Crohn's disease. Kinetics of in vitro response to interferon gamma inducers.  Gut. 1991;  32 403-407
• 81 Halstensen T S, Das K M, Brandtzaeg P. Epithelial deposits of immunoglobulin G1 and activated complement colocalise with the M(r) 40 kD putative autoantigen in ulcerative colitis.  Gut. 1993;  34 650-657
• 82 Sartor R B. Innate immunity in the pathogenesis and therapy of IBD.  J Gastroenterol. 2003;  38 43-47
• 83 Fellermann K, Wehkamp J, Herrlinger K R, Stange E F. Crohn's disease: a defensin deficiency syndrome?.  Eur J Gastroenterol Hepatol. 2003;  15 627-634
• 84 Schmid M, Fellermann K, Wehkamp J, Herrlinger K, Stange E F. The Role of Defensins in the Pathogenesis of Inflammatory bowel disease.  Z Gastroenterol. 2004;  42 1-6