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Dimitrios P. Bogdanos

Autoimmunity in Inflammatory Bowel Diseases. Dimitrios P. Bogdanos. Professor of Immunopathology The Sheila Sherlock Medalist. Disclosure statement. 2008-2013

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Dimitrios P. Bogdanos

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  1. Autoimmunity in Inflammatory Bowel Diseases Dimitrios P. Bogdanos Professor of Immunopathology The Sheila Sherlock Medalist

  2. Disclosure statement 2008-2013 I have received in the past Lecture Honoraria, Consultation Fees, Expert Panel Fees, Accommodation/Travel Expenses Coverage INOVA, EUROIMMUN, Generic Assays, FALK, BIORAD, (King’s College Hospital Charitable Trust) Part of travel/accommodation expenses are covered by the Organizers I do not have shares or any other relevant financial or other relationship with a commercial organization that could influence the content of my presentation ALL FEES OR HONORIA SUPPORT MY FELLOWS’S RESEARCH INITIATIVES/CONFERENCE TRAVEL EXPENSES

  3. I have received diagnostic reagents free of charge and/ or participated in collaborative projects EUROPE AID Biorad CyBio Diarect Euclone EUROIMMUN Generic Assays InnoVision Invitrogen- MabTech Mardx Meridian LS Menarini Miltenyi Molecular ProbesPeproTech Pharmacia Roche Disclosure statement II AMERICA Gilead INOVA IMCCO Virusys JAPAN MBL

  4. Inflammatory Bowel Diseases (IBD) Immunology of IBD Autoimmunity in IBD

  5. IBD: EPIDEMIOLOGY & STATASTICS • Estimated prevalence – Active cases 100/100,000 of general population • Estimated approx 1 million cases in US split equally among CD and UC • More Prevalent in developed/ developing countries • Equal distribution among Male:Female • etiopathogenesis not resolved yet • autoimmunitymayplay a role • subsets • Crohn’s disease • Ulcerative colitis • Colitis indeterminate

  6. Ulcerative Colitis • Autoimmune Process ????????????????? • Inflammation confined to colon • Bimodal Incidence (Ages 15-40 yrs OR 50-80 yrs) • Signs and symptoms: Rectal bleeding, loose bloody stools, passage of mucus from rectum, abdominal pain • Complications: perforation, stricture, megacolon, cancer

  7. Ulcerative Colitis • Inflammation confined to Treatment: • Medical: • Mild/moderate disease—5-ASA, corticosteroids • Severe disease—IV steroids or immunosuppressants for refractory disease • Surgical: Proctocolectomy (curative) • Indications: Failure of medical therapy, increasing risk of cancer with long standing disease, bleeding, perforation • Prognosis: Approximately 1-2% risk of cancer at 10 years, 1%/year thereafter

  8. Imaging Ulcerative Colitis • Barium Enema vs. CT • Barium Enema is no longer the test of choice • Findings • Continuous lesions from rectum proximally with circumferential involvement • Lead Pipe Sign • Repeated episodes of mucosal ulceration and marked muscularis hypertrophy results in shortening, narrowing and smoothing out of the normal haustral markings. • “Lead pipe” appearance of colon due to chronic scarring and retraction/loss of haustra Weinstein A et al. A super ‘lead pipe’ colon: radio-pathological correlation of long-standing ulcerative colitis. SA Journal of Radiology;2008 Oct:70-72

  9. Imaging Crohn’s Disease • Small bowel contrast study vs CT • SBFT useful for characterizing length of involvement and areas of stricture • Characteristic Findings • Mucosal nodularity • Narrowed lumen • Ulceration • String sign • Abscesses or fistula • String Sign • Term often applied to the appearance of any marked narrowing of the lumen, but originated as descriptor of reversible narrowing in Crohn disease. • Narrowing caused by incomplete filling as result of irritability/spasms associated with ulceration. String Sign Masselli G. The gastrointestinal string sign. Radiology. 2007 Feb;242(2):632-3.

  10. Extraintestinal Manifestations • Dermatologic features: erythema nodosum, pyoderma gangrenosum

  11. Extraintestinal Manifestations • Ocular: episcleritis, anterior uveitis • Rheumatic: arthritis, ankylosing spondylitis, sacroiliitis • Hepatobiliary: steatohepatitis, cholelithiasis, primary sclerosing cholangitis

  12. Features of UC versus CD Feature UCCD Depth of inflamation Mucosal Transmural Pattern of disease Contiguous Skip areas Location Colorectal Mouth-Anus Rectal involvement Usual less common Ileal disease Backwash 10-15% Common Fistulas Rare Common Perianal Disease Rare Common Granulomas Unlikely 10-30% pts Overt Bleeding Usual less common Malnutrition Unlikely more common Cancer Risk CRC, CholangioCRC,SmBwl Tobacco use Protective Harmful

  13. Laboratory testing • CBC (high rate of anemia, due to chronic inflamm., blood loss, B12 malabsorption) • ESR, CRP often elevated • Albumin (often low due to chronic inflamm., blood loss, malabsorption) • Stool studies to rule out infection • Noncaseating granulomas on biopsy suggest CD

  14. ImmunoPathogenesis of UC Bogdanos and Polymeros Gastroentrol 2004 Sartor Nat Clin Pract Gastroenterol Hepatol 2006, Stephen Gastr Hepatol 2009 Bamias Cur Opin Gastroenterol 2013

  15. Immunology and Cytokines in IBD: A Basic Dichotomy

  16. ImmunoPathogenesis of UC Strobe and Fuss Gastroenterol 2013

  17. Immunology of Chron’s disease

  18. Autoantibodies in Crohn‘s disease • (Auto)antibodies to glycans specific for Crohn’s disease • ASCA, Main et al., 1988 • anti-chitobioside carbohydrate ab (ACCA) • anti-laminaribioside carbohydrate ab (ALCA) • anti-mannobioside carbohydrate ab (AMCA) • ELISA, Altstock et al., 2005 • Antibodies to bacterial antigens • Outer-membrane porin of E.coli (OmpC), • Flagellin CBir1 • Pseudomonas fluorescens ass. Sequence I2 • Pancreatic autoantibodies - autoantibodies to exocrine pancreas • 30% Crohn’s disease patients • indirect immunofluorescence, Stöcker et al., 1984

  19. Clumpy staining in the lumen of pancreatic acinar type 1 Speckled cytoplasmic staining in pancreatic acinar cells, type 2 Pancreatic autoantibodies, type 1 and type 2 Stöcker W et al., 1987 Scand J Gastroenterol BogdanosAutoimmun Rev 2011

  20. PAB, type 1 and type 2 Pancreatic acinus type I staining type II staining Roggenbuck D et al., 2013 Adv ClinChem Komorowski L et al., 2012 JCC BogdanosAutoimmun Rev 2011 PavlidisClin Dev Immun 2013

  21. Is there any connection between Pancreas and Colon in IBD? Pavlidis and Bogdanos Clin Dev Immun in press Roggenbuck Adv Clin Chem 2013 Bogdanos and Forbes Clin Dev Immun 2013

  22. Identification of PAB target Two-dimensional electrophoresis and immunoblot Roggenbuck D et al., 2009 Gut

  23. IFT huGP2 in HEK293 GP2 specific IgG and IgA in patients with PAB-positive and PAB-negative CD, UC, and blood donors detected by IIF using GP2 transfected HEK293 cells Roggenbuck D et al., 2009 Gut

  24. Identification of PAB target MALDI-TOF mass spectrometry:GP2, zymogen granule glycoprotein 2 Roggenbuck D et al., 2009 Gut

  25. GP2 in human intestine • Physiological roleof GP2 • not fully understood yet • homology to Tamm-Horsfall protein (uromodulin) • first line defense against microbial agents • Interaction with type 1 fimbriae of E.coli(FimH) • Transcytotic receptor in M cells – regulation of innate and acquired immunity

  26. GP2 – M cellreceptor Hase K et al., 2009 Nature

  27. Peyer‘s patches Ohno and Hase., 2010 Gut Microbes

  28. Peyer‘s patches

  29. Pancreatic autoantigen: GP2 in human intestine First confirmation of GP2 in human intestine, the side of inflammation in IBD * * A CD, n=4B CU, n=4D controls, n=5 * p<0.02 Roggenbuck et al., 2009 Gut Pavlidis Gut 2012

  30. Thus the pancreatic GP2 autoantigen is also an intestinal protein Roggenbuck et al., 2009 Gut Pavlidis Gut 2012 LiaskosClin Dev Immunol 2013

  31. Peyer‘s patches Hase K et al., 2009 Nature

  32. Scavengerreceptorbinding Hölzlet al., 2010 Cell Immunol

  33. Putative physiological function GP2 antimicrobial IgG P FAE Fim H + B Fim H + D M T D intestinal lumen mucosa associated lymphoid tissue Roggenbuck D et al., 2013 Adv ClinChem

  34. Expression of recombinant GP2 Purification of recombinant GP2 (baculovirus expression system) A reducing SDS-PAGE B immunoblot - anti-HIS C immunoblot using anti-human GP2 1 cell culture supernatant of transfected SF9 cells 2 Ni-chelate chromatography 3 anion exchange chromatography on Mono Q Roggenbuck et al., 2011 ClinChimActa

  35. Anti-GP2 IgG ELISA A: PAB-positive CD patients (n = 72) B: PAB-negative CD patients (n = 106) C: UC patients (n = 100) D: BD (n = 162) Roggenbuck and Bogdanos 2011 ClinChimActa

  36. Anti-GP2 IgA ELISA A: PAB-positive CD patients (n = 72) B: PAB-negative CD patients (n = 106) C: UC patients (n = 100) D: BD (n = 162) Roggenbuck, Bogdanoset al., 2011 ClinChimActa

  37. Disease phenotype in CD Bogdanos et al., 2012 BMC Gastroenterol

  38. Disease phenotype in CD

  39. Prevalence of CD specific Ab

  40. Disease phenotype in CD Association with disease location * * * * * Bogdanos et al., 2012 BMC Gastroenterol

  41. Disease phenotype in CD Association with disease location P = 0.0128 Pavlidiset al., 2012 Clin Dev Immunol 2012

  42. Disease phenotype in CD Association with disease behavior * * * Bogdanos D et al., 2012 BMC Gastroenterol Roggenbuck D et al., 2012 JPGN Rieder F et al., 2012 Gastroenterol

  43. At diagnosis Association with disease activity 2 months on immunosuppressive Tx 60 mo on Tx 3 mo on Tx 36 mo on Tx Correlation with disease activity? Similarity to anti-ASGPR in autoimmune hepatitis serology 12 mo on Tx Anti-ASGPR (BI) Rigopoulouet al., 2012 Autoimmun Rev Roggenbuck et al., 2012 Autoimmun Highlights

  44. Liaskos Autoimmun 2013

  45. Liaskos Autoimmun 2013

  46. GP2 expression on PBMCs unstimulated CD3 activated GP2 expression 50 * GP2 40 30 Percent expression 20 β actin 10 unstimulated CD3 activated Werner et al., 2012 J Immunol

  47. GP2 effect on epithelium Apoptosis 50 40 Percent AnV+PI- positive cells * 30 T84 ** hIECs 20 10 0 10ug/ml 20ug/ml GP2 Werner et al., 2012 J Immunol

  48. GP2 effect on epithelium Proliferation 1 * 0.8 * O.D. ** T84 0.6 hIECs 0.4 0.2 0 10ug/ml 20ug/ml GP2 Werner et al., 2012 J Immunol

  49. GP2 – phagocytosis of E-coli ** 180 * 170 Epithelial T84 Monocytes 160 150 140 Percent effect 130 120 110 100 90 GP2: 0 5ug/ml 10ug/ml Werner et al., 2012 J Immunol

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