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Vol. 27, No. 4, 2009
Issue release date: November 2009
Section title: Pathogenesis of IBD
Free Access
Dig Dis 2009;27:455–464
(DOI:10.1159/000235851)

Inflammation in the Intestinal Tract: Pathogenesis and Treatment

Blumberg R.S.
Gastroenterology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass., USA
email Corresponding Author

Abstract

Over the past decade a major hypothesis has emerged for the etiopathogenesis of inflammatory bowel disease (IBD). This hypothesis proposes that IBD represents a dysregulated mucosal immune response to antigens derived from the commensal microbiota in a genetically susceptible host that initially derives from innate immune abnormalities leading to an excessive proinflammatory cytokine derived from CD4+ T cells (T-helper 1, T-helper 2, and T-helper 17 cytokines) over and above the response that is normally associated with tolerance and immunoregulation derived from T-regulatory cells. Given that the genetic predisposition has increasingly been recognized to affect the regulation of innate and adaptive immunity, intestinal epithelial cell physiologic barrier function and the potential inappropriate access of antigens to the mucosal immune system through this dysfunctional barrier function, a key point in understanding IBD pathophysiology is to understand the immunoregulatory pathways associated with the intestinal immune system as they apply to IBD. Therefore, immunogenetic pathways associated with innate and adaptive immunity, the cytokines secreted by innate and adaptive immune cells, the epithelial factors and leukocyte factors that are associated with inflammation and structures on the endothelium that regulate the recruitment of leukocytes define potential pathways that may be amenable to therapeutic manipulation in IBD.

© 2009 S. Karger AG, Basel


  

Key Words

  • Inflammatory bowel disease
  • Innate immunity
  • Adaptive immunity
  • Inflammation
  • Intestines

References

  1. Kaser A, et al: XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008;134:743–756.
  2. Hanauer SB, et al: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–333.
  3. Ito H, et al: A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 2004;126:989–996.
  4. Present DH, et al: Inflimximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–1405.
  5. Sandborn WJ, et al: Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357:228–238.
  6. Targan SR, et al: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. N Engl J Med 1997;337:1029–1035.
  7. Mannon PJ, et al: Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 2004;351:2069–2079.
  8. Hommes DW, et al: Fontulizumab, a humanized anti-interferon-γ antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn’s disease. Gut 2006;55:1131–1137.

  

Author Contacts

Richard S. Blumberg, MD
Gastroenterology Division, Brigham and Women’s Hospital
Harvard Medical School, 75 Francis Street, Thorn Research Building, Rm 1419
Boston, MA 02115 (USA)
Tel. +1 617 732 6917, Fax +1 617 264 5185, E-Mail rblumberg@partners.org

  

Article Information

Published online: November 04, 2009
Number of Print Pages : 10
Number of Figures : 5, Number of Tables : 1, Number of References : 8

  

Publication Details

Digestive Diseases (Clinical Reviews)

Vol. 27, No. 4, Year 2009 (Cover Date: November 2009)

Journal Editor: Malfertheiner P. (Magdeburg)
ISSN: 0257-2753 (Print), eISSN: 1421-9875 (Online)

For additional information: http://www.karger.com/DDI


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Over the past decade a major hypothesis has emerged for the etiopathogenesis of inflammatory bowel disease (IBD). This hypothesis proposes that IBD represents a dysregulated mucosal immune response to antigens derived from the commensal microbiota in a genetically susceptible host that initially derives from innate immune abnormalities leading to an excessive proinflammatory cytokine derived from CD4+ T cells (T-helper 1, T-helper 2, and T-helper 17 cytokines) over and above the response that is normally associated with tolerance and immunoregulation derived from T-regulatory cells. Given that the genetic predisposition has increasingly been recognized to affect the regulation of innate and adaptive immunity, intestinal epithelial cell physiologic barrier function and the potential inappropriate access of antigens to the mucosal immune system through this dysfunctional barrier function, a key point in understanding IBD pathophysiology is to understand the immunoregulatory pathways associated with the intestinal immune system as they apply to IBD. Therefore, immunogenetic pathways associated with innate and adaptive immunity, the cytokines secreted by innate and adaptive immune cells, the epithelial factors and leukocyte factors that are associated with inflammation and structures on the endothelium that regulate the recruitment of leukocytes define potential pathways that may be amenable to therapeutic manipulation in IBD.

© 2009 S. Karger AG, Basel


  

Author Contacts

Richard S. Blumberg, MD
Gastroenterology Division, Brigham and Women’s Hospital
Harvard Medical School, 75 Francis Street, Thorn Research Building, Rm 1419
Boston, MA 02115 (USA)
Tel. +1 617 732 6917, Fax +1 617 264 5185, E-Mail rblumberg@partners.org

  

Article Information

Published online: November 04, 2009
Number of Print Pages : 10
Number of Figures : 5, Number of Tables : 1, Number of References : 8

  

Publication Details

Digestive Diseases (Clinical Reviews)

Vol. 27, No. 4, Year 2009 (Cover Date: November 2009)

Journal Editor: Malfertheiner P. (Magdeburg)
ISSN: 0257-2753 (Print), eISSN: 1421-9875 (Online)

For additional information: http://www.karger.com/DDI


Article / Publication Details

First-Page Preview
Abstract of Pathogenesis of IBD

Published online: 11/4/2009
Issue release date: November 2009

Number of Print Pages: 10
Number of Figures: 5
Number of Tables: 1

ISSN: 0257-2753 (Print)
eISSN: 1421-9875 (Online)

For additional information: http://www.karger.com/DDI


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Kaser A, et al: XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008;134:743–756.
  2. Hanauer SB, et al: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–333.
  3. Ito H, et al: A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 2004;126:989–996.
  4. Present DH, et al: Inflimximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–1405.
  5. Sandborn WJ, et al: Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357:228–238.
  6. Targan SR, et al: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. N Engl J Med 1997;337:1029–1035.
  7. Mannon PJ, et al: Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 2004;351:2069–2079.
  8. Hommes DW, et al: Fontulizumab, a humanized anti-interferon-γ antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn’s disease. Gut 2006;55:1131–1137.