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New Concepts in the Pathophysiology of Inflammatory Bowel Disease

Giorgos Bamias, MD; Mark R. Nyce, MD; Sarah A. De La Rue, PhD; and Fabio Cominelli, MD, PhD
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From University of Virginia, Charlottesville, Virginia.

Acknowledgments: The authors thank the entire personnel of the Digestive Health Center of Excellence at the University of Virginia.

Grant Support: By the United States Public Health Service/National Institutes of Health grants DK-42195, DK-44540, and DK-55812 to Fabio Cominelli and The UVa Digestive Health Research Center (P30 DK-67629).

Potential Financial Conflicts of Interest: Honoraria : F. Cominelli (UCB Pharmaceuticals, Inc., Centocor, Elan, Sigma-Tau).

Requests for Single Reprints: Fabio Cominelli, MD, PhD, Division of Gastroenterology and Hepatology, P.O. Box 800708, University of Virginia Health System, Charlottesville, VA 22908; e-mail, fc4q@virginia.edu.

Current Author Addresses: Drs. Bamias, Nyce, De La Rue, and Cominelli: Digestive Health Center of Excellence, University of Virginia, P.O. Box 800708, Charlottesville, VA 22908-0708.

Ann Intern Med. 2005;143(12):895-904. doi:10.7326/0003-4819-143-12-200512200-00007
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The innate immune system is the body's nonspecific defense against pathogens; it responds immediately or within the first few hours after a challenge. This is commonly considered the first line of defense and includes such physical barriers as the skin and the intestinal mucosa as well as immune cells that identify and remove foreign bodies. The innate immune system reacts to the chemical properties of the antigen rather than to the specific antigen itself. The acquired immune system, however, responds specifically to antigens. The antigen is processed and recognized, and immune cells that are specific to that antigen are then selectively proliferated. Memory is also a part of adaptive immunity, which improves the efficiency of future immunologic responses.

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Figure 1.
The traditional paradigm for the pathogenesis of inflammatory bowel disease (IBD).

Presentation of intraluminal antigens to mucosal lymphocytes by antigen-presenting cells (APCs) leads to the generation of effector responses. In the normal gut (left), overt inflammation is prevented by controlling the activation of mucosal effector T cells (Teff) through at least 2 distinct mechanisms. First, regulatory T-cell subpopulations (Treg) in the mucosal immune system suppress effector T-cell activity in part through the production of interleukin-10 and transforming growth factor-β. Second, control is also provided by eliminating T by apoptosis, thereby preventing undesired overexpansion. In individuals with IBD, both of these regulatory mechanisms seem to be defective ( effright). Aberrant signaling of regulatory cytokines such as transforming growth factor-β has been well described in Crohn disease.

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Figure 2.
Proposed functional significance of NOD2 mutations in Crohn disease.

Intracellular NOD receptors and transmembrane Toll-like receptors (TLRs) are important molecules for the recognition of pathogen-associated molecular patterns, activation of the innate immune system, and maintenance of mucosal homeostasis. Muramyl dipeptide, a component of the bacterial cell wall, binds to CARD15/NOD2, which then activates nuclear factor-κB (NF-κ). NOD2 is expressed in macrophages (right) and in Paneth cells at the base of intestinal crypts (left). An epithelial-oriented “loss of function” pathway may be associated with inability to effectively clear intraluminal microorganisms, as a result of decreased antibacterial peptide (defensins) secretion by Paneth cells (left). Alternatively, the “loss of function” may also affect the ability of NOD2 to attenuate signaling through TLR-2 in macrophages, the net result being enhanced NF-κB activation and proinflammatory cytokine production (right ). An alternative hypothesis describes a “gain-of-function” phenotype, that is, direct MPD/NOD2-mediated increase in NF-κB signaling, with a similar end result of increased secretion of proinflammatory cytokines and chronic intestinal inflammation. More important, none of the NOD2 mutations results in spontaneous colitis in mice.

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Figure 3.
Immunopathogenesis of chronic ileitis in SAMP1/YitFc mice.

Ileitis in SAMP1/YitFc mice develops through 2 distinct phases. Top. During the induction phase, which takes place between 4 and 8 weeks of age, there is little or no evidence of histologic injury in the terminal ileum. Defective epithelial barrier function with augmented intestinal permeability occurs early and leads to increased invasion of the lamina propria by intraluminal antigens. The original effector response is T-helper (Th1)–polarized, as indicated by increased production of intestinal interferon-γ (IFN-γ) and tumor necrosis factor (TNF) by mucosal lymphocytes. During this phase, recruitment of leukocytes into the bowel is dependent on a single adhesion molecule pathway. Bottom. At approximately 10 weeks of age, severe ileitis is established in SAMP1/YitFc mice and various immunologic pathways drive the maintenance of inflammation. The effector response that is mounted during this phase bears a mixed Th1/Th2 phenotype, with a substantial increase in Th2 cytokine production. Also, expansion of a B-cell population blocks the function of regulatory T cells (Treg) and allows the unopposed expansion of Th1 and Th2 clones. During the maintenance phase, multiple redundant adhesion pathways direct recruitment of leukocytes into the inflamed bowel. CCR9 = chemokine receptor 9; CCL25 = chemokine ligand 25; IL = interleukin; PPAR-γ = peroxisome proliferator–activated-γ; VCAM-1 = vascular cell adhesion molecule-1.

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Figure 4.
Future therapeutic approaches in inflammatory bowel disease.

On the basis of the new concepts that researchers have developed, future therapeutic strategies can be tailored to individual characteristics. In the preclinical stage, before the development of disease, strategies can be used that will prevent the onset of disease in predisposed persons (left). Strategies that address single pathways will be effective in the early or induction phases of disease development (center). Combined strategies that target multiple pathways or mechanisms will probably be required in the later or chronic phases of the disease (right). Th = T-helper.

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