Mechanisms

MechanismsofofDisease
Disease:
The
TheScience
Scienceof
ofIBD
IBD
Date of preparation: 06/11 2013
IBD/2013-11-01
64002
Table of Contents
IBD Background and Disease Management

Etiology and Pathophysiology

Lymphocyte Trafficking and Inflammation

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IBD Background and
Disease Management

3
 Inflammatory Bowel Disease
Description

Group of idiopathic
conditions characterized
by chronic GI tract
inflammation1

Most common subtypes are

Crohns disease and
ulcerative colitis2

Affects approximately
1.4 million Americans,
2.2 million Europeans, and
200,000 Canadians3-5

1. Knigge KL. Inflammatory bowel disease. Clin Cornerstone. 2002;4(4):49-60. 2. Eksteen B, et al. Lymphocyte homing and its role in the pathogenesis of IBD. Inflamm Bowel Dis. 2008;14(9):1298-1312. 3. Loftus
EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-1517. 4. Centers for Disease Control and Prevention.
Inflammatory bowel disease (IBD). http://www.cdc.gov/ibd. Accessed February 13, 2012. 5. The Crohns and Colitis Foundation of Canada. The burden of inflammatory bowel disease (IBD) in Canada. 2008.
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 IBD Symptoms and Complications

Crohns Disease (CD) Ulcerative Colitis (UC)

Can affect any portion of the gastrointestinal Limited to the colon and rectum1,4
tract, predominantly the ileum1,2
Inflammation is limited to mucosal
Potential transmural involvement of all tissue layer of colonic tissue1,4
layers (full-thickness inflammation)1
Symptoms may include bloody
Symptoms may include diarrhea, abdominal diarrhea, abdominal pain, weight loss,
pain, weight loss, fever, rectal bleeding, fever, anemia, rectal bleeding, and
perianal disease, signs of malnutrition, signs of malnutrition3,4
abdominal mass, and growth failure in children
and adolescents2,3
Complications may include perforated
bowel and toxic megacolon1
Complications may include bowel obstruction,
stricture, perforation, fistula, abscess, and
cancer1-3 Increased risk of colorectal cancer1
Related to length of disease
(more than 8 to 10 years)
Increased risk of colorectal cancer1
Related to length of colon involved
Related to length of disease (more than 8 to
10 years)
Related to length of colon involved

1. Crohns and Colitis Foundation of America. The Facts About Inflammatory Bowel Diseases. 2011. http://www.ccfa.org/media/pdf/PPS_Brochures/ibdfactbook. Accessed February 16, 2012. 2. National
Institute of Diabetes and Digestive and Kidney Diseases. Crohns disease. 2011. http://digestive.niddk.nih.gov/ddiseases/pubs/crohns/. Accessed March 28, 2012. 3. Podolsky DK. Inflammatory bowel disease. N
Engl J Med. 2002;347(6):417-429. 4. National Institute of Diabetes and Digestive and Kidney Diseases. Ulcerative colitis. 2011. http://digestive.niddk.nih.gov/ddiseases/pubs/colitis/. Accessed March 28, 2012.
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 Economic Burden of IBD
IBD Direct Costs ($5.2 Billiona in US)1
Inpatient Costs1 Outpatient Costs1 Medication Costs1
Medical ER Visits Outpatient
Surgical Office Visits
GI Endoscopy
Lab, Pathology
Radiology

a$3.1 billion for CD, $2.1 billion for UC.1

In the US, the public health burden of IBD, including economic costs, is quite substantial1

Annual indirect costs are estimated at an additional $5.5 billion in the US, between 8 billion and 28 billion
in Europe, and over $1 billion in Canada2-5

In addition, productivity losses due to absenteeism and short-term disability also contribute to the economic
burden of IBD6

1. Kappelman MD, et al. Direct healthcare costs of Crohns disease and ulcerative colitis in United States children and adults. Gastroenterol. 2008;135(6):1907-1913. 2. Park KT, et al. Inflammatory bowel disease-attributable costs and
cost-effective strategies in the United States: a review. Inflamm Bowel Dis. 2011;17(7):1603-1609. 3. Yu AP, et al. The costs of Crohns disease in the United States and other Western countries : a systematic review. 2008;24(2):319-328.

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4. Cohen RD, et al. Systematic review: the costs of ulcerative colitis in Western countries. Aliment Pharmacol Ther. 2010;31(7):693-707. 5. Canadian Digestive Health Foundation. Statistics. http://www.cdhf.ca/digestive-
disorders/statistics.shtml. Accessed February 22, 2012. 6. Gibson TB, et al. The direct and indirect cost burden of Crohns disease and ulcerative colitis. J Occup Environ Med.2008; 50(11):1261-1272.
 Clinical and Social Challenges of IBD

Interference Clinical
Psychosocial
With Daily Features
Burden
Activities

In a survey of patients with IBD Results from two surveys (N=4514 About 50% of patients with UC have
(n=5576 evaluable respondents) evaluable respondents) of a relapse in any year5
by European national IBD patient Canadian patients with IBD, or a
organizations affiliated with the similar bowel disorder, Approximately 70% to 80% of
EFCCA1: demonstrated higher rates of patients with CD will require
depression in adult patients surgery within their lifetime5
Approximately 75% of patients compared to the general
reported that symptoms affect population2
In one study of 30 patients with CD,
ability to enjoy leisure recurrent inflammation was
activities1 Delayed puberty and body image observed in 73% and 93% of patients
issues in some younger patients3,4 3 months and 1 year post-surgery,
Approximately 69% of patients
respectively6
reported that symptoms affect
ability to perform at work1
Social awkwardness due to
disease symptoms and medication
side effects among some children
and adolescents4

EFCCA, European Federation of Crohns and Ulcerative Colitis Associations

1. Ghosh S, et al. Impact of inflammatory bowel disease on quality of life: results of the European Federation of Crohns and Ulcerative Colitis Associations (EFCCA) patient survey. J Crohns Colitis. 2007;1(1):10-20. 2.Fuller-Thomson E, et al. Depression and
inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflamm Bowel Dis. 2006;12(8):697-707. 3. Crohns and Colitis Foundation of America. The Facts About Inflammatory Bowel Diseases. 2011.
http://www.ccfa.org/media/pdf/PPS_Brochures/ibdfactbook. Accessed February 16, 2012. 4. Herzer M, et al. Patient and parent psychosocial factors associated with health-related quality of life in pediatric inflammatory bowel disease. 7
J Pediatr Gastroenterol Nutr. 2011;52(3):295-299. 5. Carter MJ, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53(suppl V):v1-v16. 6. Olaison G, et al. Natural course of Crohns disease after ileocolic resection:
endoscopically visualized ileal ulcers preceding symptoms. Gut. 33(3):331-335.
Etiology and
Pathophysiology

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 While the Causes of IBD Are Unknown,
Several Hypotheses Have Been Suggested by Studies

Chronic
Genetic
Predisposition + Environmental
Triggers + Immune
System = and Aberrant
Inflammation

Over 100 potential Foreign substances (antigens) Bacteria may stimulate Once the inflammation is
susceptibility may be the immune system to produce triggered, the IBD
genes identified1 direct cause of inflammation2 inflammation2 patients immune system
has difficulty turning off
Genes involved in ability to the immune response2
recognize bacteria
(eg, NOD2) and autophagy (eg,
ATG16L1)1

Risk Factors
Age more likely among younger patients3
Ethnicity more likely among Caucasians, in particular Ashkenazi Jews3
Family history 10 to 30 times greater risk if close relative has disease2
Geography more common in US and Europe4,5
Smoking Active smokers are more than 2 times as likely to develop CD than nonsmokers, but less
likely to develop UC3

1. Vermeire S, et al. Inflammatory bowel disease and colitis: new concepts from the bench and the clinic. Curr Opin Gastroenterol. 2011;27(1):32-37. 2. Crohns and Colitis Foundation of America. About Crohns disease. 2009.
http://www.ccfa.org/info/about/crohns. Accessed March 28, 2012. Accessed March 28, 2012. 3. Crohns and Colitis Foundation of America. The facts about inflammatory bowel diseases. 2011. http://www.ccfa.org/media/pdf/PPS_Brochures/ibdfactbook.
Accessed March 28, 2012. 4. Crohns and Colitis Foundation of America. About the epidemiology of IBD. 2009. http://www.ccfa.org/about/press/epidemiologyfacts. 5. Kappelman MD, et al. The prevalence and geographic distribution of Crohn's disease and 9
ulcerative colitis in the United States. Clin Gastroenterol Hepatol. 2007;5(12):1424-1429.
The GI Tract Is a Tightly Controlled
Environment

Gut Lumen
Mucus

Epithelium

Lamina Propria

Lymphocyte
Endothelium
Blood Vessel

Intestinal Mucosa [microscopic view]

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 Normal Host Defenses in the Gut
Bacteria and Dietary Antigens
Within Gut Lumen

Epithelium

Dendritic Cell Tight Junctions

Protective
(Antigen Presenting Cell) Between Cells
Mucus Layer
Lamina Propria
Lymphocyte
Macrophage

Circulating Lymphocytes

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 Inflammatory Bowel Disease Reflects an Imbalance
of Inflammatory Response

Disrupted Protective 1 Dendritic cells

Mucus Layer 2 sample luminal
Dendritic cells
bacteria
present antigen

3 Proinflammatory
cytokines released
(eg, TNF-, interleukins)

4 Increase in
adhesion molecules Increase in
vascular permeability
1. Sartor RB. Mechanisms of disease: pathogenesis of Crohns disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(7):390-407. 2. Shih DQ, et al. Insights into IBD pathogenesis. Curr
Gastroenterol Rep. 2009;11(6):473-480. 3. Sewell GW, et al. The immunopathogenesis of Crohns disease: a three-stage model. Curr Opin Immunol. 2009;21(5):506-513. 4. Koizumi M, et al. Expression of 12
vascular adhesion molecules in inflammatory bowel disease. Gastroenterol. 1992;103(3):840-847.
1. Esposito E, et al. TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Curr
Med Chem. 2009;16(24):3152-3167. 13
 Accumulation of Excess Infiltrating
Lymphocytes Is a Hallmark of IBD

Inappropriate and
sustained recruitment of
inflammatory T cells

Infiltrating
Lymphocytes

Vascular Permeability

1. Lee SC, et al. Cutaneous injection of human subjects with macrophage inflammatory protein-1 induces significant recruitment of neutrophils and monocytes. J Immunol. 2000;164(6):3392
3401. 2. Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 2006;12(suppl 1):S3-S9. 3. Xavier RJ, et al. Unravelling the 14
pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427-434.
 Lymphocyte Migration Reflects the Presence of
Tissue-Specific Adhesion Molecules

Adhesion Molecule

Integrin

1. Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767-804. 2. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity
and diversity. Cell. 1991;67(6):1033-1036. 3. Picker LJ, et al. Physiological and molecular mechanisms of lymphocyte homing. Annu Rev Immunol. 1992;10:561-591. 4. Springer TA. Traffic
signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994;76(2):301-314.
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Lymphocyte Trafficking
and Inflammation

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 Lymphocytes Are Migratory Cells
That Traffic to Specific Tissues
Integrins,
Chemokine
Receptors1,2

Adhesion
Molecules,
Chemokines1,2

Intricate system to guide lymphocytes to

areas of inflammation3

Imprinting of activated lymphocytes

allows for preferential migration into
tissues3

1. Sheriden BS, et al. Regional and mucosal memory T cells. Nat Immunol. 2011;12(6):485-491. 2. von Andrian UH, et al. T-cell function and migration. N Engl J Med. 2000;343(14):1020-1034.
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3. Salmi M, et al. Lymphocyte homing to the gut: attraction, adhesion, and commitment. Immunol Rev. 2005;206:100-113.
 Lymphocyte Trafficking Requires a
Multistep Adhesion Cascade
Chemo-
E-Selectin P-Selectin PNAd VCAM-1 MAdCAM-1 Attractants* ICAM-2 ICAM-1 VCAM-1 MAdCAM-1

Glycoprotein (Activated) (Activated)

or glycolipid PSGL-1 L-Selectin 41 47 7 TMR L2 M2 41 47

Tethering Rolling Activation Arrest

Lymphocyte

* Chemokines, C5a, PAF, LTB4, formyl peptides

1. von Andrian UH, et al. T-cell function and migration. N Engl J Med. 2000;343(14):1020-1034.
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 Lymphocyte Trafficking to the Gut

e.g.
47 integrin
CCR9 receptor

Several molecules are involved in the

lymphocyte trafficking/adhesion cascade1

However, only a few are responsible for

e.g. mucosal specificity of the lymphocyte homing
MAdCAM-1
process. Among these are2,3:
CCL25 CCR9 chemokine receptor and its ligand CCL25
47 integrin and its ligand MAdCAM-1

1. von Andrian UH, et al. T-cell function and migration. N Engl J Med. 2000;343(14):1020-1034. 2. Salmi M, et al. Lymphocyte homing to the gut: attraction, adhesion, and commitment.
Immunol Rev. 2005;206:100-113. 3. Koenecke C, et al. CCR9 and inflammatory bowel disease. Expert Opin Ther Targets. 2009;13(3):297-306. 19
 Multiple Chemokines Have Been
Implicated in IBD

Chemokines are a family of small proteins that play an important role in

recruitment and activation of lymphocytes1,2

Biological effects of chemokines result from binding to chemokine receptors1,2

Several chemokines and their receptors play a role in homeostasis of mucosal

immunity and pathogenesis of IBD. Some examples include:2
CCL20-CCR6
CCL25-CCR9
CCL28-CCR10

1. Yoshie O, et al. Chemokines in immunity. Adv Immunol. 2001;78:57-110. 2. Nishimura M, et al. Chemokines as novel therapeutic targets for inflammatory bowel disease. Ann N Y Acad Sci.
2009;1173:350-356. 20
 Lymphocyte Recruitment Into Gut Mucosa
Role of 47 and MAdCAM-1
47-MAdCAM-1 interactions likely
mediate selective lymphocyte
trafficking to normal GI mucosa and
MAdCAM-1 gut-associated tissues1

47
integrin

MAdCAM-1
Lymphocyte Integrins

1. Briskin M, et al. Human mucosal addressin cell adhesion molceule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol. 1997;151(1):97-110.
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 47 and MAdCAM-1
Implicated in IBD
MAdCAM-1 expression is increased at sites of
inflammation in IBD1

47 and MAdCAM-1 adhesion mechanism may be

closely involved in lymphocyte trafficking to the
site of inflammation in the gut1

MAdCAM-1MAdCAM-1

Lymphocyte 47 Integrin

1. Briskin M, et al. Human mucosal addressin cell adhesion molceule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol. 1997;151(1):97-110.
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 In summary
IBD is characterized by chronic GI tract inflammation, and can cause debilitating
symptoms and serious clinical complications.

The etiology of IBD likely involves a complex interplay of genes, environmental triggers,
and immune-mediated reactions that culminate in chronic inflammation. Once the
inflammatory process is triggered, the immune system has difficulty shutting down its
response.

TNF is increased in the mucosa and serum of patients with IBD. The actions of TNF
contribute to the uncontrolled inflammatory response and ensuing intestinal tissue
damage that are characteristic of IBD and some other inflammatory diseases.

Although a number of molecules are involved in lymphocyte trafficking, only a few are
responsible for mucosal specificity of the lymphocyte homing process.
Among these are the chemokine-receptor pair CCL25-CCR9 and the 47
integrin/MAdCAM-1 adhesion mechanism.

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