The multifactorial pathogenesis of The multifactorial pathogenesis of inflammatory bowel disease inflammatory bowel disease Claudio Fiocchi Claudio Fiocchi Department of Pathobiology, Lerner Research Institute Department of Pathobiology, Lerner Research Institute Department of Gastroenterology & Hepatology Department of Gastroenterology & Hepatology The Cleveland Clinic Foundation The Cleveland Clinic Foundation Cleveland, Ohio, USA Cleveland, Ohio, USA
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The multifactorial pathogenesis of inflammatory bowel …€¦ · The multifactorial pathogenesis of inflammatory bowel disease ... Tuberculosis 1955 75 85 9565 ... F proteinF protein
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Department of Pathobiology, Lerner Research Institute Department of Pathobiology, Lerner Research Institute Department of Gastroenterology & HepatologyDepartment of Gastroenterology & Hepatology
The Cleveland Clinic FoundationThe Cleveland Clinic FoundationCleveland, Ohio, USACleveland, Ohio, USA
The clinical spectrum ofinflammatory bowel diseases (IBD)
Cumulative number of IBD patients registered in JapanUlcerative colitis Crohn’s disease
Courtesy of Dr. H. Ogata
Increasing incidence of IBD in Korea
Seoul
1990 20001995
Courtesy of Dr. Won Ho Kim
Seoul
Ulcerative colitis Crohn’s disease
1990 1995 2000
0
50
100
150
200
250
300
350
400
450
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
Hospitalized
Screened
Numbers of Chinese UC patients hospitalized and screened by endoscopy from 1990-2003
Courtesy of Dr. Qin Ouyang
Courtesy of Dr. K.L. Goh
Increasing incidence of IBD in Malaysia
Kitahora et al., 1995
Appleyard et al. Inflam Bowel Dis 10:106, 2004
Increasing incidence of IBD in Puerto Rico
0
5
10
15
20
Age
at d
iagn
osis
Age
at d
iagn
osis
19701970’’ 19801980’’0
5
10
15
20
% E
ntire
CD
pop
ulat
ion
% E
ntire
CD
pop
ulat
ion
19701970’’ 19801980’’
Changes in frequency and age of pediatric IBD
Crohn’s disease
Ulcerative colitis
Indeterminate colitis
Distribution of new onset pediatricIBD cases in Wisconsin
from 2000 to 2001
129
10
60
Kugathasan et al. J Pediatr 143:525, 2003
New IBD diagnosis
87 %6 %4 %2 %
0.5 %
General population
Asian
Other
Hispanic
African-American
Caucasian
Distribution among various racial groups andfamilial incidence of new onset pediatric IBD in Wisconsin
1st degree
2nd degree
No family history
IBD families
86 %6 %4 %2 %2 %
89 %
8 %
3 %
Kugathasan et al. J Pediatr 143:525, 2003
The incidence of The incidence of infectiousinfectious diseases has diseases has decreaseddecreasedand of and of immuneimmune disorders has disorders has increasedincreased
over the last four decades over the last four decades
IDDM
Multiple sclerosis
Crohn's disease
Asthma
1955 75 85 95
100
50
Infectious diseases
%
100
200
Immune disorders
%300
065
Hepatitis A
Rheumatic fever
Measles
Tuberculosis
1955 75 85 9565
temporarily
Bach J-F. N Engl J Med 2002; 347:911
Liver diseaseLiver disease
Heart diseaseHeart disease
19001900
DiphteriaDiphteria
BronchitisBronchitis
CancerCancer
StrokeStroke
InjuriesInjuries
DiarrheaDiarrhea
PneumoniaPneumonia
TuberculosisTuberculosis
20002000
Chronic liver diseaseChronic liver disease
Chronic kidney diseaseChronic kidney disease
SuicideSuicide
DiabetesDiabetes
Pneumonia/influenzaPneumonia/influenza
InjuriesInjuries
Chronic lung diseaseChronic lung disease
StrokeStroke
CancerCancer
Heart diseaseHeart disease
The ten leading causes of deathThe ten leading causes of deathin the United States during the last centuryin the United States during the last century
Cohen, M.L. Nature 2000, 406: 762-767
Increase inautoimmune diseases
Increase inautoimmune diseases
Increase inhost susceptibility
Restricted immunesystem stimulation
Selectivenutrition
Shelteredhousing
Lack ofparasites
Hygiene &sanitation
Clean food& water
New antigenexposure
Cohen, M.L. Nature 2000, 406: 762-767
Decrease ininfectious diseases
Decrease ininfectious diseases
Decrease inhost susceptibility
Decrease indisease transmission
Betternutrition
Betterhousing Antibiotics
Hygiene &sanitation
Safer food& water
Immunizations
The hygiene hypothesis:The hygiene hypothesis:an explanation for the rise in allergic and autoimmune diseases?an explanation for the rise in allergic and autoimmune diseases?
Epidemiological evidenceEpidemiological evidence
•• The prevalence of atopy (allergy) is directly related toThe prevalence of atopy (allergy) is directly related tosocioeconomic statussocioeconomic status and and educationeducation
Different types and concentration of bacteria inDifferent types and concentration of bacteria inthe human gastrointestinal tractthe human gastrointestinal tract
Mucosal Mucosal immuneimmune
responseresponseEntericEnteric
floraflora
The enteric flora contains 2x10The enteric flora contains 2x101414
bacteriabacteria
Composed by over 2 billionsComposed by over 2 billionscells per gram of stoolcells per gram of stool
Constituted of over 400 speciesConstituted of over 400 species
About 80% of stool dry weightAbout 80% of stool dry weightis made up by bacteriais made up by bacteria
F proteinF protein FlagellinFlagellin ssRNAssRNA CpGCpG
MyD88MyD88 MalMal TRIFTRIF TRAMTRAM
Defensins: immune and non-immune functions
Selsted ME & Oulette AJ, Nat Immunol 2005;5:551LTA
LPS (TLR4) MDP (NOD2)
Bacteria CpG (TLR9)
T-cell, monocyte,mast cell chemotaxis
Dendritic cellrecruitment
and maturation
Neovascularization,wound closure
Mast celldegranulation
Epithelial cellproliferation
Defensins and otherantimicrobial peptides
NOD2 expression in terminal ileum crypt cells
NOD2
NOD2
NOD2
NOD2
NOD2
NOD2
Lysozyme
Lysozyme
Control
Ogura Y et al., Gut 2003;52:1591
Reduced Paneth cell α-defensins and antimicrobial activityin ileal Crohn’s disease
Wehkamp Wehkamp J et al. PNAS 2005; 102:18129J et al. PNAS 2005; 102:18129
The study of the flora is as challenging, but potentially asThe study of the flora is as challenging, but potentially asrewarding as the study of geneticsrewarding as the study of genetics
The flora plays a key role in most animal models of IBD, asThe flora plays a key role in most animal models of IBD, aswell as in humanswell as in humans
The flora of IBD patients differs from that of control subjectThe flora of IBD patients differs from that of control subjects,s,is is unstableunstable and shows and shows reduced diversityreduced diversity
Some Some E. coliE. coli and and B. B. vulgatusvulgatus may play a special detrimentalmay play a special detrimentalrole in IBDrole in IBD
Characteristics of the enteric flora in IBDCharacteristics of the enteric flora in IBD
Adapted from:Adapted from: Marteau Marteau P. et al., AlimentP. et al., Aliment Pharmacol Ther Pharmacol Ther 2004; 20 (2004; 20 (SupplSuppl.):18.):18--2323
Is an IBD infectious agent like Waldo in a crowd?
ANIMAL MODELS OF IBDANIMAL MODELS OF IBDSpontaneousSpontaneous InducedInduced
Administration of Administration of Gene targeting:Gene targeting: Cell transfer intoCell transfer intoexogenous agents knock out/transgenic immunodeficienexogenous agents knock out/transgenic immunodeficient animals t animals
DD’’ Haens Haens G et al., Gastroenterology 114:262, 1998G et al., Gastroenterology 114:262, 1998
Recurrence of ileal CrohnRecurrence of ileal Crohn’’s diseases diseasebefore and after infusion of intestinal contentsbefore and after infusion of intestinal contents
Courtesy of Dr. L.Courtesy of Dr. L. DielemanDieleman
Loss of tolerance to autologous enteric flora in IBDLoss of tolerance to autologous enteric flora in IBD
Evidence implicating the gut flora in theEvidence implicating the gut flora in thepathogenesis of IBDpathogenesis of IBD
Occurrence of IBD lesions in gut segments with the Occurrence of IBD lesions in gut segments with the highest concentrations of bacteriahighest concentrations of bacteria
Increased numbers of bacteria in the mucosa of IBDIncreased numbers of bacteria in the mucosa of IBDpatientspatients
Beneficial effect of fecal stream diversion in preventingBeneficial effect of fecal stream diversion in preventingCD and recurrence upon restoration of fecal flowCD and recurrence upon restoration of fecal flow
Attenuation of IBD by antibiotics and probioticsAttenuation of IBD by antibiotics and probiotics
Immunological reactivity against bacterial antigens inImmunological reactivity against bacterial antigens inIBD patients IBD patients
Patterns of intestinal immune responsesPatterns of intestinal immune responses
POLARIZATION OF IMMUNE RESPONSES IN IBDPOLARIZATION OF IMMUNE RESPONSES IN IBD
Th1Th1 (IL(IL--12, IL12, IL--18, IFN18, IFN--γγ))
Th2Th2 (IL(IL--4, IL4, IL--5, IL5, IL--13)13)
Th1Th1 (IL(IL--2, IFN2, IFN--γγ))
““Th2Th2””(IL(IL--4, IL4, IL--5, IL5, IL--13)13)
UlcerativeUlcerativecolitis (UC)colitis (UC)
CrohnCrohn’’ssdisease (CD)disease (CD)
F. Pallone, 2002
POLARIZATION OF IMMUNE RESPONSES IN IBDPOLARIZATION OF IMMUNE RESPONSES IN IBD
Th1Th1 (IL(IL--12, IL12, IL--18, IFN18, IFN--γγ))
Th2Th2 (IL(IL--4, IL4, IL--5, IL5, IL--13)13)
Th1Th1 (IL(IL--2, IFN2, IFN--γγ))
““Th2Th2””(IL(IL--5, IL5, IL--13)13)
UlcerativeUlcerativecolitis (UC)colitis (UC)
CrohnCrohn’’ssdisease (CD)disease (CD)
Fuss IJ, et al. J Clin Invest 2004;113:1490
Distinct mucosal cytokine profiles in control, CD and UC patients
IL-1
3
IFN
-γIL
-4IL-5
0
50
100
150N
umbe
r of T
- ce l
lsX 1
04
0 1 2 3 4 5Weeks in culture with IL-2
Ulcerative colitis
Chronic nonspecific colitis
Indeterminate colitisCrohn’s disease
Normal control
Differential proliferation of biopsyDifferential proliferation of biopsy--derived Tderived T--cells incells invarious forms of intestinal inflammationvarious forms of intestinal inflammation
Differential proliferation and apoptosis ofnormal, Crohn’s disease and ulcerative colitis mucosal T-cells
ControlCDUC
0
50
100
150
200
250
300**
* *
**
*
*
*
*
Unstimulated CD2 CD3
*
*
*
*
*
0
20
40
60
* *
*
% a
popt
osis
CPM
X103
Sturm A, et al. Gut 2004;53:1624
DiDi Sabatino Sabatino A, et al. Gut 2004; 53:70A, et al. Gut 2004; 53:70
Increased numbers of apoptotic cells in the lamina propriaIncreased numbers of apoptotic cells in the lamina propriaof infliximabof infliximab--treated Crohntreated Crohn’’s disease patientss disease patients
Marks DJB et al., Lancet 2006;367:668Marks DJB et al., Lancet 2006;367:668
Impaired erythema, swelling and blood flowImpaired erythema, swelling and blood flowupon upon E. coliE. coli injection in Crohninjection in Crohn’’s diseases disease
ControlControl
CrohnCrohn’’s diseases disease
ControlControl
Leukocyte-endothelial interactions: molecular locks and keys
E n d o t h e l i a l c e l l
E n d o t h e l i a l c E n d o t h e l i a l c e l l e l l
T h e l o c k:T h e l o c k:ce l l a d h e s i o n m o l e c u l ece l l a d h e s i o n m o l e c u l e
T h e k e y:T h e k e y:c e l lc e l l--b o u n d / s e c r e t e d l i g a b o u n d / s e c r e t e d l i g a
n dn d
CD
UC
CD
NL
Increased angiogenesis in IBD mucosa
Danese S et al. Gastroenterology 2006 (in press)Danese S et al. Gastroenterology 2006 (in press)
Adh
eren
t MO
LT4
cells
/ m
m2
0
500
1000
1500
2000
2500
Unst. IL-1β LPS TNF-α IL-4 IFN-γ0
500
1000
1500
2000
2500
Unst. IL-1β LPS TNF-α IL-4 IFN-γ
CONTROL IBD
Increased leukocyte adhesiveness of IBD microvasculatureIncreased leukocyte adhesiveness of IBD microvasculature
Switch in cytokine profiles (Th1Switch in cytokine profiles (Th1 Th2) in ILTh2) in IL--1010--//-- micemiceduring the clinical course of colitisduring the clinical course of colitis
Prolonged response to infliximab therapy in earlyProlonged response to infliximab therapy in earlybut not late pediatric Crohnbut not late pediatric Crohn’’s diseases disease
0
25
50
75
100Fr
actio
nal r
emis
sion
Weeks following infliximab infusion20100 30
Kugathasan S. et al. 1999
40
EarlyEarly(n=6)(n=6)
LateLate(n=6)(n=6)
CrohnCrohn’’s disease and ulcerative colitis share epidemiological ands disease and ulcerative colitis share epidemiological andclinical features, but represent distinct entities with uniqclinical features, but represent distinct entities with uniqueuemechanisms of inflammation in each conditionmechanisms of inflammation in each condition
Environmental changesEnvironmental changes, , genetic predispositiongenetic predisposition, the , the entericentericcommensal floracommensal flora, and the , and the mucosal immune responsemucosal immune response are the keyare the keycomponents of IBD pathogenesiscomponents of IBD pathogenesis
Loss of immune toleranceLoss of immune tolerance against the autologous enteric floraagainst the autologous enteric floraappears to be a central event in IBD pathogenesis, and appears to be a central event in IBD pathogenesis, and
modulationmodulationof the floraof the flora and/or the hostand/or the host’’s s immune responseimmune response against it seemagainst it seemessential to control gut inflammationessential to control gut inflammation
Current biological therapies are a direct result of an improveCurrent biological therapies are a direct result of an improveddunderstanding of IBD pathogenesis, and further progress understanding of IBD pathogenesis, and further progress willwillcontinuecontinue to generate to generate better formsbetter forms of therapyof therapy