pathogenesis of crohn's disease presented on kmc,kol july, 2013
TRANSCRIPT
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Pathophysiology of intestinal manifestations of Crohn’s disease
Speaker: Dr. Dibbendhu Khanra
Chairperson: Dr. K. D. Biswas
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Discourse along history
Part IPathology
Part IIImmunology
Part IIIGenetics
Part IVFuture & beyond
1900-1950
1950-1990
1990-2010
21st century
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Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
?
1900: Sorrow of Prince Albert
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Terminal ileitisRegional ileitis
Granulomatous entreocolitisCrohn’s disease
1932
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M=F
Sedentary life style
Developed nations
OCP
Smoking
Appediculectomy
Use of refrigerator
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Part I: Pathology
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Small Bowel : 70 - 80 %
Small And Large Bowel : 50 %
Large Bowel Only : 15 - 20 %
Aphthous ulcer ‘Cobblestone’ Perianal disease
Inflammatory symptoms
Obstructive symptoms
Fistulous symptoms
Perianal diseases
Macroscopic appearance
Mycobacterium paratuberculosis
E. coli Yersinia Listeria Measles
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Transmural ulcer
Crypt abscess Aphthoid ulcer in Peyer’s patch
Non-caseating granuloma
Microscopic appearance
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Microscopic appearance: CD vs UC
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Fat halo sign Comb sign
String sign
Radiological appearance
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Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
Crohn’s disease
Surgery
Sorrow of Prince Charming
antimicrobials
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What kind of disease is Crohn’s disease?
Is it infective disease?
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Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
1950: Sorrow of Miss America
Crohn’s disease
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Part II: Immune dysregulationsPower struggle & sensitivity issues
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POWER JUSTICEV/S
Microbial Invasion
Immune response
Inflammation
GutBlood vessels
Organized war
Epithelial damage
Increased small intestinal
permeability
Malabsorption & deficiency
Dis-organized
INJUSTICE
Innate Immunity
Adaptive Immunity
Barrier function
Innate Immunity
Adaptive Immunity
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inadequate innate
immunity
Adaptive immunity
Lymphocyte
Th0
Th1 Th2 Th17
IL12IL4, 23
IL6, TGFb
IFN gamma IL4, 5 13 IL17, 21
Macrophage Neutrophil
TNFa, IL1, IL6CAM-
Integrin
Granulomatous inflammation
Superficial ulceration
Neutrophilic recruitment
Extraintestinal manifestations
Extraintestinal manifestations
Adaptive immunity
Genetic predisposition
inadequate microbial
elimination
Th1
Th2
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Abdominal pain
1. Stretch receptors stimulated as a food bolus passes through stenotic bowel
2. ganglia of the myenteric plexuses increased in size and number
3. Substance P receptors have increased around lymphoid follicles, microvasculature, and enteric neurons
Diarrhea
1. Increased mucosal permeability2. Cytokines, PG, ROS3. imbalance in the luminal
concentration of bile salts relative to dietary fat
4. Bacterial overgrowth5. Disordered colonic motility
Fever & weight loss: TNF-alpha
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Antibodies in Crohn’s disease
ASCA is present in ITB (50%) and CD (50%) both
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Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
Steroid
1950: Sorrow of Miss America
1950
Immunomodulators1960
Surgery
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What kind of disease is Crohn’s disease?
Is it immunologic disease?
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Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +ve
2000: Sorrow of a Rock diva
Crohn’s disease
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Part III: Genetics & Innate Immunity - Days of glory
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Adaptive immunit
y
Innate immunity
Immune dysregulations 2
L/O oral tolerance
L/O autophagy
L/O NODing
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T reg cells
Fox P3 transcription
factor
IL10TGF-b
Anti-inflammation
Oral tolerance T reg cells
depleted
Inflammation
L/O Oral tolerance
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L/O Autophagy
ATG16L1 protein
inadequate microbial
elimination
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Role of NOD
inadequate microbial
elimination
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Microbial invasion Innate
Immunity
Mucosal integrity
Adaptive Immunity
TLR4LPS
signaling defect
DLG 5Chr 10
OCTN 1Chr 15
NOD2/ CARD15Chr 16
TNFSF15
Genetic determinism
ATG16L1Chr 2
IL23R
CTLA4
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Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +ve
Crohn’s victim to Crohn’s survivor
Crohn’s disease
Biologics 2000
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What kind of disease is Crohn’s disease?
Is it genetic disease?
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Chronic diarrheaAbdominal cramps
Weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
2010: a magician in trouble
Crohn’s disease
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Part IV: What lies aheadTheory of everything
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NODophagy meets Autophagy
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Endoplasmic reticulum stress and unfolded protein response
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miRNA
inadequate microbial
elimination
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Chronic diarrheaAbdominal cramps
weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
A magic trick
Rapamycin2013
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What kind of disease is Crohn’s disease?
What we have learned today?
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NODophagy
Autophagy
ER stress & UPR
miRNA
Crohn’s disease
Summary 1
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Summary 2
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Summary 3
Abdominal pain
Diarrhea fistula Weight loss
Malnutrition
Stricture Mass
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Thank you
Genetic determinism
Immune injustice
Defective GUT
Crohn’s disease