pathogenesis of Crohn's disease presented on KMC,kol july, 2013
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Transcript of pathogenesis of Crohn's disease presented on KMC,kol july, 2013
Pathophysiology of intestinal manifestations of Crohn’s disease
Speaker: Dr. Dibbendhu Khanra
Chairperson: Dr. K. D. Biswas
Discourse along history
Part IPathology
Part IIImmunology
Part IIIGenetics
Part IVFuture & beyond
1900-1950
1950-1990
1990-2010
21st century
Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
?
1900: Sorrow of Prince Albert
Terminal ileitisRegional ileitis
Granulomatous entreocolitisCrohn’s disease
1932
M=F
Sedentary life style
Developed nations
OCP
Smoking
Appediculectomy
Use of refrigerator
Part I: Pathology
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
Transmural ulcer
Crypt abscess Aphthoid ulcer in Peyer’s patch
Non-caseating granuloma
Microscopic appearance
Microscopic appearance: CD vs UC
Fat halo sign Comb sign
String sign
Radiological appearance
Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
Crohn’s disease
Surgery
Sorrow of Prince Charming
antimicrobials
What kind of disease is Crohn’s disease?
Is it infective disease?
Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
1950: Sorrow of Miss America
Crohn’s disease
Part II: Immune dysregulationsPower struggle & sensitivity issues
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
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
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
Antibodies in Crohn’s disease
ASCA is present in ITB (50%) and CD (50%) both
Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
Steroid
1950: Sorrow of Miss America
1950
Immunomodulators1960
Surgery
What kind of disease is Crohn’s disease?
Is it immunologic disease?
Chronic diarrheaBleeding PR
Abdominal crampsSevere weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +ve
2000: Sorrow of a Rock diva
Crohn’s disease
Part III: Genetics & Innate Immunity - Days of glory
Adaptive immunit
y
Innate immunity
Immune dysregulations 2
L/O oral tolerance
L/O autophagy
L/O NODing
T reg cells
Fox P3 transcription
factor
IL10TGF-b
Anti-inflammation
Oral tolerance T reg cells
depleted
Inflammation
L/O Oral tolerance
L/O Autophagy
ATG16L1 protein
inadequate microbial
elimination
Role of NOD
inadequate microbial
elimination
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
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
What kind of disease is Crohn’s disease?
Is it genetic disease?
Chronic diarrheaAbdominal cramps
Weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
2010: a magician in trouble
Crohn’s disease
Part IV: What lies aheadTheory of everything
NODophagy meets Autophagy
Endoplasmic reticulum stress and unfolded protein response
miRNA
inadequate microbial
elimination
Chronic diarrheaAbdominal cramps
weight loss
Intestinal inflammation
Terminal ileum involved
Granuloma +veAFB -ve
A magic trick
Rapamycin2013
What kind of disease is Crohn’s disease?
What we have learned today?
NODophagy
Autophagy
ER stress & UPR
miRNA
Crohn’s disease
Summary 1
Summary 2
Summary 3
Abdominal pain
Diarrhea fistula Weight loss
Malnutrition
Stricture Mass
Thank you
Genetic determinism
Immune injustice
Defective GUT
Crohn’s disease