Pathophysiology of intestinal
manifestations of Crohn’s disease
Speaker: Dr. Dibbendhu Khanra
Chairperson: Dr. K. D. Biswa...
Part I
Pathology

19001950

Part II
Immunology

19501990

Part III
Genetics

19902010

Part IV
Future &
beyond

21st
centu...
1900: Sorrow of Prince Albert
Chronic diarrhea
Bleeding PR
Abdominal cramps
Severe weight loss
Intestinal
inflammation
Ter...
Terminal ileitis
Regional ileitis
Granulomatous entreocolitis
Crohn’s disease
M=F
Sedentary life style
Developed nations
OCP

Smoking
Appediculectomy
Use of refrigerator
Part I: Pathology
Macroscopic appearance

Aphthous ulcer
 Mycobacterium
paratuberculosis
 E. coli
 Yersinia
 Listeria
 Measles

‘Cobble...
Microscopic appearance

Transmural ulcer

Crypt abscess

Non-caseating
granuloma

Aphthoid ulcer in
Peyer’s patch
Microscopic appearance: CD vs UC
Radiological appearance
String sign

Fat halo sign

Comb sign
Sorrow of Prince Charming
Chronic diarrhea
Bleeding PR
Abdominal cramps
Severe weight loss
Intestinal
inflammation
Termina...
What kind of disease is
Crohn’s disease?

Is it infective disease?
1950: Sorrow of Miss America
Chronic diarrhea
Bleeding PR
Abdominal cramps
Severe weight loss
Intestinal
inflammation
Term...
Part II: Immune dysregulations
Power struggle & sensitivity issues
POWER

V/S

INJUSTICE
JUSTICE
Blood
vessels

Gut

Innate
Innate
Immunity
Immunity
Organized
Disorganized
war

Microbial
In...
Adaptive
immunity

inadequate
inadequate
Genetic
innate
microbial
predisposition
immunity
elimination
Adaptive
immunity

N...
Abdominal
pain
1. Stretch receptors stimulated as a
food bolus passes through stenotic
bowel
2. ganglia of the myenteric p...
Antibodies in Crohn’s disease

ASCA is present in ITB (50%) and CD (50%) both
1950: Sorrow of Miss America
Chronic diarrhea
Bleeding PR
Abdominal cramps
Severe weight loss
Intestinal
inflammation
Term...
What kind of disease is
Crohn’s disease?

Is it immunologic disease?
2000: Sorrow of a Rock diva
Chronic diarrhea
Bleeding PR
Abdominal cramps
Severe weight loss

Intestinal
inflammation
Term...
Part III: Genetics & Innate Immunity
- Days of glory
Immune dysregulations 2

L/O oral
tolerance

L/O
autophagy

L/O
NODing
L/O Oral
Oral
tolerance

T reg cells
depleted

Fox P3
transcription
factor
IL10
TGF-b

Inflammation
Antiinflammation
L/O Autophagy

ATG16L1 protein

inadequate
microbial
elimination
Role of
NOD

inadequate
microbial
elimination
NOD2/
CARD15
Chr 16

Genetic
determinism

ATG16L1
Chr 2
TLR4
LPS
signaling
defect

Microbial
invasion

Innate
Immunity

Ad...
Crohn’s victim to Crohn’s survivor
Chronic diarrhea
Bleeding PR
Abdominal cramps
Severe weight loss
Intestinal
inflammatio...
What kind of disease is
Crohn’s disease?

Is it genetic disease?
2010: a magician in trouble
Chronic diarrhea
Abdominal cramps
Weight loss

Intestinal
inflammation
Terminal ileum
involved...
Part IV: What lies ahead
Theory of everything
NODophagy meets Autophagy
Endoplasmic reticulum stress
and unfolded protein response
miRNA
inadequate
microbial
elimination
A magic trick
Chronic diarrhea
Abdominal cramps
weight loss

Intestinal
inflammation
Terminal ileum
involved
Granuloma +ve...
What kind of disease is
Crohn’s disease?

What we have learned today?
Summary 1
Summary 2
Summary 3

Abdominal
pain

Diarrhea

fistula

Weight
loss

Mal
nutrition

Stricture

Mass
Crohn’s
disease
Defective
GUT
Genetic
determinism

Immune
injustice

Thank you
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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"

  1. 1. Pathophysiology of intestinal manifestations of Crohn’s disease Speaker: Dr. Dibbendhu Khanra Chairperson: Dr. K. D. Biswas
  2. 2. Part I Pathology 19001950 Part II Immunology 19501990 Part III Genetics 19902010 Part IV Future & beyond 21st century Discourse along history
  3. 3. 1900: Sorrow of Prince Albert Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve ?
  4. 4. Terminal ileitis Regional ileitis Granulomatous entreocolitis Crohn’s disease
  5. 5. M=F Sedentary life style Developed nations OCP Smoking Appediculectomy Use of refrigerator
  6. 6. Part I: Pathology
  7. 7. Macroscopic appearance Aphthous ulcer  Mycobacterium paratuberculosis  E. coli  Yersinia  Listeria  Measles ‘Cobblestone’ Perianal disease  Inflammatory symptoms Small Bowel : 70 - 80 % Small And Large Bowel : 50 % Large Bowel Only : 15 - 20 %  Obstructive symptoms  Fistulous symptoms  Perianal diseases
  8. 8. Microscopic appearance Transmural ulcer Crypt abscess Non-caseating granuloma Aphthoid ulcer in Peyer’s patch
  9. 9. Microscopic appearance: CD vs UC
  10. 10. Radiological appearance String sign Fat halo sign Comb sign
  11. 11. Sorrow of Prince Charming Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve Crohn’s disease antimicrobials Surgery
  12. 12. What kind of disease is Crohn’s disease? Is it infective disease?
  13. 13. 1950: Sorrow of Miss America Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve Crohn’s disease
  14. 14. Part II: Immune dysregulations Power struggle & sensitivity issues
  15. 15. POWER V/S INJUSTICE JUSTICE Blood vessels Gut Innate Innate Immunity Immunity Organized Disorganized war Microbial Invasion Immune response Adaptive Adaptive Immunity Immunity Inflammation Barrier function Epithelial damage Increased small intestinal permeability Malabsorption & deficiency
  16. 16. Adaptive immunity inadequate inadequate Genetic innate microbial predisposition immunity elimination Adaptive immunity Neutrophil IL12 Th0 IL4, 23 Th1 CAMIntegrin Extraintestinal manifestations Macrophage Lymphocyte Th2 IFN gamma IL4, 5 13 Granulomatous inflammation Superficial ulceration IL6, TGFb Th17 IL17, 21 Neutrophilic recruitment TNFa, IL1, IL6 Extraintestinal manifestations
  17. 17. 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 Fever & weight loss: TNF-alpha 1. Increased mucosal permeability 2. Cytokines, PG, ROS 3. imbalance in the luminal concentration of bile salts relative to dietary fat 4. Bacterial overgrowth 5. Disordered colonic motility
  18. 18. Antibodies in Crohn’s disease ASCA is present in ITB (50%) and CD (50%) both
  19. 19. 1950: Sorrow of Miss America Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve 1950 1960 Steroid Immuno modulators Surgery
  20. 20. What kind of disease is Crohn’s disease? Is it immunologic disease?
  21. 21. 2000: Sorrow of a Rock diva Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve Crohn’s disease
  22. 22. Part III: Genetics & Innate Immunity - Days of glory
  23. 23. Immune dysregulations 2 L/O oral tolerance L/O autophagy L/O NODing
  24. 24. L/O Oral Oral tolerance T reg cells depleted Fox P3 transcription factor IL10 TGF-b Inflammation Antiinflammation
  25. 25. L/O Autophagy ATG16L1 protein inadequate microbial elimination
  26. 26. Role of NOD inadequate microbial elimination
  27. 27. NOD2/ CARD15 Chr 16 Genetic determinism ATG16L1 Chr 2 TLR4 LPS signaling defect Microbial invasion Innate Immunity Adaptive Immunity TNFSF15 IL23R CTLA4 Mucosal integrity DLG 5 Chr 10 OCTN 1 Chr 15
  28. 28. Crohn’s victim to Crohn’s survivor Chronic diarrhea Bleeding PR Abdominal cramps Severe weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve Crohn’s disease 2000 Biologics
  29. 29. What kind of disease is Crohn’s disease? Is it genetic disease?
  30. 30. 2010: a magician in trouble Chronic diarrhea Abdominal cramps Weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve Crohn’s disease
  31. 31. Part IV: What lies ahead Theory of everything
  32. 32. NODophagy meets Autophagy
  33. 33. Endoplasmic reticulum stress and unfolded protein response
  34. 34. miRNA inadequate microbial elimination
  35. 35. A magic trick Chronic diarrhea Abdominal cramps weight loss Intestinal inflammation Terminal ileum involved Granuloma +ve AFB -ve 2013 Rapamycin
  36. 36. What kind of disease is Crohn’s disease? What we have learned today?
  37. 37. Summary 1
  38. 38. Summary 2
  39. 39. Summary 3 Abdominal pain Diarrhea fistula Weight loss Mal nutrition Stricture Mass
  40. 40. Crohn’s disease Defective GUT Genetic determinism Immune injustice Thank you
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