1. Crohn's disease is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract from mouth to anus, caused by a dysregulated immune response to the gut microbiome in genetically predisposed individuals. 2. Over the 20th century, research into Crohn's disease progressed from viewing it as an infectious disease, to recognizing its immunological basis involving T cell dysregulation and inflammatory cytokines like TNF-alpha. 3. Genetic factors were identified in the late 20th century, including mutations in autophagy and bacterial sensing genes like NOD2 that impair the innate immune response to gut microbes.

1. Pathophysiology of intestinal
manifestations of Crohn’s disease
Speaker: Dr. Dibbendhu Khanra
Chairperson: Dr. K. D. Biswas

2. Part I
Pathology
19001950
Part II
Immunology
19501990
Part III
Genetics
19902010
Part IV
Future &
beyond
21st
century
Discourse along history

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. Terminal ileitis
Regional ileitis
Granulomatous entreocolitis
Crohn’s disease

5. M=F
Sedentary life style
Developed nations
OCP
Smoking
Appediculectomy
Use of refrigerator

6. Part I: Pathology

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. Microscopic appearance
Transmural ulcer
Crypt abscess
Non-caseating
granuloma
Aphthoid ulcer in
Peyer’s patch

9. Microscopic appearance: CD vs UC

10. Radiological appearance
String sign
Fat halo sign
Comb sign

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. What kind of disease is
Crohn’s disease?
Is it infective disease?

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. Part II: Immune dysregulations
Power struggle & sensitivity issues

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. 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. 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. Antibodies in Crohn’s disease
ASCA is present in ITB (50%) and CD (50%) both

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. What kind of disease is
Crohn’s disease?
Is it immunologic disease?

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. Part III: Genetics & Innate Immunity
- Days of glory

23. Immune dysregulations 2
L/O oral
tolerance
L/O
autophagy
L/O
NODing

24. L/O Oral
Oral
tolerance
T reg cells
depleted
Fox P3
transcription
factor
IL10
TGF-b
Inflammation
Antiinflammation

25. L/O Autophagy
ATG16L1 protein
inadequate
microbial
elimination

26. Role of
NOD
inadequate
microbial
elimination

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. 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. What kind of disease is
Crohn’s disease?
Is it genetic disease?

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. Part IV: What lies ahead
Theory of everything

32. NODophagy meets Autophagy

33. Endoplasmic reticulum stress
and unfolded protein response

34. miRNA
inadequate
microbial
elimination

35. A magic trick
Chronic diarrhea
Abdominal cramps
weight loss
Intestinal
inflammation
Terminal ileum
involved
Granuloma +ve
AFB -ve
2013
Rapamycin

36. What kind of disease is
Crohn’s disease?
What we have learned today?

37. Summary 1

38. Summary 2

39. Summary 3
Abdominal
pain
Diarrhea
fistula
Weight
loss
Mal
nutrition
Stricture
Mass

40. Crohn’s
disease
Defective
GUT
Genetic
determinism
Immune
injustice
Thank you