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