Lecture 20 (11B) - Inflammatory Bowel Disease Flashcards Preview

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Flashcards in Lecture 20 (11B) - Inflammatory Bowel Disease Deck (38):
1

Inflammatory bowel disease affects

1:500 people in the developed world

2

2 major forms of IBD

• Crohn's disease
• Ulterative colitis

3

Crohn's disease

patchy transmural inflammation anywhere in GI tract
• mouth to anus
• Th1/Th17 responses
• deep

4

Ulcerative colitis

• superficial continuous colon lesion extending from rectum
• not well understood

5

Crohn's disease peak onset

second or third decade

6

Crohn's disease symptoms

• bloody diarrhea
• abdominal pain
• weight loss
• failure to thrive in youth
• remitting and relapsing course
• can cause strictures and fistulae
• extra-intestinal manifestations occur in 1/3 of patients (skin/eye inflammation)
• currentmedical and surgical treatments inadequate
• recurrence after surgery common
• repeated surgery can lead to intestinal failure

7

Fistulae

tracts between intestinal tissue

8

Crohn's disease first described by...

Burrill Crohn, Leon Ginzburg, and Gordon Oppenheimer in 1932
• an immunological disease of the modern world

9

Crohn's disease is an inappropriate immune response to

commensal bacteria
• the immune system responds to commensal bacteria as if they were pathogens and attempts to clear the infection
• result - chronic inflammation

10

Regulator and effector

• in health = Treg > Th1/17

• Crohn's disease = altered innate response, Th1(/17) > Treg --> TNFα, IFNγ, etc
• fibroblasts make MMPs

11

Crohn's disease is

immune mediated
• bone marrow transplantation can "cure" Crohn's disease
- 6 patients with Crohn's disease and leukemia
--> allogenic bone marrow transplant
= 1 dead, 4 crohn's free, 1 recurs (chimeric - mixed immune system)

12

Mutations in genes involved in immune regulation can result in

intestinal inflammation (not IBD, shares features)
• IPEX = X-linked, results from mutations in Foxp3 gene
• IL-10 receptor genes (IL10RA, IL10RB)
• genes encoding the PHOX enzyme complex used by phagocytes to generate reactive oxygen species that kill bacteria. mutations lead to chronic granulomatous disease (CGD)

13

HIV infection indicates

CD4+ T cells are important in Crohn's

14

Gut bacteria

are the antigen in Crohn's disease
• no evidence for a specific pathogen - commensals
• disease occurs when bacteria are most numerous
• diversion of the fecal stream can lead to disease remission
• re-exposure to fecal contents leads to recurrence
• antibiotics can have some impact
• disase associated with changes in the microbiota

15

Studies in germfreemice support the concept that

intestinal inflammation is driven by gut bacteria
• disruption of many genes involved in immune regulation lead to colitis - only when bacteria are present
• IL-10 signalling defects
• no bacteria = no disease

16

Crohn's disease is caused by

Th1 CD4+ T cellss
• CD4+ T cells below are all elevated in Crohn's disease
• IFNγ, IL-12, IL-23

17

In a healthy intestine, regulatory cells

are dominant (more) than effector cells

18

In Crohn's disease, regulatory vs effector cells

• either less regulatory cells than normal (so effector dominant)
• or same amount of regulatory cells but more effector cells than usual

19

Crohn's disease is a complex multifactorial condition without a single cause

• both genetic and environmental factors (gut microbiota, diet, smoking, vitamin D) are implicated

20

Crohn's disease - multifactorial condition
genes

• concordance rates for monozygotic twins is up to 50%
• having a sibling with the disease increases risk up to 35-fold
• 200 genetic variants are now associated with Crohn's disease
• many suggestive of genes associated with innate immunity, T cell activation, or intestinal barrier function
• but the risk associated with each variant is small
• but even now only 40% of the effect of genes can be accounted for
• but these are markers of variation, not necessarily causal genes
• but the biology is poorly understood

21

Some Crohn's disease risk lock

• NOD2 - PRR
• IL-23R - cytokine receptor
• ATG16L1 - autophagy
• PTPN22 - T cell activation

22

NOD2 variants

• NOD2 is an intracellular PRR that recognizes muramul dipeptide (MDP) - a breakdown product of peptidoglycan
• is expressed by DC and Paneth cells

variants
• 3 major variants in ligand recognition domain are associated with Crohn's
• account for about 15% of Crohn's
• increase disease risk 2- to 4-fold for heterozygotes, 15- to 40-fold for homozygotes/cmpound heterozygotes
--> loss of function

23

NOD2

• NOD2 is an intracellular PRR that recognizes muramul dipeptide (MDP) - a breakdown product of peptidoglycan
• is expressed by DC and Paneth cells

24

Autophagy

a cellular process used to remove effete organelles
• utilized in the immune system to eliminate pathogens and generate peptides for presentation
• NOD2, ATGL1, IRGM = genes involved in autphagy, implicated in Crohn's disease

25

Genes involved in autophagy, implicated in Crohn's disease

• NOD2
• ATGL1
• IRGM

26

IL-23 signalling in Crohn's disease

multiple genes involved in IL-23 signalling are associated with Crohn's disease, supporting animal data that IL-23 is important for intestinal inflammation

27

Move from area with little Crohn's to area with a lot of Crohn's

person not affected, but increase in children

28

Crohn's disease - an immunological disease of the modern world

as infectious diseases have declined, diseases linked to over-activity of the immune system have increased
• the hygiene hypothesis attempts to explain this
(less exposed to key microbes in youth in clean, developed areas)

29

The ... is altered in Crohn's disease

intestinal microbiota is altered

dysbiosis in Crohn's disease
• reduced bacterial diversity
• increased adherent - invasive E. coli
• decreased Faecalibacterium prausnitzii

30

Faecalibacterium prausnitzii

across intestinal epithelium, make soluble factor that leads to Treg accumulation (IL-10 production)
• absent = less Treg

31

Role for helminths

• co-evolution of host and worms
• co-existence facilitated by worms ability to manipulate host immune response to reduce inflammation
• potential to harness these effects to treat inflammatory disease

(worms induce regulatory response)

32

IBD more common where

helminth infections are low

33

Treating IBD with Trichuris suis

• pig whipworm
• survives in people for a few months (because usually in pigs)
• remains in gut
• safe
• clinical trials in IBD

• need bigger studies
• UC and Crohn's

34

Monoclonal antibodies for Crohn's disease therapy

Infilximab (anti-TNFα)
• antibody from mouse, people's antibodies kill it (foreign)
• replace mouse Ig with increasing amount of humans
• all but variable region replaced with human Ig
(part that specifies - receptor - still mouse)

35

Anti-TNFα therapy
(Infliximab)

major impact on treatment of Crohn's disease, rheumatoid arthritis, psoriasis
BUT
• some patients don't respond
• some lose response
• potential complications with infancy and malignancy
• many anti-cytokine therapies have not worked well

36

Natalizumab
(α4β7)

a humanized monoclonal antibody to α4 integrin
• reacts with α4β7 and α4β1
(α4β7 integrin to MAdCAM-1 on intestinal epithelium)
• Natalizumab blocks this
• activity against α4β7 blocks lymphocyte recruitment to the gut - clinical benefit in Crohn's disease and MS

37

Natalizumab - a cautionary tale

• a small number of treated patients developed fatal PML (progressive multifocal leukoencephalopathy)
• caused by reactivation of a latent JC virus infection
• related to immune surveillance of CNS?
• only in context of other immunosuppressive drugs? α4β1 for surveillance
• risk 1:1,000
• more selective anti-α4β7 antibodies are now entering the clinic for treatment of IBD

38

Summary

• the immune system responds to commensal bacteria as if they were pathogens
• disease is mediated by CD4+ T Cells - Th1 (and Th17)
• defective innate handling of bacteria underlies the dysregulated T cell response
• biological drugs that modulate the immune system are already in the clinic for Crohn's disease