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Basic Immunology > Lecture 20 (11B) - Inflammatory Bowel Disease > Flashcards

Lecture 20 (11B) - Inflammatory Bowel Disease Flashcards

1
Q

Inflammatory bowel disease affects

A

1:500 people in the developed world

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2
Q

2 major forms of IBD

A
  • Crohn’s disease

* Ulterative colitis

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3
Q

Crohn’s disease

A

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

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4
Q

Ulcerative colitis

A
  • superficial continuous colon lesion extending from rectum

* not well understood

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5
Q

Crohn’s disease peak onset

A

second or third decade

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6
Q

Crohn’s disease symptoms

A
  • 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
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7
Q

Fistulae

A

tracts between intestinal tissue

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8
Q

Crohn’s disease first described by…

A

Burrill Crohn, Leon Ginzburg, and Gordon Oppenheimer in 1932

• an immunological disease of the modern world

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9
Q

Crohn’s disease is an inappropriate immune response to

A

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

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10
Q

Regulator and effector

A

• in health = Treg > Th1/17

  • Crohn’s disease = altered innate response, Th1(/17) > Treg –> TNFα, IFNγ, etc
  • fibroblasts make MMPs
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11
Q

Crohn’s disease is

A

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)

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12
Q

Mutations in genes involved in immune regulation can result in

A

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)

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13
Q

HIV infection indicates

A

CD4+ T cells are important in Crohn’s

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14
Q

Gut bacteria

A

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

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15
Q

Studies in germfreemice support the concept that

A

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

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16
Q

Crohn’s disease is caused by

A

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

17
Q

In a healthy intestine, regulatory cells

A

are dominant (more) than effector cells

18
Q

In Crohn’s disease, regulatory vs effector cells

A
  • either less regulatory cells than normal (so effector dominant)
  • or same amount of regulatory cells but more effector cells than usual
19
Q

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

A

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

20
Q

Crohn’s disease - multifactorial condition

genes

A
  • 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
Q

Some Crohn’s disease risk lock

A
  • NOD2 - PRR
  • IL-23R - cytokine receptor
  • ATG16L1 - autophagy
  • PTPN22 - T cell activation
22
Q

NOD2 variants

A
  • 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
Q

NOD2

A
  • NOD2 is an intracellular PRR that recognizes muramul dipeptide (MDP) - a breakdown product of peptidoglycan
  • is expressed by DC and Paneth cells
24
Q

Autophagy

A

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
Q

Genes involved in autophagy, implicated in Crohn’s disease

A
  • NOD2
  • ATGL1
  • IRGM
26
Q

IL-23 signalling in Crohn’s disease

A

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
Q

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

A

person not affected, but increase in children

28
Q

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

A

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
Q

The … is altered in Crohn’s disease

A

intestinal microbiota is altered

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

30
Q

Faecalibacterium prausnitzii

A

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

31
Q

Role for helminths

A
  • 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
Q

IBD more common where

A

helminth infections are low

33
Q

Treating IBD with Trichuris suis

A
  • 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
Q

Monoclonal antibodies for Crohn’s disease therapy

A

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
Q

Anti-TNFα therapy

Infliximab

A

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
Q

Natalizumab

α4β7

A

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
Q

Natalizumab - a cautionary tale

A
  • 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
Q

Summary

A
  • 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

Basic Immunology (15 decks)

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