Lecture 20 (11B) - Inflammatory Bowel Disease Flashcards
Inflammatory bowel disease affects
1:500 people in the developed world
2 major forms of IBD
- Crohn’s disease
* Ulterative colitis
Crohn’s disease
patchy transmural inflammation anywhere in GI tract
• mouth to anus
• Th1/Th17 responses
• deep
Ulcerative colitis
- superficial continuous colon lesion extending from rectum
* not well understood
Crohn’s disease peak onset
second or third decade
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
Fistulae
tracts between intestinal tissue
Crohn’s disease first described by…
Burrill Crohn, Leon Ginzburg, and Gordon Oppenheimer in 1932
• an immunological disease of the modern world
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
Regulator and effector
• in health = Treg > Th1/17
- Crohn’s disease = altered innate response, Th1(/17) > Treg –> TNFα, IFNγ, etc
- fibroblasts make MMPs
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)
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)
HIV infection indicates
CD4+ T cells are important in Crohn’s
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
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
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
In a healthy intestine, regulatory cells
are dominant (more) than effector cells
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
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
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
Some Crohn’s disease risk lock
- NOD2 - PRR
- IL-23R - cytokine receptor
- ATG16L1 - autophagy
- PTPN22 - T cell activation
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
NOD2
- NOD2 is an intracellular PRR that recognizes muramul dipeptide (MDP) - a breakdown product of peptidoglycan
- is expressed by DC and Paneth cells
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
Genes involved in autophagy, implicated in Crohn’s disease
- NOD2
- ATGL1
- IRGM
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
Move from area with little Crohn’s to area with a lot of Crohn’s
person not affected, but increase in children
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)
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
Faecalibacterium prausnitzii
across intestinal epithelium, make soluble factor that leads to Treg accumulation (IL-10 production)
• absent = less Treg
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)
IBD more common where
helminth infections are low
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
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)
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
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
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
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
