D3 IBD

Question 1

IBD arrises due to

Answer 1

a breakdown of tolerance to own gut flora

Question 2

Describe change in epithelial cells due to inflammatory damage
- give an example of disease

Answer 2

Inflammatory insult e.g. LPS = perturbation of epithelial cells

1. Proliferative phase: Laminal propria produces growth factors & differentiation factors
2. Destructive: crypt hyperplasia + cytotoxic & cytolytic factors

long crypts but villi destroyed therefore cant absorb nutrients = malnourishment

e.g. celiac disease

Question 3

Chrons disease affects where

Which Th type & what cells involved

Answer 3

• Any part of GI (from mouth to anus) (patchy)
• Th1/Th17 via epithelial production of IL-18
• infiltration of macrophages and neutrophils –> leads to fibrosis

Question 4

Ulcerative colitis disease affects where
Which Th type & what cells involved
- Blocking what is protective

Answer 4

Large intestine (colon) and rectum
Continuous inflammation in inner layer of colon lining
- Th2 via IL-13 production –> which drives fibrosis
- activation of mast cells, goblet & eosinophils
Results in mast cell hyperplasia and subsequent release of inflammatory mediators
Blocking IL-4Rα is protective (and receptor for IL-13)

Question 5

What drives IBD

Answer 5

Environmental factors - smoking, antigens

Gut bacteria
- epithelial cell defect: loss of tight junction allows microbiome to enter

Abnormal immune response
- auto-antigens: cross reactivity w/ environmental antigens

Genetics
- MHC,

Question 6

Summary: list 4 key points leading to IBD

why it happens & what does this eventually lead to

Answer 6

1. Induced following interactions between genes, environment and immune system
2. Perturbation of the epithelium
3. Dysregulated inflammatory responses
4. Tissue remodelling

Question 7

What happens to sterile mice (no maternal immunity)

Answer 7

Unable to develop MALT immune response

• small/ underdeveloped Peyers patches w/ no germinal centres (no Tc production)
• Low no. IgA producing cells
• reduced CD4 cells in lamina propria
• reduced no. of aBTCR CD8 IEL
• -> dont develop IBD: present of bacteria therefore induces

Question 8

Name the below functions of the microflora

1. Metabolic
2. Trophic
3. Protective

Answer 8

1. Fermentation of non-digestible dietary products & mucus
   Salvage of energy,
   Vit K production
   Ion absorption
2. Epithelial proliferation & differentiation control
3. Protection against pathogens (barrier)
   Good bacteria

Question 9

How do probiotic work

- name one

Answer 9

Compete w/ ~pathogenic bacteria
Treg induced to modulate immune response from Th1/th17 or Th2
Increased IgA secretion - upreg production of TGFb (by Tc & epithelial cells)
Digestion of lactose
- Lactococcus

Question 10

Possible immunological intervention for the treatment of IBD (8)

Answer 10

Anti-inflammatory cytokines: IL-1ra, IL-10, IFN-a, TGF-B
Antibodies against cytokine: Anti-TNF-a, anti-IFN-y, anti-IL-12
Cytokine transcription: Anti-sense oligonucleotide against NF-kB
T helper cells: Anti-CD4
Antigen-specific: Anti-T-cell receptor (Car Tc therapy)
Adhesion molecules: Anti-sense oligonucleotide against ICAM-1, Ab against MAdCAM, a4B7
Non-specific inflammatory mediators: PGE1, leukotriene, thromboxane inhibitors or receptor antagonists, platelet activating factor antagonist, nitric oxide
Oral tolerance: Haptenised colonic proteins, Alter immunogenically & feed to problem- will restore oral tolerance, Hapten carrier effect (make it look diff to immune system)
Manipulation of luminal contents: Antibiotic treatment, probiotics, Fermented foods, Faecal transplant therapy

Question 11

Name endogenous factors defects that may alter the antigenicity of luminal antigens and/or increase
intestinal permeability

Answer 11

defects to
gastric acid, proteolytic enzymes (can make antigens less antigenic)
anti-microbial molecules (defensins, cryptidins)
trefoil peptides, neuroendocrine system, substance P

Question 12

Can early inflammation be reversed

Answer 12

Yes

Question 13

What is the relationship between no. Of antibiotics kids prescribed & disruption to microbiome

Answer 13

Positive correlation

Cures pathogenic bacteria but also wipes out microbiome –> when restored will be a diff composition

Question 14

Name mice models which dont get IBD

Answer 14

Germ free IL-2 KO, IL-10 KO, TCR-α KO, HLA-B27 tg

Question 15

Describe macrobiotic change

Answer 15

Decrease diversity
Decrease firmicutes
Increase proteobacteria
Increase instability over time