D3 IBD Flashcards
IBD arrises due to
a breakdown of tolerance to own gut flora
Describe change in epithelial cells due to inflammatory damage
- give an example of disease
Inflammatory insult e.g. LPS = perturbation of epithelial cells
- Proliferative phase: Laminal propria produces growth factors & differentiation factors
- Destructive: crypt hyperplasia + cytotoxic & cytolytic factors
long crypts but villi destroyed therefore cant absorb nutrients = malnourishment
e.g. celiac disease
Chrons disease affects where
Which Th type & what cells involved
- 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
Ulcerative colitis disease affects where
Which Th type & what cells involved
- Blocking what is protective
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)
What drives IBD
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,
Summary: list 4 key points leading to IBD
why it happens & what does this eventually lead to
- Induced following interactions between genes, environment and immune system
- Perturbation of the epithelium
- Dysregulated inflammatory responses
- Tissue remodelling
What happens to sterile mice (no maternal immunity)
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
Name the below functions of the microflora
- Metabolic
- Trophic
- Protective
- Fermentation of non-digestible dietary products & mucus
Salvage of energy,
Vit K production
Ion absorption - Epithelial proliferation & differentiation control
- Protection against pathogens (barrier)
Good bacteria
How do probiotic work
- name one
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
Possible immunological intervention for the treatment of IBD (8)
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
Name endogenous factors defects that may alter the antigenicity of luminal antigens and/or increase
intestinal permeability
defects to
gastric acid, proteolytic enzymes (can make antigens less antigenic)
anti-microbial molecules (defensins, cryptidins)
trefoil peptides, neuroendocrine system, substance P
Can early inflammation be reversed
Yes
What is the relationship between no. Of antibiotics kids prescribed & disruption to microbiome
Positive correlation
Cures pathogenic bacteria but also wipes out microbiome –> when restored will be a diff composition
Name mice models which dont get IBD
Germ free IL-2 KO, IL-10 KO, TCR-α KO, HLA-B27 tg
Describe macrobiotic change
Decrease diversity
Decrease firmicutes
Increase proteobacteria
Increase instability over time
