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PATH30003- Frontiers in Human Disease > Lecture 20- IBD; Crohn's disease > Flashcards

Lecture 20- IBD; Crohn's disease Flashcards

1
Q

2 primary functions of the GIT

A
  • absorption of nutrients

- barrier between environment and internal organs (ensure bacteria don’t get into lumen)

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2
Q

GIT is a reservoir of?

A

important nerve cell reservoir of the peripheral nervous system

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3
Q

is GIT an endocrine or exocrine organ?

A

endocrine

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4
Q

what does the GIT have a physiological interaction with?

A

the microbiota

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5
Q

where is IBD prominent?

A
  • westernised countries (low with increasing incidence)
  • environmental influence
  • eastern asia- increasing due to life changes, westernised diet
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6
Q

IBD subdivided into?

A

Crohn’s disease and ulcerative colitis

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7
Q

compare UC and CD in terms of localisation of disease

A 
UC
- limited to inner lining of intestinal wall
-distal colon, rectum
-superficial
-continuous 
CD
- deep inflammation
-transumral, cross barrier, goes to inner layer, affect other tissues 
-ascending colon, ileum 
-discontinuous (skip lesions)
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8
Q

what is the distinguishing symptom between CD and UC?

A

CD- continuous evolution with relapsing and remitting stages (periods when feeling normal and disease comes back)
UC- continuous evolution with severe and lighter stages (disease always present, severity changes)

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9
Q

IBD patients have an increased risk of?

A

colorectal cancer

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10
Q

common symptoms between UC and CD?

A
  • abdominal pain, diarrhea, rectal bleeding
  • anal alterations
  • alterations of general condition (fatigue, weight loss)
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11
Q

possible complications of IBD

A

bowel obstruction
ulcers
malnutrition

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12
Q

CD- type of onset

A

bimodal

  • 15-30yrs
  • 55-60yrs
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13
Q

epidemiology of CD

A

higher in USA, Northern Europe, Australia

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14
Q

environmental influencers for CD

A
  • place of residence (affects diet you’re exposed to)
  • immigrants from low incidence countries see risk increase when coming to high risk countries
  • role of gut microbiota
  • smoking (protective for UC)
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15
Q

genetic component for CD

A

strong genetic component

  • > 70 susceptibility genes
  • ethnicity (caucasians, ashkenazi jews- higher risk)
  • family history (higher risk- close relative has disease)
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16
Q

CD, immune response and microbiota, genetic factor statement

A

abnormal immune response to the intestinal microbiota in genetically predisposed individuals

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17
Q

what is important for CD diagnosis?

A

determination of inflammatory state crucial for assessment of disease activity and tailoring therapy

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18
Q

comparison between invasive non-invasive methods to diagnose CD

A 
invasive- analyse biopsies
- time consuming and expensive
non-invasive
- markers
-indirect assessment of disease activity
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19
Q

healthy intestine vs CD intestine

A

healthy
-smooth and vascularised
CD
- superficial- inflammation, areas in between normal
-advanced- granulomas, huge infiltration of immune cells

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20
Q

current treatments for CD

A
  • anti inflammatory
  • immunosuppressive drugs (steroids)
  • surgery
  • anti - TNFalpha
  • NO life long cure
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21
Q

what two things are required to be understood to get a diagnosis better and earlier and make better treatments?

A
  • how intestinal homeostasis works

- what causes the disease

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22
Q

what are transit amplifying cells in the intestine

A

heavily proliferating cells, bulk up number of epithelial cells , push each other up

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23
Q

what cells do the stem cells in the intestine make?

A

absorptive cells
goblet cells
enteroendocrine cells
tuft cells (less known antibacterial cells)

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24
Q

what is anoikis?

A

cell death

-cells detach from layer and degrade in lumen at the top of the villus

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25
paneth cells in crypts
remain at the bottom, dont migrate up, remain interspersed with stem cells, number doesnt increase
26
what does the epithelial layer of the intestine serve a barrier between?
gut and environment | - first barrier
27
what are the 3 main functional/protective barriers against pathogens in the intestine? what do they do/contain in simple terms?
``` 1- microbiota - educates immune system, promotes homeostasis 2-physical barrier -epithelial cells, self-renewal, mucus, anti bacterial peptide 3a-innate immune barrier - M cells, myeloid cells 3b-adaptive immune barrier - lymphocytes ```
28
what happens to the main barriers of the intestine in CD?
alterations to all barriers - layers start failing - layers only activated when they need to be (consecutive checkpoints)
29
xenobiotic metabolism definition
metabolism of drugs, alcohol by bacteria before they penetrate the epithelial layer
30
microbiota interacts with?
``` pathogenic bacteria (e.g. E coli), gut parasites, viruses, yeasts, fungi - usually protective ```
31
3 main things intestinal microbiota is involved in?
- involvement in immune system maturation - intestinal response to injury (injury of epithelial layer, need replenishment) - xenobiotic metabolism
32
CD intestinal microbiota compared to healthy individuals
- reduced number of microorganisms - reduced variability in the microbiota - altered composition in bacterial families * qualitative distribution of microbiota is less, maybe before disease develops- could be biomarker?
33
what happens to tight junctions in CD?
altered tight junction expression/localisation
34
what does JAM-A do?
JAM-A - regulates tight junctions - key role in protecting epithelial layer
35
JAM-A in CD
decreased expression
36
what happens to JAM-A KO mouse?
- mouse dead, very bad inflammation within 5 days
37
defensin production in CD
defect
38
what do intestinal paneth cells produce?
defensins and other bacterial peptides
39
JAM A expression in WT mouse with dextran sodium sulfate outcome?
some inflammation, not detrimental compared to JAM-A KO
40
transgenic mice overexpressing huDEFA5 defensin gene outcome?
-decreased presence of filamentous bacteria -decreased activation of the adaptive immune response (no IL-17A expression)
41
what are the physical barrier alterations in CD?
- altered tight junction expression (JAM-A) | - defect in defensin production
42
pattern recognition receptors expressed by ?
intestinal epithelial cells and myeloid cells
43
function of PRRs?
sensors of microbial motifs and host-derived damage signals
44
examples of PRRs
toll-like receptors, NOD, nod-like receptors
45
what do PRRs do in epithelial cells?
TLR - favour epithelial repair mechanisms (restitution) - crosstalk with ER stress and autophagy pathway (degradation of pathogens)
46
what does MyD88 promote?
tight junction strengthening epithelial proliferation anti-bacterial response bacteria degradation
47
what happens to autophagy pathway in CD
alteration of pathway
48
absence of Atg16L1 autophagy gene in mouse outcome?
promoting activation of the inflammatory response | - pro inflammatory cytokine secretion (IL-1beta, IL-18)
49
what does TLR do in myeloid cells?
TLR involved in maintaining equilibrium between anti-inflammatory and pro-inflammatory response
50
anti inflammatory response in innate immunity
activation of autophagy
51
pro inflammatory response in innate immunity
- increased secretion of pro inflammatory cytokines (NFkB pathway) - induction of cell death (Caspase 1)
52
NOD2
nucleotide oligomerisation domain 2
53
function of NOD2?
intracellular switch that keeps inflammation in check and promotes tolerance - minimises activation of MyD88/NFkB pathway and Caspase 1 - activates autophagy pathway
54
NOD2 is involved in?
adaptive immunity and physical barrier
55
what happens to NOD2 in CD?
deficiency in CD-->chronic inflammation (adaptive immune response) - first susceptibility gene identified for CD
56
outcomes of NOD2 KO mice
- altered defensin production - decreased epithelial proliferation - impact on TLR-induced innate response - switch of adaptive immune response towards an effector subtype - ->increased colitis
57
what happens in adaptive immunity under homeostatic conditions?
- DCs present Ags to naive CD4+ T cells in secondary lymphoid organs (peyers patches and mesenteric lymph nodes) - favours differentiation along the Treg lineage - promotes tolerance
58
what do Treg cells express?
FOXP3- to minimise differentiation to other Th cells that activate pro inflammatory response
59
what happens to adaptive immunity in CD?
pro inflammatory response takes over
60
what Th cells expressed in CD? what do they regulate?
Th1 cells- cellular response to foreign pathogens (less) | Th17 cells- anti infectious, tissue damage (primarily)
61
what Th cells expressed in normal homeostasis?
Th2 cells- humoral response | Treg- regulatory
62
Th17 pathway activates MMPs- outcomes?
facilitate infiltration of immune cells
63
what does Th17 promote?
chronic inflammation
64
a4b7/MadCAM-1 interaction type?
integrin-adhesion interaction
65
a4b7/MadCAM-1 interaction enables?
lymphocyte recruitment from blood vessels into surrounding tissues; and tissue inflammation in CD - interaction essential for lymphocytes to dock to epithelium, rolling and enter organ
66
where is MadCAM-1 expressed?
surface of endothelial cells
67
where is a4b7 expressed?
surface of lymphocytes
68
using GWAS to detect SNPs in CD?
essential insight into pathogenesis of CD - identification of potential biomarkers for increased risk factor - sum of SNPs- determine worse or better version of the disease - onset of disease, location of disease, activity of disease, enhanced risk of cancer- can SNPs tell us these things?
69
strongest and most robust CD risk factors?-SNPs
NOD2 IL23R ATG16L1
70
screening for genetic susceptibility genes
important for families- identify risk as early as possible
71
what interactions can be targeted in CD?
a4b7/MadCAM-1- specific treatment very good, increased therapeutic benefit TNF-alpha JAK pathway

PATH30003- Frontiers in Human Disease (20 decks)

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