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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
Q

paneth cells in crypts

A

remain at the bottom, dont migrate up, remain interspersed with stem cells, number doesnt increase

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26
Q

what does the epithelial layer of the intestine serve a barrier between?

A

gut and environment

- first barrier

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27
Q

what are the 3 main functional/protective barriers against pathogens in the intestine? what do they do/contain in simple terms?

A 
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
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28
Q

what happens to the main barriers of the intestine in CD?

A

alterations to all barriers

  • layers start failing
  • layers only activated when they need to be (consecutive checkpoints)
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29
Q

xenobiotic metabolism definition

A

metabolism of drugs, alcohol by bacteria before they penetrate the epithelial layer

30
Q

microbiota interacts with?

A 
pathogenic bacteria (e.g. E coli), gut parasites, viruses, yeasts, fungi
- usually protective
31
Q

3 main things intestinal microbiota is involved in?

A
  • involvement in immune system maturation
  • intestinal response to injury (injury of epithelial layer, need replenishment)
  • xenobiotic metabolism
32
Q

CD intestinal microbiota compared to healthy individuals

A
  • 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
Q

what happens to tight junctions in CD?

A

altered tight junction expression/localisation

34
Q

what does JAM-A do?

A

JAM-A

  • regulates tight junctions
  • key role in protecting epithelial layer
35
Q

JAM-A in CD

A

decreased expression

36
Q

what happens to JAM-A KO mouse?

A
  • mouse dead, very bad inflammation within 5 days
37
Q

defensin production in CD

A

defect

38
Q

what do intestinal paneth cells produce?

A

defensins and other bacterial peptides

39
Q

JAM A expression in WT mouse with dextran sodium sulfate outcome?

A

some inflammation, not detrimental compared to JAM-A KO

40
Q

transgenic mice overexpressing huDEFA5 defensin gene outcome?

A

-decreased presence of filamentous bacteria
-decreased activation of the adaptive immune response
(no IL-17A expression)

41
Q

what are the physical barrier alterations in CD?

A
  • altered tight junction expression (JAM-A)

- defect in defensin production

42
Q

pattern recognition receptors expressed by ?

A

intestinal epithelial cells and myeloid cells

43
Q

function of PRRs?

A

sensors of microbial motifs and host-derived damage signals

44
Q

examples of PRRs

A

toll-like receptors, NOD, nod-like receptors

45
Q

what do PRRs do in epithelial cells?

A

TLR

  • favour epithelial repair mechanisms (restitution)
  • crosstalk with ER stress and autophagy pathway (degradation of pathogens)
46
Q

what does MyD88 promote?

A

tight junction strengthening
epithelial proliferation
anti-bacterial response
bacteria degradation

47
Q

what happens to autophagy pathway in CD

A

alteration of pathway

48
Q

absence of Atg16L1 autophagy gene in mouse outcome?

A

promoting activation of the inflammatory response

- pro inflammatory cytokine secretion (IL-1beta, IL-18)

49
Q

what does TLR do in myeloid cells?

A

TLR involved in maintaining equilibrium between anti-inflammatory and pro-inflammatory response

50
Q

anti inflammatory response in innate immunity

A

activation of autophagy

51
Q

pro inflammatory response in innate immunity

A
  • increased secretion of pro inflammatory cytokines (NFkB pathway)
  • induction of cell death (Caspase 1)
52
Q

NOD2

A

nucleotide oligomerisation domain 2

53
Q

function of NOD2?

A

intracellular switch that keeps inflammation in check and promotes tolerance

  • minimises activation of MyD88/NFkB pathway and Caspase 1
  • activates autophagy pathway
54
Q

NOD2 is involved in?

A

adaptive immunity and physical barrier

55
Q

what happens to NOD2 in CD?

A

deficiency in CD–>chronic inflammation (adaptive immune response)
- first susceptibility gene identified for CD

56
Q

outcomes of NOD2 KO mice

A
  • altered defensin production
  • decreased epithelial proliferation
  • impact on TLR-induced innate response
  • switch of adaptive immune response towards an effector subtype
  • ->increased colitis
57
Q

what happens in adaptive immunity under homeostatic conditions?

A
  • 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
Q

what do Treg cells express?

A

FOXP3- to minimise differentiation to other Th cells that activate pro inflammatory response

59
Q

what happens to adaptive immunity in CD?

A

pro inflammatory response takes over

60
Q

what Th cells expressed in CD? what do they regulate?

A

Th1 cells- cellular response to foreign pathogens (less)

Th17 cells- anti infectious, tissue damage (primarily)

61
Q

what Th cells expressed in normal homeostasis?

A

Th2 cells- humoral response

Treg- regulatory

62
Q

Th17 pathway activates MMPs- outcomes?

A

facilitate infiltration of immune cells

63
Q

what does Th17 promote?

A

chronic inflammation

64
Q

a4b7/MadCAM-1 interaction type?

A

integrin-adhesion interaction

65
Q

a4b7/MadCAM-1 interaction enables?

A

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
Q

where is MadCAM-1 expressed?

A

surface of endothelial cells

67
Q

where is a4b7 expressed?

A

surface of lymphocytes

68
Q

using GWAS to detect SNPs in CD?

A

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
Q

strongest and most robust CD risk factors?-SNPs

A

NOD2
IL23R
ATG16L1

70
Q

screening for genetic susceptibility genes

A

important for families- identify risk as early as possible

71
Q

what interactions can be targeted in CD?

A

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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