Lecture 20- IBD; Crohn's disease Flashcards
2 primary functions of the GIT
- absorption of nutrients
- barrier between environment and internal organs (ensure bacteria don’t get into lumen)
GIT is a reservoir of?
important nerve cell reservoir of the peripheral nervous system
is GIT an endocrine or exocrine organ?
endocrine
what does the GIT have a physiological interaction with?
the microbiota
where is IBD prominent?
- westernised countries (low with increasing incidence)
- environmental influence
- eastern asia- increasing due to life changes, westernised diet
IBD subdivided into?
Crohn’s disease and ulcerative colitis
compare UC and CD in terms of localisation of disease
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)
what is the distinguishing symptom between CD and UC?
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)
IBD patients have an increased risk of?
colorectal cancer
common symptoms between UC and CD?
- abdominal pain, diarrhea, rectal bleeding
- anal alterations
- alterations of general condition (fatigue, weight loss)
possible complications of IBD
bowel obstruction
ulcers
malnutrition
CD- type of onset
bimodal
- 15-30yrs
- 55-60yrs
epidemiology of CD
higher in USA, Northern Europe, Australia
environmental influencers for CD
- 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)
genetic component for CD
strong genetic component
- > 70 susceptibility genes
- ethnicity (caucasians, ashkenazi jews- higher risk)
- family history (higher risk- close relative has disease)
CD, immune response and microbiota, genetic factor statement
abnormal immune response to the intestinal microbiota in genetically predisposed individuals
what is important for CD diagnosis?
determination of inflammatory state crucial for assessment of disease activity and tailoring therapy
comparison between invasive non-invasive methods to diagnose CD
invasive- analyse biopsies - time consuming and expensive non-invasive - markers -indirect assessment of disease activity
healthy intestine vs CD intestine
healthy
-smooth and vascularised
CD
- superficial- inflammation, areas in between normal
-advanced- granulomas, huge infiltration of immune cells
current treatments for CD
- anti inflammatory
- immunosuppressive drugs (steroids)
- surgery
- anti - TNFalpha
- NO life long cure
what two things are required to be understood to get a diagnosis better and earlier and make better treatments?
- how intestinal homeostasis works
- what causes the disease
what are transit amplifying cells in the intestine
heavily proliferating cells, bulk up number of epithelial cells , push each other up
what cells do the stem cells in the intestine make?
absorptive cells
goblet cells
enteroendocrine cells
tuft cells (less known antibacterial cells)
what is anoikis?
cell death
-cells detach from layer and degrade in lumen at the top of the villus
paneth cells in crypts
remain at the bottom, dont migrate up, remain interspersed with stem cells, number doesnt increase
what does the epithelial layer of the intestine serve a barrier between?
gut and environment
- first barrier
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
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)
xenobiotic metabolism definition
metabolism of drugs, alcohol by bacteria before they penetrate the epithelial layer
microbiota interacts with?
pathogenic bacteria (e.g. E coli), gut parasites, viruses, yeasts, fungi - usually protective
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
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?
what happens to tight junctions in CD?
altered tight junction expression/localisation
what does JAM-A do?
JAM-A
- regulates tight junctions
- key role in protecting epithelial layer
JAM-A in CD
decreased expression
what happens to JAM-A KO mouse?
- mouse dead, very bad inflammation within 5 days
defensin production in CD
defect
what do intestinal paneth cells produce?
defensins and other bacterial peptides
JAM A expression in WT mouse with dextran sodium sulfate outcome?
some inflammation, not detrimental compared to JAM-A KO
transgenic mice overexpressing huDEFA5 defensin gene outcome?
-decreased presence of filamentous bacteria
-decreased activation of the adaptive immune response
(no IL-17A expression)
what are the physical barrier alterations in CD?
- altered tight junction expression (JAM-A)
- defect in defensin production
pattern recognition receptors expressed by ?
intestinal epithelial cells and myeloid cells
function of PRRs?
sensors of microbial motifs and host-derived damage signals
examples of PRRs
toll-like receptors, NOD, nod-like receptors
what do PRRs do in epithelial cells?
TLR
- favour epithelial repair mechanisms (restitution)
- crosstalk with ER stress and autophagy pathway (degradation of pathogens)
what does MyD88 promote?
tight junction strengthening
epithelial proliferation
anti-bacterial response
bacteria degradation
what happens to autophagy pathway in CD
alteration of pathway
absence of Atg16L1 autophagy gene in mouse outcome?
promoting activation of the inflammatory response
- pro inflammatory cytokine secretion (IL-1beta, IL-18)
what does TLR do in myeloid cells?
TLR involved in maintaining equilibrium between anti-inflammatory and pro-inflammatory response
anti inflammatory response in innate immunity
activation of autophagy
pro inflammatory response in innate immunity
- increased secretion of pro inflammatory cytokines (NFkB pathway)
- induction of cell death (Caspase 1)
NOD2
nucleotide oligomerisation domain 2
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
NOD2 is involved in?
adaptive immunity and physical barrier
what happens to NOD2 in CD?
deficiency in CD–>chronic inflammation (adaptive immune response)
- first susceptibility gene identified for CD
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
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
what do Treg cells express?
FOXP3- to minimise differentiation to other Th cells that activate pro inflammatory response
what happens to adaptive immunity in CD?
pro inflammatory response takes over
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)
what Th cells expressed in normal homeostasis?
Th2 cells- humoral response
Treg- regulatory
Th17 pathway activates MMPs- outcomes?
facilitate infiltration of immune cells
what does Th17 promote?
chronic inflammation
a4b7/MadCAM-1 interaction type?
integrin-adhesion interaction
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
where is MadCAM-1 expressed?
surface of endothelial cells
where is a4b7 expressed?
surface of lymphocytes
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?
strongest and most robust CD risk factors?-SNPs
NOD2
IL23R
ATG16L1
screening for genetic susceptibility genes
important for families- identify risk as early as possible
what interactions can be targeted in CD?
a4b7/MadCAM-1- specific treatment very good, increased therapeutic benefit
TNF-alpha
JAK pathway
