case 4 - immunology of the gut Flashcards
what type of surface does the GI tract have
an undulating surface, which increases surface area for absorption and secretion
what is mucus secreted by
goblet cells
what does this mucus do
lubricant
Prevents mechanical stress on epithelium
Thick layer provided stable microenvironment
Prevents invasion
Essential environment for microflora
what helps to maintain the acidic environment in the stomach
the gastric glands and gastric pits
what is the protection of the gastric epithelium carried out by
mucus and secretion of neutralising bicarbonate by specialised epithelial cells
what does the mucus provide
a pH gradient - lumen pH is around 1-2 and the mucus pH is around 7
what is this pH gradient due to
the bicarbonate
what is the strongest known risk for gastric cancer
h pylori
what is the upper layer of mucus colonised by
bacteria
what does the absence of gut bacteria affect
behaviour
Gut homeostasis
Immune response under stress
Body weight
Brain development and gene expression
what is the clostridium difficile infection
a spore forming gram positive bacillus which is part of normal healthy flora in 4% of healthy indivudals
what does this infection lead to
pseudomembranous ulcerative colitis
what can it result in and what is the mortaility rate
can result in organ failure and the mortality rate it 35-80%
how does one fix this infection
infusion of donor faeces
how do we maintain a healthy microbiome
antimicrobial peptides
Alpha and beta defensins that are secreted by the paneth cells
there is good experimental evidence that gut bacteria actually stimulate secretion of antimicrobial peptides maintaining homeostasis
what is the specific antibody responsible for the primary defence against bacteria
IgA
what coats colitogenic bacteria with high affinity
SIgA
what do the paneth cells do to the crypt
keep it sterile
what happens in coeliac disease
the villi get smaller and no epithelium
what is in the sub epithelial layer
antigen specific responses
Macrophages and dendritic cells
T cells and innate lymphoid cells
features of dendritic cells
distinct yet complimentary function
Migratory
Excellent primers of T cells via antigen presentation
Discrete subsets with different function
CD11b+/-CD103+/-
Derive from a committed progenitor
features of macrophages
Non-migratory
Express CD64, CD11b, CD11c, CX3CR1
Replenished by blood monocytes
phagocytes
what are resident macrophages
in mice, CX3CR1 macrophages control translocation of luminal bacteria to the draining lymph ode
front line cells that clean up any bacteria that gets though
what does Th1 do
defence against intracellular parasites
what does Th2 do
allergy, asthma, controls parasite and extracellular pathogens
what does Th17 do
defence against pathogens, autoimmunity, transplantation rejection and cancer
what does Treg do
immune homeostasis and maintains tolerance
what does Tfh do
help germinal centre B cells to make antibodies, affinity maturation and antibody class switching
what are innate lymphoid cells and some features of them
derived from common lymphoid progenitor
Rely on IL2R signalling (as do T cells)
INNATE lymphocytes i.e no T cell receptor
Stimulated by cytokines or microbes - probably directly
Present at very low number in steady state
Characterised as ILC1,2, or 3
what is ILC1, what does it produce and what does it expres
produces IFN gamma
includes natural killer cells
it expresses T-bet
what is ILC2, what does it express and what does it produce
IL5/IL13 producers
Express RORalpha and GATA3
Seen in allergy
Respond to IL25 and IL33
Also called nuocytes, natural helper cells
what is ILC3 and what does it express and produce
contribute to mucosal homeostasis
IL17A&F and IL22 producers
Express RORgammaT
Respond to IL23
Important in fetal lymphoid organogenesis
Important for GALT formation
Important in mucosal homeostasis
Loss of ILC3 has been associated with HIV+ progression in aids
what can all ILCs be
both pro and anti tumorgenic
what happens in cancer with ILC2 and ILC3
ILC3s are lost and ILC2 go up and ILC3 can potentially help with anti tumour response and if they are lost they lose the help it provides to keep the barrier in tact
what is Treg, what are the key factors
the two key factors are TGFbeta and IL10
T cell populations contribute to homeostasis
Helps to keep everything happen particularly the ILC3s
If the dendritic cells pick up something pathogenic, it triggers the production of inflammatory cytokines which drive inflammation
To resolve the inflammation you need to produce more Treg
what cell surface receptors also put a break on inflammation
PD-1/PD-L1
CTLA4/B71 or 2
what interaction stops T cell activation
CTLA4/B7 interaction between T cell and antigen presenting cell stops T cell activation
what activates T cells
CD28 on T cell binds to B7 on dendritic cells to activate T cell
what is engaged to stop T cells working
By engaging CTLA4, it binds to B7 and stops T cells working
what is PT1
an off switch
what interaction reduces T cell activation
PD1/PD-L1 interaction
features of PD1/PD-L1
PD1 is an immune suppressive molecule to avoid over activation
Expressed by infected cells - prevents efficient immunity to virally infected cells
Expressed on APCs and tissue - prevents immune recognition of self
Expressed on tumour cells - tumour evasion mechanism
what is sporadic colorectal cancer
in non-IBD patients, it usually begins as a non-cancerous polyp
what are the chancers of developing it
Man has a 1 in 17 chance
Woman has a 1 in 18 chance
what is the main thing about Crohn’s disease
dysregulation of host flora contributes to disease
what are the paneth cell defects in Crohn’s disease
reduced secretion of HD5
what are the other paneth cell defects
NOD2 polymorphisms potentially affecting microbiome and response to commensal flora
that is the cancer inflammation parafgm
Intrinsic pathway to inflammation (in tumour cells)
And balanced with:
Extrinsic pathway driven by chronic inflammation e.g IBD, dysbiosis
what is the intrinsic pathway to inflammation
normal tissue homeostasis disrupted
sequential mutations
epigenetic alterations
oxidative stress - Bcl2, p53
proliferation / apoptosis dysregulation
what is the extrinsic pathway driven by chronic inflammation
inflammatory tumour microenvironment
inflammatory cytokines (TNF alpha, IFN gamma, IL1)
reduced regulatory cytokines - IL10, TGF
disrupted homeostasis
proliferation and apoptosis disregulation
