immunology of the gut Flashcards
the GIT has an undulating surface which increases SA for ______ and ______
absorption and secretion
what kind of epithelium?
simple columnar
what are the functions of mucus secreted by goblet cells?
- lubricant
- prevents mechanical stress on epithelium
- thick layer provide stable micro environment
- prevents invasion
- essential environment for micro flora
in a bad E.coli outbreak, what did some people go on to develop?
rare haemolytic uraemic syndrome
enteroaggregative strain of E.coli had acquired what?
Shiga toxin which causes haemolytic uraemic syndrome — the toxic could get through the mucus layer
muslce in the stomach?
3 layers to churn food — longitudinal, circular, oblique
what does the low pH of the stomach enable?
pepsin to degrade protein
describe gastrin epithelium
columnar epithelium with gastric pits — with gastric glands - help maintain acidic pH
what is the connective tissue layer in the stomach?
serosa
how is gastric epithelium protected from the acidic pH?
specialised epithelial cells secrete bicarbonate
what are the 4 key pathogenic characteristics of H.pylori?
- flagelli so can swim through thick mucus layer
- urease to neutralise gastric acid — creates neutral environment around itself
- proliferate
- mucinase to degrade mucus, allowing acid to cause the inflammation — gastric ulcer
what is the strongest known risk factor for gastric cancer?
infection wit H pylori
what is in 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
describe antibiotics, C.difficile infection and faecal transplant theory
what is clostridium difficile?
a spore-forming gram positive bacillus which is part of normal healthy flora in 4% of healthy individuals
what are the most severe symptoms of a clostridium difficile infection? (it is a spectrum from this to asymptomatic)
- severe diarrhoea
- severe abdominal pain
- white blood cell count > 15000 cells/ul
- toxic megacolon
- organ failure
- mortality rate 35-80%
what are examples of antimicrobial peptides?
a and b defensins
what are a and b defensins secreted by?
paneth cells
where are paneth cells located?
base of crypt in SI
there is good experimental evidence that gut bacteria maintain homeostasis how?
by actually stimulating the secretion of antimicrobial peptides
what is a GI specific antibody responsible for primary defence against bacteria?
IgA
describe SIgA
- dimer
- secreted by plasma cells (mature differentiated B cells)
- enter lumen by active transport
- 1/700 people dont have sIgA
- most common immune deficiencies in europe
- antigen and T cell independent
what does SIgA seem to have some specificity for in the gut?
pathogenic bacteria — binds to all the stuff that cause colitis
what are the 3 natural defences in the gut?
mucus, micro biome and antibody
what are located between paneth cells?
pluripotent stem cells
what cells in the intestinal epithelium are responsible for opioid release?
tuft cells
what cells in the GIT are responsible for nutrients absoprtion?
enterocytes
a group of well-organized lymphoid follicles located in the_________ and ___________ of the distal portion of the small intestine - the ileum and jejunum and sometimes in the duodenum
what is this describing?
a group of well-organized lymphoid follicles located in the lamina propria and submucosa of the distal portion of the small intestine - the ileum and jejunum and sometimes in the duodenum
Peyer’s patch
what happens to the stem cells?
move up from base of crypt as they proliferate and differentiate, then slough off at top
what enable the stem cells to remain sterile?
paneth cells
coeliac disease and villi
intestinal dendritic cells vs macrophages
dendritic cells:
- migratory
- excellent primers of T cells via antigen presentation
- discrete subsets with different functions
- CD11b+/- CD103+/-
- derive from committed progenitor
- sample luminal bacteria - hard to find evidence
macrophages:
- non-migratory
- express CD64, CD11b, CD11c, CX3CR1
- replenished by blood monocytes
- phagocytes
- sample luminal bacteria?
what are the front line cells for any bacteria trying to get through?
resident macrophages
in mice, what macrophages control translocation of luminal bacteria to the draining lymph node?
CX3CR1+
name 2 Th1 cells
IFN-y and TNF-a
Th1 function
defence against intracellular parasites
name 4 Th2 cells
IL-4/5/6/13
Th2 function
allergy, asthma, controls parasites and extracelllar pathogens
name 4 Th17 cells
IL-17A/17F/21/22
Th17 functions
defence against pathogens, autoimmunity, transplantation rejection and cancer
name 2 Treg cells
TGFB, Il-10
Treg functions
immune homeostasis and maintains tolerance
name a Tfh cell
CXCR5
= T follicular helper cell
Tfh cell functions
help germinal centre B cells to make antibodies, affinity maturation and antibody class switching
what differentiates in the different T cells?
naive CD4+ T cell
what factors differentiate naive CD4+ T cell into Th1/2/17/reg/fh cells?
- IFN-y and IL-12 —> Th1
- IL-4 —> Th2
- TGFB and IL-6 —> Th17
- TGFb —> Treg
- IL-6 and IL-21 —> Tfh
describe ILCs
= innate lymphoid cells
- derived from common lymphoid progenitor
- rely on IL2R signalling (as do T cells)
- INNATE lymphocytes ie no T cell receptor
- stimulated by cytokines or microbes (probably indirectly)
- present at very low numbers in steady state (therefore hard to study)
- characterised as ILC1, 2 or 3
- mirror T cell differentiation patterns
describe ILC1
- IFNy producers
- includes NK cells
- express T-bet
describe ILC2
- IL5/IL13 produces
- express RORa/GATA3
- seen in allergy
- respond to IL25/IL33
- also called nuocytes, natural helper cells
describe ILC3
- IL17A and F / IL22 producers (may be IFNy)
- express RORyt
- respond to IL23
- important in foetal lymphoid organogenesis
- important in GALT formation
- important in mucosal homeostasis
- loss of ILC3 has been associated with HIV+ progression to AIDS
ILC1/ILC2/ILC3 and NK cells frequency in colorectal cancer?
ILC1 ILC2 NK cells = increased frequency
ILC3 = decreased frequency = very bad for gut health = lose help to keep barrier intact
what 2 things ‘keep everything happy’ (esp ILC3) in gut homeostasis?
IL-10 and TGF-B = Treg cells
Treg cells put a brake on inflammation
what do dendritic cells do if there is an insult?
trigger production of inflammatory cytokines — drive inflammation
— need regulatory cytokines to resolve inflammation once pathogen gone
what cell surface receptors put a brake on inflammation?
PD-1/PD-L1
CTLA4/B71 or 2
CTLA4/B7 interaction between T cell and antigen presenting cell has what affect?
stops T cell activation
interaction between T cell and dendritic cell requires what 3 signals?
- cytokine signal
- T cell receptor and MHC
- CD28
what affect does PD-1/PD-L1 interaction have?
reduces T cell activation
PD-1 is an immune ______ molecule to avoid _______
- suppressive
- over-activation
where are PD-1 and PD-L1 expressed?
- infected cells — prevents efficient immunity to virally infected cells
- APCs and tissue — prevents immune recognition of self
- tumour cells — tumour evasion mechanism
in non-IBD patients, colorectal cancer usual;lymph begins as what?
a non-cancerous (or benign) polyp
what is a polyp?
- a growth inside the colon or rectum that is not normal
- can be several types
- is not always cancerous
what is seen in colorectal cancer in terms of epithelial cells?
- decreased epithelial cell turnover
- overgrowth of cells on epithelial lining of gut
malignant stem cells —> adenoma formation
what are the chances of developing CRC for a man and women in their lifetime?
a man has a 1/17 chance, woman has a 1/18 chance
in most people, how does sCRC develop?
slowly over a period of several years (10-20 years)
what does an inflammatory micro environment promote?
tumourigenesis
what is the biggest risk factor for CRC?
inflammation
what is loss of barrier function possibly due to?
loss of ILCs due to chronic inflammation or dysbiosis (gut bacteria releasing toxins which damage the barrier and mucus)
what happens when mucosal homeostasis is lost?
inflammatory bowel disease
- ulcerative colitis (tends to start in rectum)
- crohn’s disease (can be anywhere in GIT)
what pathological things happen i. Crohn’s disease?
- barrier defects : tight junction dysfunction
- defective neutrophil function
- paneth cell defects : reduces secretion of HD5
- defective cell migration
- effector T cell / T reg imbalance
- paneth cell defects : NOD2 polymorphisms potentially affecting microbiome and response to commensal flora
DYSREGUALTION OF HOST FLORA CONTRIBUTES TO DISEASE
having IBD and type 2 diabetes are risk factors for what?
colorectal cancer
what is the overall increased risk of CRC for someone with IBD?
10-15%
by how much does having a personal history of type 2 diabetes increase your risk of having CRC and colorectal polyps?
50%
describe the intrinsic pathway to inflammation in tumour cells
- normal tissue homeostasis disrupted
- sequential mutations (prob in stem cell compartment)
- epigenetic alterations
- oxidative stress (Bcl2, p53)
- proliferation / apoptosis dysregualtion
- tumour progression
describe the extrinsic pathway driven by chronic inflammation (eg IBD, dysbiosis)
- inflammatory tumour micro environment
- inflammatory cytokines (TNFa, IFNy, IL1)
- reduced regulatory cytokines (IL10, TGFb)
- disrupted homeostasis
- proliferation / apoptosis dysregulation
- tumour progression
