1b// Immunology of the Gut Flashcards
What’s the SA of the GI tract?
200m^2
How would describe the GI tract antigen load?
Massive
What is the state of the GI tract immunology?
State of restrained activation:
- Tolerance vs active immune response
- Dual immunological role
What does the homeostasis of the gut and development of healthy immune system require?
presence of bacterial microbiota
What odes germ free mice mean?
have selected microbiota (not lots of strains)
What site is affected in germ-free mice during an immunological defect of the development of the small intestine? And what is the phenotype in germ-free mice compared with conventionally housed mice?
Peyer’s patches
fewer and less cellular
What site is affected in germ-free mice during an immunological defect of the expression of angiogenin-4? And what is the phenotype in germ-free mice compared with conventionally housed mice?
paneth cells
reduced
What is angiogenin 4?
Mouse angiogenin 4 (Ang4) has previously been described as a Paneth cell-derived antimicrobial peptide important in epithelial host defence in the small intestine
What are the 4 major phyla of bacteria in the gut microbiota?
bacteroidetes, firmicutes, actinobacteria, proteobacteria
and also viruses and fungi
What does the gut microbiota provide to our genetics?
Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome.
Essential nutrients; metabolism of indigestible compounds; defence against colonisation of pathogens
How is. there bacterial growth or decrease in the gut microbiota?
What chemical digestive factors does the stomach produce?
HCl
Pepsin
Gastric lipase
What chemical digestive factors does the liver produce?
bile acids
What chemical digestive factors does the pancreas produce?
trypsin
amylase
carboxypeptidase
What chemical digestive factors does the small intestine produce?
brush border
enzymes
What chemical digestive factors does the colon produce?
no host digestive factors
Rank areas of the GI tract from least to most bacterial content.
stomach
duodenum
jejunum
ileum
colon
What is dysbiosis?
an imbalance between the types of organism present in a person’s natural microflora, especially that of the gut, thought to contribute to a range of conditions of ill health.
altered microbiota composition
What are causes of dysbiosis, leading to disease development? (5)
Infection or inflammation
Diet
Xenobiotics
Hygiene
Genetics
What are xenobiotics?
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual
e.g., pollutants
What are examples of bacterial metabolites and toxins that are created by dysbiosis? (5)
TMAO
4-EPS
SCFAs
bile acids
AHR ligands
What are disease that are caused by dysbiosis?
What are the physical barriers of the mucosal defense?
anatomical:
- epithelial barrier
- peristalsis
chemical:
- enzymes
- acidic pH
What do commensal bacteria do?
occupy an ecological niche
What are the “immunological” mucosal defenses following an invasion?
MALT (Mucosa Associated Lymphoid Tissue)
GALT (Gut Associated Lymphoid Tissue)
Describe the epithelial barrier.
Mucus layer=> goblet cells
Epithelial monolayer=> Tight junctions
Paneth Cells (small intestine)
- Bases of crypts of Lieberkühn.
- Secrete Antimicrobial peptides (defensins) & lysozyme
What is MALT?
mucosa associated lymphoid tissue
Where is MALT found and in what form?
Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
the oral cavity is rich in immunological tissue
What are the follicles like in MALT?
Follicles are surrounded by HEV (high endothelial venules) postcapillary venules, allowing easy passage of lymphocytes
What is GALT?
gut associated lymphoid tissue
What is GALT responsible for?
Responsible for both adaptive & innate immune responses through generations of lymphoid cells & Abs
How are GALT organised?
Non-organised:
- Intra-epithelial lymphocytes
- Make up 1/5th of intestinal epithelium, e.g. T-cells,NK cells
- Lamina propria lymphocytes
Organised:
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
What do non-organised GALT look like?
Where are peyer’s patches found?
found in submucosa small intestine- mainly distal ileum
What are the follicles in peyer’s patches?
Aggregated lymphoid follicles covered with follicle associated epithelium (FAE).
What are FAE? And what do they (not) have?
follicle associated epithelium
no goblet cells, no secretory IgA, lack microvilli
What is required for the development of peyer’s patches?
bacterial microbiota
How would you describe the organisation of peyer’s patches?
organised collection of naive T and B cells
How many bacterial microbiota are you exposed to as a foetus/ teen?
50 by last trimester as foetus
250 by teens
What happens within FAEs?
Antigen uptake via M (microfold) cells within FAE
M cells express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer’s patches.
What else are M cells called and how can you get samples?
microfold cells
particulate antigen sampling
How do you do sampling for trans-epithelial dendritic cells?
What is the B cell adaptive response?
Mature naïve B-cells express IgM in PPs
On antigen presentation class switches to IgA
What influences B cell maturation and how?
T cells and epithelial cells via cytokine production
What do B cells mature to become?
become IgA secreting plasma cells
What do B cells populate?
lamina propria in mucosa
Describe the formation of secretory IgA (sIgA).
Up to 90% of gut B-cells secrete IgA
sIgA binds luminal antigen
→ preventing its adhesion and consequent
invasion.
IgA binds to poly-ig receptor
Describe lymphocyte homing and circulation.
How does adhesion and gut homing occur?
alpha-4 beta-7 integrin on lymphocyte attaches to MAdCAM-1 on high endothelial venule (HEV).
Causing activation and arrest and adhesion.
Then the lymphocyte enters the lamina propria, aka to peyer’s patches
What is the life span like of enterocytes and goblet cells?
short, about 36h
Rapid turnover contrasts with lifespan of weeks/months for other epithelial cell types (e.g. lung, blood vessels)
Why do enterocytes and goblet cells have a rapid turnover?
Enterocytes are first line of defense against GI pathogens & may be directly affected by toxic substances in diet.
Effects of agents which interfere with cell function, metabolic rate etc will be diminished.
Any lesions will be short-lived.
If escalator-like transit of enterocytes is interrupted through impaired production of new cells (e.g. radiation) severe intestinal dysfunction will occur
What is the mechanism of cholera infection?
Bacteria reaches small intestine →
contact with epithelium & releases cholera enterotoxin.
What is cholera?
Cholera - acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
How is cholera transmitted?
Transmitted through faecal-oral route
- Spreads via contaminated water & food
What are the main and other symptoms of cholera? (5 total)
Main symptoms
* Severe dehydration & watery diarrhoea
Other symptoms
* Vomiting, nausea & abdominal pain.
How is cholera diagnosed?
bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available.
What is the treatment for cholera?
oral-rehydration is the main management ; up to 80% of cases can be successfully treated.
Is there a vaccine for cholera?
Dukoral, oral, inactivated.
What is infectious diarrhoea called?
gastroenteritis
What are other causes of gastroenteritis?
What are rotaviruses?
RNA virus, replicates in enterocytes.
5 types A – E, type A most common in human infections.
What is the epidemiology of rotaviruses?
Most common cause of diarrhoea in infants & young children worldwide.
What is the treatment of rotaviruses?
Oral rehydration therapy
Still causes ~ 200,000 deaths/year.
Before vaccine, most individuals had an infection by age 5, repeated infections develop immunity.
Is there a vaccine for rotaviruses?
Live attenuated oral vaccine (Rotarix) against type A
What are norovirus?
Description?
Transmission?
Symptoms?
Diagnosis?
Epidemiology?
What are campylobacter?
Most common species?
Transmission?
treatment?
Epidemiology?
What is E.coli?
Escherichia coli
Diverse group of Gram-negative intestinal bacteria
Most harmless
What are the 6 ”pathotypes” associated with diarrhoea (diarrhoeagenic) of E.coli?
How do you manage C.difficile?
Clostridium difficile (C. Diff.)
Isolate patient (very contagious)
Stop current antibiotics
Metronidazole, Vancomycin
Recurrence rate 15-35% after initial infection, increasingly difficult to treat.
Faecal Microbiota Transplantation (FMT) – 98% cure rate
What is the clinical assessment like?
How would you treat a patient with acute diarrhoea?
