1b Immunology of the Gut Flashcards
Describe the antigen load in the gut?
Massive antigen load
- resident microbiota,10^14 bacteria
- dietary antigens
- exposure to pathogens
Why is the GI Tract immune system in a state of ‘restrained activation’?
It balances tolerance of food antigens and commensal bacteria vs immunoreactivity against pathogens
What are gnotobiotic mice?
These are mice which have been colonized to be germ-free
They are used in experiments to derive the relationship between microbiota and immune system’s response to them
What are the four major phyla of bacteria found in the gut microbiota?
Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, as well as viruses and fungi
What factors which the host does leads to bacterial growth?
Ingested nutrients
Secreted nutrients
Which factors leads to bacterial lysis and bacterial elimination?
Chemical digestive factors
peristalsis, contractions and defecations
In general, explain why bacterial content varies as you pass down the GI tract
The chemical digestive factors produced by the host impact viability of the bacteria to survive in different parts of the GI tract
The bacterial content increases as you pass down the GI tract because the factors produced are less hostile to bacterial growth.
List the chemical digestive factors produced by the stomach, liver, pancreas, small intestine and colon respectively
Stomach - Pepsin, gastric lipase
Liver - bile salts
Pancreas - trypsin, amylase and carboxypeptidase
Small Intestine - Brush border enzymes
Colon - nothing
What is Dysbiosis?
Altered microbiota composition
What is the balance of dysbiosis between?
Symbionts = regulation
Commensals
Pathobionts = inflammation
Define the term ‘Symbiont’
Lives with a host but no benefit/harm to either
Define commensals?
Microorganisms that benefit from association with the host but doesn’t affect the host
Define pathobiont?
Symbiont that doesn’t naturally produce an immune response but under certain environmental conditions can produce dysregulated inflammation/disease.
Give 5 factors that can either contribute to the maintenance of healthy microbiota or towards dysbiosis
1) Infection or inflammation
2) Diet
3) Xenobiotics
4) Hygiene
5) Genetics
Give 5 examples of metabolites and toxins which bacteria produce that can cause damage to body systems
TMAO
4-EPS
SCFAs
Bile acids
AHR Ligands
What are the anatomical barriers which contribute to mucosal defense?
Epithelial barrier
Peristalsis
What are the chemical barriers which contribute to mucosal defense?
Enzymes
Acidic pH
What dysfunction can TMAO cause in the body?
TMAO = Trimethylamine N-oxide
Can cause atherosclerosis due to increased cholesterol deposition
What has 4-EPS been associated with?
Increased levels of autism
What are decreased numbers of SCFA’s associated with?
SCFAs = Short-chained fatty acids
Decreased numbers of SCFAs are associated with Inflammatory bowel disease
What are increased numbers of SCFAs associated with?
Neuropsychiatric disorders like stress
What are AHR ligands associated with?
AHR ligands- aryl hydrocarbon receptor
-MS
-RA
-Asthma
What are the two immunological defense mechanisms following an invasion?
MALT (Mucous associated lymphoid tissue)
GALT (Gut associated lymphoid tissue)
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Where is MALT tissue particularly rich?
MALT is particularly rich within the oral cavity ( the three tonsils - palatine, lingual and pharyngeal (adenoid))
It is found in the submucosa below the epithelium as a lymphoid mass containing lymphoid follicles
What cells make up the mucus layer?
Goblet cells
What are paneth cells and how are they used in mucosal defense?
They are cells of the small intestine, found at the bases of the crypts of lieberkuhn and they secrete anti-microbial peptides (defensins) and lysozyme
What is found in the epithelial monolayer?
Tight junctions
Where is MALT found?
Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
What are the lymphoid follicles of MALT surrounded by?
Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
Which tissue is rich in MALT?
Oral cavity - palatine tonsils, lingual tonsils, pharyngeal tonsils
What is GALT tissue responsible for?
Adaptive and innate immune responses
What does GALT consist of?
Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes
What are the four organised structures of GALT?
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
What are the two non-organised structures of GALT?
Intra-epithelial lymphocytes - Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells
Lamina propria lymphocytes
What are Peyer’s patches?
Aggregated lymphoid follicles covered with follicle associated epithelium ( FAE) —> Found in submucosa of small intestine eg. mainly distal ileum
What is special about FAE?
No goblet cells, No secretory IgA, no microvilli - Therefore no barrier to pathogens so Peyer’s Patches can act accordingly and increase in numbers
How does the structure of the large intestine cellular arrangement differ from the small intestine?
- Large Intestine - Outer mucus layer, inner mucus layer, and shallow crypts
- Small Intestine - Lumen, Mucus, larger crypts with microvilli
Where are peyer’s patches found?
In the submucosa of the small intestine - mainly the distal ileum
What does the development of Peyer’s Patches require?
Development requires exposure to bacterial microbiota
How do Peyer’s Patches work?
Antigen uptake via M (microfold) cells within FAE
M cells express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer’s patches.
Describe the growth of the Peyer’s patches from fetus to teenage years
Peyer’s patches contain an organized collection of naïve T cells and B cells
Development of it requires previous exposure to bacterial microbiota
Therefore, it grows over time 50 in last trimester as a foetus, 250 by the time you are a teenager.
Describe the role trans-epithelial dendritic cells play in the immunological response
Dendritic cells can open up tight junction proteins and send dendrites from the outside into the lumen of the intestinal tract where they directly sample bacteria
They can then bring the bacteria back and transport them into mesenteric lymph nodes
Describe the B cell adaptive response
Pathogen uptake via M cell —> Excreted into pocket found on the inner surface of the enterocyte containing APCs —> APCs engulf pathogen and display on their surface using MHC II —> DCs migrate to Peyers patches —>Mature naive B-cells express IgM in these Peyers patches but on antigen presentation switches to IgA.
- T-cells and epithelial cells influence B cell maturation via cytokine production
- B cells further mature to become IgA secreting plasma cells
- Populate lamina propria
Describe the formation of secretory IgA within the lumen
Enzymatic cleavage within epithelial cells converts dimeric IgA into secretory IgA which is then released into the lumen.
What is the function of sIgA?
Secretory IgA binds to luminal antigen, thereby preventing its adhesion and consequent invasion
Describe the cycle of lymphocyte homing and circulation?
Mesenteric lymph node -> thoracic duct -> circulation -> lamina propria of gut lumen (containing peyer’s patches where antigen presentation and activation occurs)
Describe alpha4beta7/ MADCAM-1 adhesion
The lymphocyte express alpha4beta7 integrin and the High Endothelial Venule express MADCAM-1
Chemotactic stimulation of lymphocytes leads to rolling, then activation, then arrest and internalization into tissue fluid from blood
Why do enterocytes and goblet cells of the small bowel have such a short life-span (36 hours)?
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
What is Cholera and what agents is it caused by?
Cholera is an acute bacterial disease caused by vibrio cholerae serogroups O1 and O139
What happens when the bacteria reaches the small intestine?
Comes into contact with the epithelium and released cholera enterotoxin
How is cholera transmitted?
Faecal-oral route - spreads through contaminated water and food
What are the main symptoms of a cholera infection?
Severe dehydration & watery diarrhoea
Other symptoms: vomiting, nausea and abdominal pain
How is cholera diagnosed?
Diagnosis: bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available.
What is the treatment for Cholera infection?
oral-rehydration is the main management ; up to 80% of cases can be successfully treated.
What class of viruses are the most common cause of diarrhoea in infants and young children worldwide?
Rotaviruses
Describe rotaviruses and which one is the most common in humans?
RNA Virus, replicates in enterocytes
5 types A-E, type A most common in human infections.
What is the treatment for rotaviruses?
Oral rehydration therapy
Rotavirus vaccine?
Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013.
What is norovirus?
It is an RNA virus with an incubation period (time between exposure and when symptoms apparent) of 24-48 hours
What is the transmission of norovirus?
Faecal-oral transmission.
Individuals may shed infectious virus for up to 2 weeks
Outbreaks often occur in closed communities
what are the symptoms of norovirus?
Acute gastroenteritis, recovery 1 – 3 days
How is Norovirus diagnosed?
Sample PCR.
What is Campylobacter?
Curved bateria
What is the transmission of campylobacter?
Undercooked meat (especially poultry), untreated water & unpasteurised milk
Low infective dose, a few bacteria (<500) can cause illness
What is the treatment for campylobacter?
Azithromycin (macrolide) is standard antibiotic
Resistance to fluoroquinolones is problematic
What does Enterotoxigenic E.Coli ( ETEC) do?
Cholera like toxin which causes watery diarrhoea
Which pathotype of E. Coli is the most harmful?
Enterohaemorrhagic or shiga-toxin producing E.Coli ( EHEC/STEC)
Which E. Coli Pathotype causes Blood diarrhoea?
Enteroinvasive E. coli (EIEC)
What is the management of C. Diff. infections?
Isolate patient
Stop current antibiotics
Give Metronidazole and Vancomycin
Faecal Microbiota transplantation- 98% cure rate
How does C. Diff cause disease?
- exogenous disturbances (e.g. antibiotics) cause dysbiosis
- C. Diff starts colonising without producing toxins
- pathogen induced disturbance creates supportive environment
- C. diff starts to produce toxins
