immunology of the gut Flashcards
What is SA of GI tract and what does that mean for its immunology?
SA 200m2 so exposed to massive antigen load (resident microbiota, dietary antigens, pathogens
What is the gut in a state of immunologically?
In a state of restrained activation to balance tolerance and active immune response.
What does immune homeostasis of the gut require?
Presence of bacterial microbiota
What is microbiota? What is microbiome?
- Microbiota is mixture of microorganisms making up a community in a specific anatomical compartment.
- Microbiome are collective genomes of all the microbiota of all anatomical niches in the body
What is gnotobiology?
Selectively colonises germ free animals and compares with controls to see effects of different microbiota
How many gut bacteria in the body? What are the major phyla? What do they provide for us?
- 10^14 gut bacteria.
- 4 major phyla: bacteriodetes, firmicutes, actinobacteria, proteobacteria + viruses/fungi.
- They provide traits we haven’t evolved on our own (essential nutrients, metabolise indigestible compounds, defense against colonisation by opportunistic pathogens, intestinal architecture)
What host factors stimulate gut bacteria? What host factors decrease bacteria numbers?
- Ingested nutrients & secreted nutrients encourage bacterial growth (increase cell numbers).
- Chemical digestive factors, peristalsis, contraction, defacation lead to bacterial lysis and elimination (decreasing cell numbers)
How do the bacterial numbers vary in different parts of GI system and why?
- In stomach lower numbers because HCL, pepsinogen, gastric lipase keep numbers low.
- In duodenum, liver bile acids keep numbers low.
- In pancreas, trypsin, amylase, keep them high.
- In illeum higher.
- In colon no digestive factors keeping them down (10^12)
What are symbionts? Commensals? Pathobionts?
- Symbionts live with host but no benefit or harm to each other.
- Commensals benefit from association but have no effect on host.
- Pathobionts are symbionts that don’t normally cause inflammatory response but can cause inflammation/disease when they start replicating
What are causes of dysbiosis? What does dysbiosis then cause?
- dysbiosis: instability of the gut microbiome
- Infection, inflammation, diet, xenobiotics, hygiene, genetics.
- Dysbiosis causes pathogens producing bacterial metabolites/toxins affecting body
What are examples of toxins produced from dysbiosis and their associations?
- TMAO (increases cholesterol deposition in arteries - atherosclerosis)
- 4-EPS (associated with autism)
- SFCAs (decreased in IBD, increases in stress/neuropsychiatric disorders),
- AHR ligands (associated with MS, RA, asthma)
What is the mucosal defence from infection?
- Physical barriers –> anatomical (epithelial barriers, peristalsis).
- Chemical barriers - enzymes, acidic pH.
- Epithelial barrier: mucus layer made of goblet cells, epithelial layer with tight junctions.
- In small intestine paneth cells in crypts of lieberkun secrete antimicrobial peptides (defensins) & lysozyme.
- Commensal bacterial occupy ecological niche
What is immunological defence following infection?
MALT (mucosa associated lymphoid tissue) & GALT (gut associated lymphoid tissue)
What is MALT, where is it found? What is its structure? Which area is rich in immunological tissue?
MALT - mucosa associated lymphoid tissue, found in submucosa below epithelium as lymphoid mass containing lymphoid follicles. Surrounded by HEV post-capillary venules allowing easy passage of lymphocytes. Oral cavity rich in this tissue (eg tonsils)
What is GALT? What does it contain?
- Gut-associated lymphoid tissue.
- Both adaptive & innate immune response.
- Has B & T cells, macrophages, APCs and specific epithelial & intra-epithelial lymphocytes.
- Non-organised - intra-epithelial lymphocytes (eg. T cells, NK cells, lamina propria lymphocytes).
- Organised: peyer’s patches, caecal patches, isolated lymphoid follicles, mesenteric lymphoid nodes
What is non-organised GALT?
- Everything comes from stem cells in crypts, migrate to top of microvillus.
- Central part of villus made of lamina propria and T, macrophages, DC found here.
- Intra-epithelial lymphocytes will be dotted between enterocytes
What are peyer’s patches? Where are they found? Structure? What do T & B cells require? How is antigen taken up?
- Immune sensors found in submucosa of small intestine (mainly distal ileum).
- Aggregated lymphoid follicles covered with follicle associated epithelium FAE which has no goblet cells, no secretory IgA and no microvilli.
- Has dome area with DC, naïve t cells (intrafollicular) and B cells.
- T & B cell development requires exposure to bacterial microbiota.
- Antigen taken up by M (microfold) cells within FAE that express IgA receptors so facilitate transfer of IgA bacteria complex into peyer’s patches
What can trans-epithelial dendritic cells do?
They can open up tight junction proteins and directly sample bacteria outside and go back to activate lymph nodes
How is the B cell adaptive response made in the gut?
- M cells take up pathogen. Excreted into pocket in inner surface of enterocyte containing APCs which engulf pathogens & present them with MCH-II molecules on surface.
- DCs migrate to peyer’s patch where T, B, DC cells aggregate and form organised lymphoid tissue.
- mature naive B cells express IgM in peyers, but on antigen presentation class switches to IgA)
- B cells activated and mature to become IgA secreting plasma cells that populate lamina propria.
- T & epithelial cells influence B cell maturation.
- Most of B cells secrete IgA that binds luminal antigen - preventing adhesion & invasion
What is lymphocyte homing? Where do lymphocyte go after the peyer’s patches?
- From peyer’s patches lymphocytes travel to mesenteric lymph nodes & return to circulation via thoracic duct.
- From there either enter peripheral immune system (skin, tonsils, BALT) or return to intestinal mucosa via vessels in lamina propria.
Why rapid turnover of enterocytes and goblet cells?
- Short life span 36h because enterocytes first line of defense against GI pathogens and may be affected by toxic substances in diet.
- Any lesions will be short lived.
How does cholera cause infection and what does it cause?
- Caused by vibrio cholerae serogroups 01 & 0139.
- bacteria reaches si, makes contact with epithelium & releases cholera enterotoxin.
- Internalised by retrograde endocytosis.
- High levels of cAMP cause active secretion of salts and water causing profuse watery diarrhoea. (CFTR-channel)
How is cholera spread?
Faecal oral route - contaminated water/food
What does cholera infection present with?
Severe dehydration secondary to diarrhoea, maybe vomiting, nausea, abdominal pain
What diagnosis for cholera infection?
- Bacterial culture from stool sample on selective agar,
- rapid dipstick tests available
What treatment for cholera infection? what is the vaccine name?
Oral rehydration. Vaccine - dukoral (oral inactivated)
What are other causes of infectious diarrhoea/gastroenteritis?
- Viral (rotavirus, norovirus)
- protozoal parasitic (giardia lambilia, enamoeba histiolytica)
- bacterial (campylobacter jejuni, E.coli, salmonella, shigella, c.diff)
How do rotaviruses work? What are the types? What is treatment? Who does it commonly infect?
- RNA virus replicated in enterocytes.
- 5 types A-E, E most common in humans.
- Most common cause of diarrhoea in infants and young kids.
- Supportive treatment - oral rehydration.
- Vaccine rotarix - live attentuated oral vaccine against type A
what is the most common cause of diarrhoea in infants & young kids?
rotavirus
How does norovirus infect people? Mode of transmission? Incubation period? How long can remain infectious for? Where do these outbreaks usually happen? Treatment? Diagnosis?
- RNA virus.
- Faecal oral route.
- Incubation 24-48h. Can remain infectious up to 2 weeks.
- Outbreaks in closed communities.
- Acute gastroenteritis recovery 1-3 days no treamtent usually.
- Diagnosis via sample PCR
What causes campylobacter transmission? Treatment? Resistance?
- Undercooked meet (especially poultry), untreated water and unpasteurised milk.
- Low infective dose (few bacteria can cause illness).
- Treatment not usually needed but azithromycin standard.
- Resistant to fluoriquinones.
- Common cause of food poisoning
What are E.coli features? What are the 6 pathotypes associated with diarrhoea and what do they cause?
- Gram negative intestinal bacteria, most harmless.
1. enterotoxigenic E.coli (ETEC): cholera-like toxin, watery diarrhoea
2. enterohaemorrhagic or shiga-toxin producing (EHEC): some get haemolytic uraemic syndrome, loss of kidney function
3. enteroinvasive E.coli (EIEC): shigella like illness, bloody diarrhoea. - Others - enteropathogenic, enteroaggregative, diffusely adherent
What is management for C.diff infection?
- Isolate patient, stop current antibiotics.
- Use metronidazole, vancomycin.
- Increasingly hard to treat with recurrence.
- FMT (faecal microbiota transplantation) high cure rate.
How does c.diff cause infection?
- Usually associated with antibiotics use.
- Exists in gut in equilibrium, dysbiosis caused by antibiotics causes c.diff overgrowth - toxin production.
