GI immunology of the gut Flashcards
What makes up the massive antigen load of the gut? (3)
- resident microbiota
- dietary antigens
- exposure to pathogens
- must balance tolerance and active immune response- “restrained activation”
What makes up the gut microbiota?
4 major phyla of bateria (bacteroidetes, firmcutes, actinobacteria, proteobacteria)
- viruses
- fungi
- -> provide traits that we didn’t have to evolve on our own: genes in gut flora 100 times our own genome
benefits of gut microbiota (4)
- provide essential nutrients that we can’t manufacture
- metabolise indigestible compounds
- defence against colonisation opportunistic pathogens
- contribute to intestinal architecture
why is the microbiome of the stomach relatively small?
its acidic pH
why is the microbiome of the liver relatively small?
bile acids
what is found in the pancreas that affects the microbiome? (3)
trypsin
amylase
carboxypeptidase
what is found in the small intestine that affects the microbiome?
- brush border
- enzymes
what is found in the colon that affects the microbiome?
no host digestive factors
three relationships that the gut flora have with the body
- symbiotic
- commensal
- pathobiont (symbionts that can cause inflammation and disease)
what is a commensal relationship
- no benefit but no harm to host
what do symbionts contribute to?
regulation of the gut
what do pathobionts contribute to?
inflammation
what can affect whether a relationship is healthy or dysbiotic? (5)
- infection/inflammation
- diet
- xenobiotics
- hygiene
- genetics
examples of bacterial metabolites and toxins in dysbiosis (5)
TMAO - associated with atherosclerosis
4-EPS- associated with autism
SCFAs- low number associated w/ IBD, high number w/ stress
bile acids
AHR ligand- associated w/ MS, rheumatoid arthritis and asthma
what are the physical gut barriers? (Anatomical (2), chemical (2))
Anatomical: - epithelial barrier - peristalsis Chemical: - enzymes - acidic pH
defensive features of the epithelial barrier (3)
- mucus layer (goblet cells)
- epithelial monolayer (tight junctions)
- Paneth cells in the base of crypts of lieberkuhn and secrete antimicrobial defensins and lysozyme
how are commensal bacteria useful for defense?
- occupy ecological niche
second line of defense
two immunological defenses following invasion
- mucosa associated lymphoid tissue (MALT)
- gut associated lymphoid tissue (GALT)
3rd line of defence
where are MALT found?
- in submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
What surrounds MALT?
HEV (postcapillary venules) - allows easy passage of lymphocytes
High endothelial venules (HEV) are specialized post-capillary venous swellings characterized by plump endothelial cells as opposed to the usual thinner endothelial cells found in regular venules. HEVs enable lymphocytes circulating in the blood to directly enter a lymph node (by crossing through the HEV).
In which cavity is lots of MALT found?
- the oral cavity
- particularly the palatine, pharyngeal and lingual tonsils
What is GALT responsible for?
both adaptive and innate immune responses
What is the largest mass of lymphoid in the body?
GALT
what does GALT consist of? (4)
B + T lymphocytes
macrophages
APC
specific epithelial + intraepithelial lymphocytes
examples of non-organised GALT tissue (2)
- intraepithelial lymphocytes - make up 1/5th of intestinal epithelium e.g. T cells and NK cells
- lamina propria lymphocytes
examples of organised GALT tissue (4)
- peyers patches (SI)
- caecal patches (SI)
- isolated lymphoid follicles
- mesenteric lymph nodes (encapsulated)
features of non-organised GALTs
- stem cells produce enterocytes and paneth cells
- eneterocytes migrate to apex of microvili
- apoptotic intra-epithelial cells
- at base, goblet cells form and go to microvili and produce mucous
- paneth cells produce antimicrobial peptides
- intraepithelial lymphocytes
- laminapropria - majority of intestinal wall immune cells here
How does the large intestines compare to the small intestines
- no villi
- lots goblet cells
- no peyer’s patches
where are peyer’s patches found?
the submucosa of the small intestine - mainly the distal ileum
what are peyers patches made of?
- aggregated lymphoid follicles covered with follicle associated epithelium (FAE)
features of FAE
- no goblet cells
- no secretory IgA
- no microvilli
- organised collection of naive T and B cells
what do peyers patches lie beneath
M cells
what are M cells for?
antigen uptake within FAE
- they express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer’s patches
M cells are specialized epithelial cells of the mucosa-associated lymphoid tissues. A characteristic of M cells is that they transport antigens from the lumen to cells of the immune system, thereby initiating an immune response or tolerance.
alternative route for antigen transport independent of m cells
- trans-epithelial dendritic cells
- open tight junctions of epithelium and sample bacteria -> transport back to mesenteric lymph nodes
What cells do M/dendritic cells activate when they are activated by a pathogen?
B cells in peyers patches so that they become IgA-secreting plasma cells
MHCII molecules of dendritic cells migrate to peyers patch -> APC and B and T cells activated and replicated
- B cells express IgM in Peyer’s patches; on presentation class switches to IgA (more matured)
- > further maturation into IgA secreting plasma cells
- populate lamina propria
what is the funciton of secretory IgA
binds luminal antigen. preventing its adhesions and consequent invasion
how are lymphocytes circulated?
via the thoracic duct (from mesenteric lymph nodes)
- from there, enter circulation
- can then enter peripheral immune system (tonsils, skin, BALT)
what is BALT?
bronchus associated lymphoid tissue
what tether lymphocytes to HEV?
MadCAM1: once this happens, activation and rolling arrests.
migrate back to lamina propria
enterocytes and goblet cells of the small bowel have a short life span (36 hours)
- rapid turnover contrasts with lifespan of week/months for other epithelial cells types e.g. lung, blood vessels
- why>?
- enterocytes are first line of defense against GI pathogens -> first to be affected by toxic substances/pathogens
- effects of agents which interfere with cells function, metabolic rate etc diminished
- any lesions are short-lived
what causes cholera?
vibrio cholerae serogroups O1 and O139
- bacteria reaches small intestine -> contact with epithelium release cholera enterotoxin
how is cholera transmitted?
faecal-oral route
contaminated food/water
main symptoms of cholera
severe dehydration + watery diarrhoea
other symptoms of cholera
- vomiting
- nausea
- abdo pain
diagnosis of cholera?
becterial culture from stool sample on selective agar = gold standard
-> rapid dipstick tests also available
treatment of cholera?
- oral rehydraion is the main management: 80% of cases can be successfully trerated
cholera cure?
vaccine
dukoral, oral inactivated
viral causes of infection diarrhoea?
rotaviru s(kids) norovirus (winter vom bug)
protozoal parasitic causes of infectious diarrhoea?
Giardia lamblia
Entamoeba histolytica
bacterial causes of infectious diarrhoea? (5)
Campylobacter jejuni Escheria coli Salmonella Shigella Clostridum difficile
Rotavirus description (type, where proliferates, how many types are there)
RNA virus
replicates in enterocytes
5 types A-E: A most common in human infections
Rotavirus epidemiology
Most common cause of diarrhoea in infants and young kids worldwide
treatment of rotavirus
oral rehydration therapy
vaccination type for rotavirus?
live attenuated oral vaccine against type A
Norovirus/ Norwalk virus description (type. incubation period)
RNA virus with incubation period 24-48 hours
Norovirus Norwalk virus transmisison
facael oral
- infected may shed infectious virus for up to 2 weeks
- outbreaks often occur in closed communities
Norovirus Norwalk virus symptoms
acute gastroenteritis
- recovery 1-3 days
Norovirus Norwalk virus treatment
not usually required
Norovirus Norwalk virus diagnosis
sample PCR
commonest campylobacter species
jejuni and coli
campylobacter transmission (3)
undercooked meat
unpasteurised milk
low infective dose - few can cause illness
campylobacter treatment
- not usually required
- azithromycin (macrolide) is standard AB
- resistance to fluoroquinolones is problematic
campylobacter epidemiology
commonest cause of food poisoning in the UK
features of e coli (gram -ve/+ve, how many pathotypes)
- gram negative intestinal bacteria
- 6 pathotypes associated with diarrhoea
enterotoxigenic e coli features and symptoms
- cholera-like toxin
2. watery diarrhoea
enteroinvasive e coli features and symptoms
. shigella like illness
- bloody diarrhoea
enterohaemorrhagic or shiga toxin producing E.coli e coli features and symptoms
- ecoli O157 serogroup, shigatoxin/verotoxin
- 5-10% get haemolytic uraemic syndrome: loss of kidney function
management of C diff in hosp
- isolate patient
- stop current ABs
- metronidaloze, vancomycin
- recurrence rate 15-35% aftr initial infection: increasingly hard to treat
- faecal microbiota transplantation = 98% cure rate
- remember metronidazole can cause c diff and gastroenteritis
