Immunology of the Gut Flashcards
what is the antigen load of the gut provided by?
resident microbiota bacteria
dietary antigens
exposure to pathogens
what is the active stage of the gut?
state of restrained activation:
- tolerance vs active immune response
tolerance (food antigens & commensal bacteria)
immunoreactivity (pathogens)
- dual immunological role
what is required for immune homeostasis of gut and health immune system
bacterial microbiota presence
what are the 4 major phyla of bacteria?
bacteroidetes
firmicutes
actinobacteria
proteobacteria
(also viruses and fungi)
how does the host increase and decrease bacterial cell numbers?
what is the site of immunological defect with development of small intestine?
peyers patches- fewer and less cellular
lamina propria- thinner and less cellular
germinal centres- fewer plasma cells
isolated lymphoid follicles- smaller and less cellular
where does an immunological defect with development of mesenteric lymph nodes affect?
germinal centres- smaller, less cellular with fewer plasma cells
what is the location of an immunological defect of CD8 T-cells?
intestinal epithelial lymphocytes- fewer cells with reduced cytotoxicity
what defects can affect the intestine epithelial cells and reduce them?
immunological defect with:
- expression MHC class II molecules
expression of TLR9
levels of IL-25
what location do immunological defects with expression of angiotensin 4 and REG3y affect?
paneth cells
what location does immunological defect in production of secretory IgA affect?
B cells
what location does an immunological defect with CD4 T cells affect?
lamina propria- fewer cells, decreased Th cells in small intestine and increased in colon
what location does an immunological defect with CD4-CD25 T cells affect?
mesenteric lymph nodes- reduce expression FOXP3 and reduces suppressive capacity
what are the chemical digestive factors produced and bacterial content for different areas of GI tract?
what is symbiosis?
living together with no harm/gain
what is commensal?
microorganisms that benefit from host but has no effects on the host
what is pathobionts?
symbiosis with inflammatory response under right environment
what is dysbiosis?
immunological disequilibrium with sway to produce pathogens -> pathobionts inflammation
what are the causes of dysbiosis?
infection/ inflammation
diet
xenobiotics
hygiene
genetics
what are the physical barriers in mucosal defense?
anatomical= epithelial barries & peistalsis
chemical= enzymes & acidic pH
what are the different layers to the epithelial barrier?
mucus layer- goblet cells
epithelial monolayer- tight junctions
paneth cells (small intestine)
where are paneth cells located?
bases of crypts of Lieberkuhn
secrete antimicrobial peptides (defensins) and lysozyme
what is the effect of commenal bacterial in mucosal defence?
ecological barrier
what is the immunological response following invasion?
- MALT (mucosa associated lymphoid tissue)
- GALT (gut associated lymphoid tissue)
where is MALT located?
found in submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
what are MALT follicles surrounded by?
HEV postcapillary venules, allowing easy passages of lymphocytes
what is the level of immunological tissue in the oral cavity?
rich
what is GALT responsible for?
- adaptive & innate immune responses
- Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes
what are the types of lymphoid tissue?
non- organised
organised
what are the types of non-organised GALT?
-
Intra-epithelial lymphocytes
- Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells
- Lamina propria lymphocytes
what are the types of organised lymphoid tissue?
- Peyer’s patches (small intestine)
- Caecal patches (large intestine)
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
what are non-organised GALT?
stem cells which produce enterocytes
how do non-organised GALT reproduce in the small and large intestine?
- migrate to APEX
- form apoptotic intraepithelial cells
- At base also get goblet cells formed and move up to produce mucous
- Stem cells also produce Paneth cells which produce anti-microbial peptides
- Within the epithelium have intraepithelial lymphocytes
- Within lamina propria have intestinal immune cells (T-cells, B-cells, macrophages and dendritic cells)
- The large intestine doesn’t have:
- Paneth cells (lots goblet cells)
- Villi (only crypts)
- the large intestine has intraepithelial lymphocytes
where are Peyer’s patch located?
- Found in submucosa small intestine – mainly distal ileum
what is the composition of Peyer’s patch?
- Aggregated lymphoid follicles covered with follicle associated epithelium (FAE).
- FAE - no goblet cells, no secretory IgA, no microvilli
- Organised collection of naïve T cells & B-cells
- Development requires exposure to bacterial microbiota
- 50 in last trimester foetus, 250 by teens
- 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 is the use of trans-epithelial dendritic cells?
way to get bacteria into cell without use of M cells
how do trans-epithelial dendritic cells work?
- open-up tight junction proteins and send dendrites outside epithelium
- sample bacteria and bring it back to process and transport to mesenteric lymph nodes
- have tight junction proteins to maintain integrity of epithelial barrier once they have taken antigen from lumen of gut
how does the B cell adaptive response work?
- Mature naïve B-cells express IgM in Peyer’s Patches
- On antigen presentation class switches to IgA
- T-cells & epithelial cells influence B cell maturation via cytokine production
- B cells further mature to become IgA secreting plasma cells.
- Populate lamina propria
how is secretory IgA produced?
- plasma cells migrate to enterocytes
- Taken up into epithelial cells
- Undergo enzymatic cleavage
- Secreted as secretory IgA
what are the effects of sIgA?
binds to luminal antigen
preventing its adhesion and consequent invasion
how does lymphocytes homing and circulation occur?
- peyer’s patch-antigen presentation & activation
- mesenteric lymph node (lymphocyte proliferation)
- thoracic duct
- circulation
5 lamina propria or peripheral immune system
where does 𝝰4β7 Integrin/MAdCAM-1 Adhesion & Gut Homing occur?
- high endothelial venules
- Express mucosal addressin cell adhesion molecule 1 (MAdCAM1)
- Lymphocytes express 𝝰4β7 Integrin
- Lymphocytes roll along HEV until tethered by activation MAdCAM1
- Rolling arrests and migrate into lamina propria
- B-Cells do the same thing
what is the life span of enterocytes and goblet cells?
- Enterocytes & goblet cells of small bowel have a short life span (about 36 hrs)
- Rapid turnover contrasts with lifespan of weeks/months for other epithelial cell types (e.g. lung, blood vessels)
why do enterocytes have such a high turn over?
- 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 the cholera infection mechanism?
- acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
- Bacteria reaches small intestine → contact with epithelium & releases cholera enterotoxin.
- Toxin internalised through retrograde endocytosis
- Causes activation adenylate cyclase and cAMP
- Active secretion salt and fluid through activation of cystic fibrosis transmembrane conductance regulator (CFTR)
- High loss salt, potassium, chloride, bicarb
- Water follows this concentration gradient causing diarrhoea
what is the transmission of cholera?
faecal-oral route
mainly spreads via contaminated water & food
main symptoms of cholera?
severe dehydration & water diarrhoea
other symptoms:
vomiting, nausea and abdo 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.
what is the prevention for cholera?
vaccine
Dukoral, oral, inactivated.
what are the viral causes of infectious diarrhoea?
- Rotavirus (children)
- Norovirus “winter vomiting bug”
what are the bacterial causes of infectious diarrhea?
- Campylobacter jejuni
- Escherichia coli
- Salmonella
- Shigella
- Clostridium difficile
what are the protozoal parasitic causes of infectious diarrhoea?
- Giardia lamblia
- Entamoeba histolytica
what are rotaviruses?
- RNA virus, replicates in enterocytes.
- 5 types A – E, type A most common in human infections.
what is the main cause of diarrhoea in infants and young children worldwide?
rotavirus
what is the treatment for rotavirus?
oral rehydration therapy
what is the prevention for rotavirus?
vaccination- live attenuated oral vaccine (Rotarix) against type A
before vaccine, most individuals infected by age 5, repeated infections develop immunity
what type of virus is norovirus?
- RNA virus
- Incubation period 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
what is the treatment of norovirus?
not usually required
what is the diagnosis of norovirus?
simple PCR
what are the most common species of campylobacter?
- Campylobacter jejuni, Campylobacter coli
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 of campylobacter?
- Not usually required
- Azithromycin (macrolide) is standard antibiotic
- Resistance to fluoroquinolones is problematic
what is the commonest cause of food poisoning in the UK
campylobacter
what are the features of E.col?
- Diverse group of Gram-negative intestinal bacteria
- most harmless
- 6 ”pathotypes” associated with diarrhea (diarrhoeagenic):
- enterotoxigenic E.coli (ETEC)
- enterohaemorrhagic or Shiga toxin-producing E.coli (EHEC/STEC)
- enteroinvasive E.coli (EIEC)
- enteropathogenic E.coli (EPEC)
- enteroaggregative E.coli (EAEC)
- diffusely adherent E.coli (DAEC)
what are the features of ETEC?
(enterotoxigenic E.coli)
- Cholera like toxin
- Watery diarrhoea
what is a consequence of Enterohaemorrhagic E.coli (EHEC/STEC)?
haemolytic uraemic syndrome: loss kidney funciton
what are the features of Enteroinvasive E.coli (EIEC)
shigella like illness
bloody diarrhoea
what is the management of 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
how does C. Diff occur?
- microbiota of healthy human can contain c.diff without problems
- Dysbiosis (usually caused by exogenous disturbance (antibiotics))
- C. diff starts colonising enterocytes in gut but not producing any toxin
- Pathogen induced disturbance crease supportive environment to produce a toxin= inflammation distal gut
- Metronidazole can cause c.diff as well as treating it!
