gut immunology Flashcards
what is the surface area of the GI tract?
200m^2
what antigen load does the gut have to deal with?
massive antigen load: resident micbrobiota 10^14 bacteria
dietary antigens
exposure to antigens
in terms of immunology what term is used to describe the state of activation of the gut?
what does this mean
restrained activation -
dual immunological role of tolerance vs active immune response
what does the Immune homeostasis of gut & development of healthy immune system require?
presence of bacterial microbiota
what does the gut show a tolerance of vs an active immune response?
tolerance of food antigens and commensal bacteria
immunoreactivity to pathogens
what are the four major phyla of bacteria in the gut? BFAP
Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria
what does the massive amount of gut microbiota provide?
Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome.
what does dysbiosis describe?
microbial imbalance that disturbs microbial composition e.g. pathogens
what trend is seen in the number of bacterial cell numbers as you move along the GI tract?
why?
increases as you move along.
inhibiting factors such as acids and digestive enzymes limit the number of bacteria, these are not found in the colon
what host factors influence bacterial cell numbers?
nutrients provide growth
digestive factors, peristalsis and defecation cause lysis and elimination
what type of bacteria causes regulation, which causes inflammation?
symbionts regulate - present with no benefit or harm from host or bacteria
pathobionts inflame - cause dysregulation
what are commensal bacteria?
organisms that benefit from host but have no effect on host
what are the causes of dysbiosis?
infection and inflammation
diet
xenobiotics
hygiene
genetics
what are xenobiotics?
small chemical compounds that enter the gut unnaturally e.g drugs or pollutants
what physical barriers in the gut provide mucosal defence?
epithelial barrier
peristalsis
enzymes
acidic pH
commensal bacteria occupy _________
an ecological niche
what are the immunological mucosal defence mechanisms of the gut following invasion?
MALT (Mucosa Associated Lymphoid Tissue)
GALT (Gut Associated Lymphoid Tissue)
what epithelial barriers provide mucosal defence in the gut?
Mucus layer - Goblet cells
Epithelial monolayer - Tight junctions
Paneth Cells (small intestine)
Bases of crypts of Lieberkühn.
Secrete antimicrobial peptides (defensins) & lysozyme.
where is MALT found?
MALT - mucosal associated lymphoid tissue is Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
in MALT, what are the lymphoid follicles surrounded by and what does this allow for?
Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
what is GALT responsible for?
Responsible for both adaptive & innate immune responses
what immune cells are found in the gut associated lymphoid tissue?
Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes
what are the two types of GALT?
non-organised and organised
what are the two 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 four types of organised GALT?
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
what is the largest mass of lymphoid tissue in the body?
GALT
what key MALTs are found in the oral cavity?
palatine tonsils
lingual tonsils
pharyngeal tonsils
how does the gut epithelium act as a barrier?
mucus layer of goblet cells
epithelial monolayer -tight junctions
paneth cells in small intestine
where are Payers patches found?
submucosal small intestine - mainly distal ileum
outline the structure of Payers patches?
aggregated lymphoid follicles covered with follicle associated epithelium and M cells.
have a sub-epithelial dome of dendritic cells.
b cell follicles
interfollicular T-cells
how does development of peyers patches naive lymphocytes occur?
development requires exposure to bacterial microbiota
what is the function of M cells?
antigen uptake via M (microfold) cells within follicle associated epithelium (FAE)
M cells express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyers patches
how can antigens enter gut mucosa?
through microfold cells (M cells) and trans-epithelial dendritic cells
outline the mechanism of antigen sampling occurring independent of M cells?
trans-epithelial dendritic cells:
dendritic cells open up tight junction proteins.
send dendrites outside epithelium
directly sample bacteria
transfer them to mesenteric lymph nodes
what antibody type is expressed by mature naive B cells in Peyers patches?
IgM
on antigen presentation what class do mature naive B cells in Peyers patches switch from and to?
switch from IgM to IgA
how do T cells and epithelial cells influence B cell maturation?
via cytokine production
Once B cells have matured due to release of cytokines from T cells and the epithelial cells, how do they further mature and what area do they then populate?
B cells further mature to become IgA secreting plasma cells.
Populate lamina propria
what is the function of secretory IgA?
Up to 90% of gut B-cells secrete IgA
sIgA binds luminal antigen
→ preventing its adhesion and consequent invasion.
how do circulating lymphocytes re-enter intestinal tissue?
lymphocytes are found in HEVs
HEVs express mucosal adressin cell adhesion moecule 1 (MAdCAM-1)
lymphocytes express alpha4beta7 integrin
lymphocytes roll along HEV until they are tethered by MadCAM-1
on binding there is activation and rolling arrest
migration back into lamina propria or into skin/tonsils/BALT
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)
Q. Why?
enterocytes are first line of defence against GI pathogens and 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
outline the mechanism of cholera infection?
bacteria reaches small intestine -> contact with epithelium and releases cholera enterotoxin
what is cholera and what is it caused by?
acute bacterial disease caused by vibrio cholerae serogroups O1 and O139
how is cholera transmitted?
through faecal-oral route (contaminated water and food)
what are the symptoms associated with a cholera infection?
Main symptoms
Severe dehydration & watery diarrhoea
Other symptoms
Vomiting, nausea & abdominal pain
how is a cholera infection diagnosed?
: bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available.
what are the treatment options for a cholera infection?
oral-rehydration is the main management ; up to 80% of cases can be successfully treated
Vaccine: Dukoral, oral, inactivated.
what are the viral causes of gastroenteritis? (infectious diarrhoea)
rotavirus (children(
norovirus
what are the protozoal parasitic causes of gastroenteritis?
Giardia lamblia
Entamoeba histolytica
what are the bacterial causes of gastroenteritis?
Campylobacter jejuni
Escherichia coli
Salmonella
Shigella
Clostridium difficile
what are rotaviruses?
RNA virus, replicates in enterocytes.
5 types A – E, type A most common in human infections.
what is the most common cause of diarrhoea in infants and young children worldwide?
rotaviruses
what are the treatment options for rotaviruses?
Oral rehydration therapy
Still causes ~ 200,000 deaths/year.
Before vaccine, most individuals had an infection by age 5, repeated infections develop immunity.
Vaccination:
Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013.
what are noroviruses?
RNA virus
Incubation period 24-48 hours
how are noroviruses transmitted?
Faecal-oral transmission.
Individuals may shed infectious virus for up to 2 weeks
Outbreaks often occur in closed communities
what are the symptoms associated with norovirus?
Acute gastroenteritis, recovery 1 – 3 days
what treatment options are there for norovirus>
not usually required
how is campylobacter transmitted?
Undercooked meat (especially poultry), untreated water & unpasteurised milk
Low infective dose, a few bacteria (<500) can cause illness
what are the treatment options for campylobacter?
Not usually required
Azithromycin (macrolide) is standard antibiotic
Resistance to fluoroquinolones is problematic
what are the six pathotypes of escherichia coli (E.coli) that are associated with diarrhoea?
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 is Enterotoxigenic E. coli (ETEC)?
Cholera like toxin
Watery diarrhoea
what is Enteroinvasive E. coli (EIEC)?
Shigella like illness
Bloody diarrhea
how is clostridium difficile (C.diff) managed?
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
