Immunology of the Gut Flashcards
What are the implications of the large surface area of the GI tract?
exposure to a massive antigen load
What does the massive antigen load consist of?
- resident microbiota
- dietary antigens
- pathogen exposure
What is the impact of this large antigen load?
GI tract is in a state of ‘restrained activation’
What is a state of ‘restrained activation’
- tolerance (food and commensal bacteria) vs active immune response
- dual immunolgoical role
What does immune homeostasis and development of a healthy immune system require?
the presence of bacterial microbiota
What are the 4 major phyla of bacteria?
- Bacteroidetes
- Firmicutes
- Actinobacteria
- Proteobacteria
What is the benefits of the gut microbiota?
- provides traits that we do not have in our genome
- essential nutrients
- metabolism of ingestible compounds
- defence against colonisation of pathogens
What is dysbiosis?
altered microbiota composition
What is the impact of symbionts on the host?
- no effect, truly neutral
- for regulation
What is the impact of commensals on the host?
no effect, but benefit from being part of the host
What is the impact of pathobionts on the host?
- no effect normally
- can cause dysregulated inflammation and disease
What are the important factors of immunological equilibrium in the gut?
- symbionts
- commensals
- pathobionts
What can cause dysbiosis?
- infection
- inflammation
- diet
- xenobiotics
- hygiene
- genetics
What happens during dysbiosis?
production of bacterial metabolites and toxins
What are the 2 primary physical types of barriers?
- Anatomical
- Chemical
What are the different types of anatomical barriers?
- epithelial barriers
- peristalsis
What are the different types of chemical barriers?
- enzymes
- acidic pH
What is involved in the epithelial barrier?
- mucus layer (goblet cells)
- epithelial monolayer, tight junctions
- paneth cells (in small intestines)
What is the role of Paneth Cells?
- bases of crypts of Lieberkuhn
- secrete antimicrobial peptides (defensins) and lysozyme
How do commensal bacteria act as barrier?
occupy an ecological niche
What is involved in the immunological barriers?
- MALT (Mucosa Associated Lymphoid Tissue)
- GALT (Gut Associated Lymphoid Tissue)
Where is MALT located?
- in submucosa below the epithelium
- as lymphoid mass containing lymphoid follicles
- follicles are surrounded by HEV postcapillary venules (easy passage of lymphocytes for a response)
What area is rich in immunological tissue?
oral cavity
- palatine tonsil
- lingual tonsils
- pharyngeal tonsils (adenoids)
What is the role of GALT?
adaptive and innate immune response through generations of lymphoid cells and Abs
What are the non-organised forms of GALT?
- intra-epithelial lymphocytes (eg: T cells and NK cells)
- Lamina propria lymphocytes
What are the organised forms of GALT?
- Peyer’s patches
- Caecal patches
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
Where are Peyer’s patches found?
small intestine
Where are Caecal patches found?
large intestine
How are non-organised GALT released?
migrate to the tip of the microvilli prior to that as well as absorptive epithelial cells
What produces mucus secreting goblet cells?
- stem cells
- crypts
Where do Paneth cells migrate to?
the bottom of the crypt of Lieberkuhn
Where are intraepithelial lymphocytes?
between entry sites
What is found in the mucosa of the microvilli?
- macrophages
- IgA B cells
- dendritic cells
- T cells
Where are Peyer’s patches?
- submucosa small intestine
- mainly in the distal ileum
What are Peyer’s patches?
aggregated lymphoid follicles covered with follicle associated epithelium (FAE)
What are characteristics of Peyer’s patches?
- no goblet cells
- no secretory IgA
- lack microvilli
What do Peyer’s patches contain?
Organised collection of naïve T cells and B-cells
What is required for the development of Peyer’s patches?
exposure to bacterial microbiota
How are antigens taken up by Peyer’s patches?
- via M cells within FAE
- expressIgA receptors, facilitating transfer of IgA-bacteria complexinto the Peyer’s patches
What can trans-epithelial dendritic cells do?
- open up tight junction proteins and send the dendrites outside into the lumen of the intestinal tract to directly sample bacteria
- cells then go to mesenteric lymph nodes
What happens in the B cell adaptive response in Peyer’s patches?
- mature-naive B cells express IgM in Peyer’s patches
- switch to IgA on antigen presentation
- T cells and epithelial cells influence B cell maturation via cytokine production
- B cells mature to become IgA secreting plasma cells
- populate lamina propria
How is secretory IgA produced?
- plasma cell produces IgA
- taken from submucosa into enterocyte vesicle
- enzymatic cleavage
- leading to secretory IgA in the lumen
What does secretory IgA do?
- bind to antigens in lumen
- prevents adhesion and invasion
(secreted by 90% of gut B cells)
What happens in lymphocyte homing and circulation?
- lymphocytes from Peyer’s patch move into the mesenteric lymphnode
- proliferate in the lymphnode
- return to circulation via the thoracic duct into the systemic venous system
- can either enter the peripheral immune system or return to the intestinal mucosa via vessels in the lamine propria
What is part of the peripheral immune system?
- skin
- tonsils
- BALT (Bronchus Associated Lymphoid Tissue)
How does the homing cascade direct circulating naive T cells to Peyer’s patches?
- rolling adhesion of T cells to HEV
- activation of T cells via binding of a4b7 integrin on T cell membrane and MAdCAM-1 on HEV walls
- T cell secreted into the lamina propria
Why do enterocytes and goblet cells have a rapid turnover?
- first line of defense and may be directly affected by toxicity
- may have impacts on function, metabolic rate
- shorten the effect of lesions
What happens if enterocyte and goblet cell turnover is interrupted?
severe intestinal dysfunction
What is the mechanism behind cholera infections?
- Vibrio cholerae serogroups O1 and O139
- bacteria reaches small intestine, contact with epithelium triggers the release of cholera enterotoxin
- cholera toxin enters cell via retrograde endocytosis
- increased adenylate cyclase acitvity
- increased cAMP
- cAMP activates ion channels which secrete Na+, K+, Cl- and HCO3- into the intestinal lumen
- water follows ions leading to osmotic diarrhoea
How is cholera transmitted?
- faecal-oral route (contaminated water and food)
What are the main symptoms of cholera?
- severe dehydration
- watery diarrhoea
- vomiting
- nausea
- abdominal pain
How do you diagnose cholera?
- bacterial culture from stool sample on selective agar (gold standard)
- rapid dipstick tests
How do you treat cholera?
oral rehydration
How do you vaccinate against cholera?
- Dukoral vaccine
- oral and inactivated
What are the possible viral causes of infectious diarrhoea/gastroenteritis?
- Rotavirus (children)
- Norovirus
What are the possible bacterial causes of infectious diarrhoea/gastroenteritis?
- Campylobacter jejuni
- E. coli
- Salmonella
- Shigella
- C. difficile
What are the possible protozoal parasitic causes of infectious diarrhoea/gastroenteritis?
- Giardia lamblia
- Entamoeba histolytica
What are rotaviruses?
- RNA virus
- replicates in enterocytes
- 5 types (A-E)
- A most common in human infection
How common are rotaviruses?
most common cause of diarrhoea in children and infants
How do you treat rotaviruses?
- oral rehydration therapy
- Rotarix vaccination (live, attenuated against type A)
What is Norovirus?
- RNA virus
- incubation: 24-48hours
How are Noroviruses transmitted?
- faecal-oral transmission
- may shed virus for up to 2 weeks
- outbreaks in closed communities common
What are the symptoms of Norovirus?
- acute gastroenteritis
- recovery in 1-3 days
How do you diagnose Norovirus?
Sample PCR
What are the causes of food poisoning?
- Campylobacter jejuni
- Campylobacter coli
How is Campylobacter transmitted?
- undercooked meat
- untreated water
- un-pasturised milk
- low infective dose
How do you treat for Campylobacter?
- not usually required
- Azithromycin is standard ABx
- Resistance to fluoroquinolones is problematic
What are the pathotypes of E. coli?
gram negative bacteria
- Enterotoxic E. coli
- Enterohaemorrhagic/Shiga toxin-producing E. coli
- Enteroinvasive E. coli
- Enteropathogenic E. coli
- Enteroaggregative E. coli
- Diffusely adherent E. coli
What symptoms is Enterotoxic E. coli associated with?
- cholera like toxin
- water diarrhoea
What symptoms is Enterohaemorrhagic/Shiga toxin-producing E. coli associated with?
- 5-10% haemolytic uraemic syndrome
- loss of kidney function
What symptoms is Enteroinvasive E. coli associated with?
- shigella like illness
- bloody diarrhoea
How does Clostridium difficile infect the body?
- always present in the gut
- exogenous disturbance e.g. antibiotics leads to dysbiosis
- intermediate dysbiotic state
- pathogen induced disturbance and toxin induction leads to diseased state
How do you manage Clostridium difficile?
- isolation
- stop current ABx
- Metronidazole (can also trigger infection)
- Vancomycin
- reccurence rate 15-35%, increasingly more difficult to treat
- faecal microbiota transplant
What symptoms would indicate a C. difficile infection?
- raised WCC and CRP
- new onset diarrhoea
- generalised tenderness
- signs of dehydration (AKI and dry mucous membranes)
How do you diagnose a C. difficile infection?
- stool sample for C. difficile toxin
- stool cultures
- Imaging (AXR)
