🍔Gastro🍔 - Immunology of the Gut Flashcards
Why must the GI tract have “restrained activation” of the immune response?
Massive antigen load
Resident microbiota 1014 bacteria
Dietary antigens
Exposure to pathogens
Tolerance vs active immune response – Dual immunological role
Immune homeostasis of gut & development of healthy immune system requires presence of bacterial microbiota
What must the immune system of the GI tract show tolerance and immunoreactivity to?
Tolerance - food antigens, commensal bacteria
Immunoreactivity - pathogens
What 4 major phyla of bacteria exist in the gut?
Bacteroidetes
Firmicutes
Actinobacteria
Proteobacteria
What host actions lead to increased cell numbers in the gut microbiota?
Ingested nutrients
Secreted nutrients
Both lead to bacterial growth
What host actions lead to decreased cell numbers in the gut microbiota?
Chemical digestive factors - bacterial lysis
Peristalsis, contractions, defecation - bacterial elimination (i.e. removal)
What functions does the gut microbiota perform?
Production of essential nutrients
Metabolism of indigestible compounds
Defence against colonisation of pathogens
What is symbiosis?
living together, doesn’t imply either partner benefits
What are symbionts?
organism that lives with a host without benefit or harm to either
What are commensals?
a microorganism which benefits from association but has no known effects on host
What are pathobionts?
symbionts that don’t normally elicit an inflammatory response BUT under particular conditions (usually environmental) has the POTENTIAL to cause dysregulated inflammation & disease
What is dysbiosis?
Unhealthy (for whatever reason) gut microbiota
What can cause dysbiosis?
Infection/inflammation
Diet
Xenobiotics - small chemical compounds that enter the gut unnaturally e.g. drugs, pollutants etc…
Hygiene
Genetics
What is gnotobiology?
selective colonisation of germ-free animals
What are the physical barriers of the mucosa?
Anatomical - epithelial barrier, peristalsis
Chemical - enzymes, acidic pH
What role do commensal bacteria play in immune defence of the gut?
They occupy an ecological niche
They compete with potential pathogens for space and nutrients
What are the immunological tissues present in the GI tract?
MALT (Mucosa Associated Lymphoid Tissue)
GALT (Gut Associated Lymphoid Tissue)
What are the components of the epithelial barrier?
Mucus layer - goblet cells
Epithelial monolayer - tight junctions
Paneth cells (small intestine)
What are paneth cells?
Found in the bases of crypts of Lieberkühn
Secrete antimicrobial peptides (defensins) and lysozymes
What is MALT?
Mucosa Associated Lymphoid Tissue
Present in the submucosa below epithelial layers as lymphoid masses (e.g., follicles surrounded by HEVs)
What are HEVs?
high endothelial venules (HEV) postcapillary venules
help lymphocytes migrate from bloodstream
Outline the importance of HEVs
Immune surveillance: identify foreign invaders and changes in the body’s own cells, such as neoantigens in cancer
Lymphocyte recirculation: support high levels of lymphocyte extravasation from the blood.
Immune responses: help initiate and maintain immune responses in lymph nodes
What are the key MALTs in the oral cavity?
Palatine tonsils
Lingual tonsils
Pharyngeal tonsils
What is GALT?
Gut Associated Lymphoid Tissue (GALT)
Responsible for both adaptive & innate immune responses through generations of lymphoid cells & antibodies
What are the non-organised components of GALT?
Intra-epithelial lymphocytes
-Make up 1/5th intestinal epithelium, e.g. T-cells, NK cells
Lamina propria lymphocytes
What are the organised components of GALT?
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
Outline the non-organised GALT in the small intestine
Epithelium - goblet cells and intraepithelial lymphocytes
Crypts contain paneth cells
Lamina propria contains T cells, IgA B cells, macrophages, DCs
How does the non-organised GALT in the large intestine compare to that of the small intestine?
No paneth cells in the crypts
Increased number of goblet cells
What are Peyer’s patches?
Found in submucosa small intestine – mainly distal ileum
Aggregatedlymphoid follicles covered with follicle associated epithelium (FAE)
Organised collection of naïve T cells and B-cells
How do the naïve lymphocytes develop in the Peyer’s patches?
Development requires exposure to bacterial microbiota
What is the follicle associated epithelium (FAE)?
Specialised epithelium that is associated with a follicle
No goblet cells, no secretory IgA, lack microvilli
Contain microfold (M) cells that allow antigen uptake
What are M cells?
Microfold cells
Cells within FAE that express IgA receptors
Facilitate transfer of IgA-bacteria complexes into the Peyer’s patches
How does antigen sampling occur independently of M cells?
Trans-epithelial dendritic cells
How do trans-epithelial dendritic cells sample antigens?
Dendritic cells open up tight junctions proteins (they express their own proteins)
Send dendrites outside of the epithelium
Directly sample bacteria, transferring them to mesenteric lymph nodes
What do mature naïve B-cells express in Peyer’s patches?
IgM
What happens to mature naïve B-cells upon antigen presentation in Peyer’s patches?
Switches class from IgM to IgA
What happens to B cells when they further mature?
T-cells and epithelial cells influence B-cell maturation via cytokine production
B-cells further mature to become IgA secreting plasma cells
Populate the lamina propria
What is the function of secretory IgA?
sIgA binds luminal antigen
preventing its adhesion and consequent invasion
How is IgA secreted into the lumen?
Describe the lymphocyte circulation
How do circulating lymphocytes re-enter intestinal tissue?
Lymphocytes in HEVs
HEVs express MAdCAM-1, lymphocytes express α4β7 integrin
Lymphocytes roll along HEV until they are tethered by MAdCAM-1
On binding there is activation and rolling arrest, followed by migration into the lamina propria
How does the turnover of enterocytes compare to other epithelial 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 doe enterocytes have such a rapid turnover?
Enterocytes are first line of defence 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 due to elimination of cells
Any lesions will be short-lived
What significance does the rapid turnover of enterocytes have pathologically?
If escalator-like transit of enterocytes is interrupted through impaired production of new cells (e.g. radiation) severe intestinal dysfunction will occur
(also rapidly dividing cells leads to higher risk of tumours/cancers)
What is the mechanism of cholera infection?
Cholera - acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
Bacteria reaches small intestine → contactwith epithelium & releasescholera enterotoxin
What effect does the cholera enterotoxin have?
Increases adenylate cyclase activity, increasing cAMP levels
Causes Na, K, Cl and HCO3 to leave cells, along with water
Leads too diarrhoea
Outline the transmission and symptoms of cholera
Transmitted via the faecal-oral route - contaminated water and food
Main symptoms - severe dehydration and watery diarrhoea
Other symptoms - vomiting, nausea, abdominal pain
How is cholera diagnosed and what is the treatment?
Diagnosis - bacterial culture from stool sample on selective agar, rapid dipstick tests also available
Treatment - oral-rehydration is main management, successfully treats 80% of cases
What is the vaccine for cholera?
Dukoral, oral, inactivated
What is gastroenteritis?
Infectious diarrhoea
What are the causes other than cholera of gastroenteritis?
Viral - rotavirus (children), norovirus
Protozoal parasitic - Giardia lamblia, Entamoeba histolytica
Bacterial - Campylobacter jejuni, E. coli, Salmonella, Shigella, C. difficile
What are rotaviruses?
RNA virus, replicates in enterocytes
5 types A – E, type A most common in human infections
Most common cause of diarrhoea in infants & young children worldwide.
What is the treatment for rotaviruses?
Oral rehydration therapy
What is the vaccination for rotaviruses?
Live attenuated oral vaccine (Rotarix) against type A
Outline Norovirus (genus) Norwalk virus (species)
RNA virus, Incubation period 24-48 hours
Estimated 685 million cases & 200,000 deaths/year
How is norovirus/norwalk virus transmitted?
Faecal-oral transmission
Individuals may shed infectious virus for up to 2 weeks, even after recovery
Outbreaks often occur in closed communities
What are the symptoms of norovirus?
Acute gastroenteritis, recovery 1-3 days
How is norovirus diagnosed?
Sample PCR
Outline campylobacter
“curved bacteria”
Most common species:
Campylobacter jejuni, Campylobacter coli
How is campylobacter transmitted?
Undercooked meat (especially poultry), untreated water & unpasteurised milk
Low infective dose, a few bacteria (<500) can cause illness
What is the treatment for campylobacter?
Not usually required
Azithromycin (macrolide) is standard antibiotic
Resistance to fluoroquinolones is problematic
Outline the epidemiology of campylobacter in the UK
Estimated 280,000 cases per year in UK, 65,000 confirmed
Commonest cause of food poisoning in the UK
Outline Escherichia coli (E. coli)
Diverse group of Gram-negative intestinal bacteria
Most harmless
6 pathotypes associated with diarrhoea (diarrhoeagenic)
What are the 6 pathotypes of E. coli?
Enterotoxigenic E. coli (ETEC)
Enteroinvasive E. coli (EIEC)
Enterohaemorrhagic or Shiga toxin-producing E. coli (EHEC/STEC)
Enteropathogenic E. coli (EPEC)
Enteroaggregative E. coli (EAEC)
Diffusely adherent E. coli (DAEC)
What are the symptoms of Enterotoxigenic E. coli (ETEC)?
Cholera-like toxin
Watery diarrhoea
What are the symptoms of Enteroinvasive E. coli (EIEC)?
Shigella-like illness
Bloody diarrhoea
What are the symptoms of Enterohaemorrhagic or Shiga toxin-producing E. coli (EHEC/STEC)?
E. coli O157 serogroup, Shigatoxin/verotoxin
5-10% get haemolytic uraemic syndrome: loss of kidney function
What is the management for c. difficile?
Isolate patient (very contagious)
Stop current antibiotics
Metronidazole, Vancomycin
Recurrence 15-35%
Increasingly difficult to treat.
Faecal Microbiota Transplantation (FMT): 98% cure rate
What are the 4 questions that should be asked in the clinical assessment of a patient with suspected gastroenteritis?
“When did it start?” – Onset of symptoms
“What does it look like?” – Amount, consistency and frequency
“How do you feel?” – Associated symptoms
“Where have you been recently?” – Travel, diet and lifestyle
What onset of symptoms would suggest gastroenteritis?
Within one to two days of ingesting food suggests contaminated food
What amount, consistency or frequency of stools suggests gastroenteritis?
Higher volume and/or frequency of watery stools
Blood, mucus and/or pus in stools suggest severe inflammation and/or infectious cause
Mucus and pus indicate a chronic inflammatory cause or infective pathogen
What associated symptoms would you be looking in a case of suspected gastroenteritis?
Pain, bloating, nausea, vomiting, fever, tenesmus
Thirsty but no appetite
What travel, diet and lifestyle factors may make someone more susceptible to developing gastroenteritis?
Recent travel or consumption of foods, such as meat, eggs, dairy or seafood, are suggestive of infection
Exposure to pets or cattle suggests infectious cause
Individuals who work in day care centres, hospitals or nursing homes suggests infection
Social history, such as sexual practice, alcohol use or drug use
IBD (prevalence 0.5–1.0%), coeliac (prevalence of 0.5–1.0%), IBS (prevalence 10.0–13.0%)
