GUT IMMUNOLOGY Flashcards
Why does the gut need a strong immune system?
Massive antigen load:
- resident microbiota
- dietary antigens
- exposure to pathogens
Describe the balance of the GI tract immunology
Tolerance (food antigens, commensal bacteria)
versus
Active immune response (pathogens)
What causes gut microbiota numbers to grow?
Ingested nutrients
Secreted nutrients
What causes gut microbiota numbers to decrease?
Chemical digestive factors - bacterial lysis
Peristalsis, contractions, defecation - bacterial elimination
What are the 4 things the gut microbiota does for us?
Provide essential nutrients that we can’t make ourselves
Metabolise indigestible compounds
Defence against colonisation
Contributes to intestinal architecture
How does bacterial content change as you move down the GI system?
Increases since less and less chemical digestive factors produced by host
What are the 3 different classes of micro-organsims which may live in the microbiota?
Symboints - no over benefit over other party
Commensals - microorgansim which benefits from hosts but doesn’t have a positive/negative effect on host
Pathobionts - microorgansim which have potential to cause dysregulated inflammation and disease
What are the factors which influence the microbiota and dysbiosis?
Infection or inflammation Diet Xenobiotics Hygiene Genetics
Give examples of bacterial metabolites and toxins and explain what they do
TMAO - increase cholesterol deposition -> atherosclerosis
4-EPS - associated with autism
SCFAs - low = IBD associated, high = neuro problems
AHR ligands - associated with multiple sclerosis, rheumatic arthritis, asthma
What does the GI tract have in terms of mucosal defence?
Physical barriers
Commensal bacterial
Immunological
What are the physical barriers of the GI tract?
Anatomical - epithelial barrier, peristalsis
Chemical - enzymes, acidic pH
What are the immunological defences of GI mucosa?
MALT (mucosa associated lymphoid tissue)
GALT (gut associated lymphoid tissue)
What is MALT and where is it found?
Lymphoid mass containing lymphoid follicles found in submucosa below epithelium
Oral cavity is rich in this (palatine, lingual and pharyngeal tonsils)
What is the structure of MALT?
Lymphoid mass containing lymphoid follicles.
Follicles surrounded by HEV postcapillary venules - allows easy passage of lymphocytes
What is GALT and what cell types are present?
Gut associated lymphoid tissue responsible for adaptive and innate immune response
Contains B and T lymphocytes, macrophages, APC (dendritic), specific epithelial and intra-epithelial lymphocytes
List the 2 non-organised GALTs and their locations
Intra-epithelial lymphocytes (between enterocytes)
Lamina propria lymphocytes (centre of villi)
List the organised GALTs and their locations
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymphoid lymph nodes (encapsulated)
Where are Peyer’s patches mainly found?
Distal ileum of small intestine submucosa
What are Peyer’s patches?
“Immune sensors”
Aggregated lymphoid follicles with follicle associated epithelium (FAE)
Organised collection of naive T/B cells whose development requires exposure to bacterial microbiota
What is follicle associated epithelium (FAE)?
Epithelium with no goblet cells, no secretory IgA and no microvilli
Covers aggregated lymphoid follicles e.g Peyer’s patches
How is the Peyer’s patch sensitised to the antigen?
Microfold (M) cells express IgA receptors which bind to the antigen, facilitating transfer of the complex into the Peyer’s patch
Draw the structure of a Peyer’s patch and FAE with the location of its cells
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Other than via the Peyer’s patch what is another method of sensitising the GI tract to micro-organisms?
Antigen sampling by trans-epithelial dendritic cells
DCs open tight junction and directly samples antigen and brings it back to the mesenteric lymph nodes
Describe the immune response including Peyer’s patches in full
Pathogen taken up by M cell and excreted into pocket on inner surface of enterocytes. Pocket contains DCs which present it via MHC II and migrate to the Peyer’s patches where the T/B cells are aggregated into organised lymphoid follicles. Some DCs escape these follicles and activate T/B cells in the mesenteric lymph nodes. Some of activated cells return to circulation and then Lamina Propria to produce IgA antibodies (plasma cells) into lumen.
What percentage of gut B cells secrete IgA?
90%
What are high endothelial venules (HEVs)?
Blood vessels especially adapted for lymphocyte trafficking
Found usually in secondary lymphoid organs
What protein do lymphocytes express when migrating from an HEV to e.g. lamina propria
Alpha4beta7 integrin
Why do enterocytes have a rapid turnover?
Enterocytes are first line of defence against GI pathogens and may be directly affected by toxic substances in diet
Allows for any lesions to be short lived
Effects of agents which interfere with cell function/metabolic rate will be short lived
What causes cholera?
Infection by Vibrio cholerae serogroups O1 and O139
What is the mechanism of a cholera infection?
Bacteria reaches small intestine, contacts with epithelium and releases enterotoxin which increases adenylate cyclase activity and thus you get increased cAMP.
This causes Na+, K+, Cl-, HCO3- to move out of cell and water follows which is excreted as diarrhoea.
How does cholera spread?
Faecal-oral route (contaminated water and food)
What are the symptoms of cholera?
Severe dehydration Watery diarrhoea Vomiting Nausea Abdominal pain
How do you diagnose cholera?
Bacterial culture from stool sample
Rapid dipstick tests
What is the treatment for patients with cholera?
Oral rehydration
Most patients will get better by themselves
Vaccine Dukoral (oral, inactivated) is available
What are some causes of gastroenteritis (infectious diarrhoea) other than Vibrio cholerae?
Viral:
- Rotavirus (children)
- Norovirus
Bacterial:
- Campyolbacter jejuni
- E. coli
- Salmonella
- Shigella
- C. diff
Protozoal parasitic:
- Giardia lamblia
- Entamoeba histolytica (amoebic dysentery)
What are rotaviruses?
RNA virus which replicates in enterocytes
5 type A-E, A is most common in human infections
Most common cause of diarrhoea in infants and young children
What is the treatment and vaccination for rotaviruses?
Oral rehydration therapy
Live attenuated oral vaccine (Rotarix) against type A
What is norovirus norwalk virus?
RNA virus which causes acute gastroenteritis. Spread by faecal-oral route and incubates for 24-48 hours. Recovery after 1-3 days
Individuals may shed infectious virus for up to 2 weeks
What is the treatment for norovirus norwalk virus?
None usually required
How is norovirus norwalk virus diagnosed?
Sample PCR
What are Campylobacter?
“curved bacteria” transmitted through undercooked meat, untreated water and unpasteurised milk
Low infective dose
Commonest cause of food poisoning in UK
What is the treatment for Campylobacter treatment?
Not usually required
Azithromycin is standard antibiotic
Resistance to fluoroquinolones
What is E. coli?
Diverse group of Gram -ve intestinal bacteria
Most harmless - 6 pathotypes are diarrhoeagenic
What are the 6 pathotypes of E. coli?
Enterotoxigenic E. coli (ETEC)
- cholera like toxin, watery diarrhoea
Enteroinvasive E. coli (EIEC)
- shigella like illness, bloody diarrhoea
Enterohaemorrhagic/Shiga toxin-producing E. coli (EHEC/STEC)
Enteropathogenic E. coli (EPEC)
Enteroaggregative E. coli (EAEC)
Diffusely adherent E. coli (DAEC)
What is the management for a patient with C. diff?
Isolate patient
Stop current antibiotics
Metronidazole, Vancomycin
Faecal microbiota transplantation (FMT) - 98% cure rate
What is the recurrence rate of C. diff?
15-35% with increasing difficulty in treating with each infection
What are the stages of C. diff?
Healthy stable state
Intermediate dysbiotic state:
(disturbance sensitive commensal decrease, inflammation tolerant commensal increase)
Diseased state
