Immunology of the Gut Flashcards
(90 cards)
1
Q
What is the surface area of the GI tract?
A
200m^2
Size of tennis court
2
Q
What does the gut have to deal with?
A
Massive antigen load
3
Q
What comprises the massive antigen load of the gut?
A
Resident microbiota 1014 bacteria
Dietary antigens
Exposure to pathogens
4
Q
What is the permanent state of the gut?
A
“restrained activation”
– Tolerance vs active immune response
– Dual immunological role.
5
Q
What must the gut develop tolerance towards?
A
Food antigens
Commensal bacteria
6
Q
What is Gnotobiology?
A
Gnotobiology
Take germ free animals and you selectively colonise them with selective bateria
Observe differences in these mice to conventioanlly housed mice
e.g. development of peyer’s patches, paneth cells
7
Q
How many gut bacteria are there?
A
10^14 gut bacteria and 10^13 cells in body - most densely populated “ecosystem” on Earth
8
Q
What are the 4 major phyla of bacteria?
A
Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria
9
Q
Why is the gut microbiota important?
A
Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome
10
Q
Give example of functions of the gut microbiota?
A
Provide essential nutrients that cannot be manufactures
Metabolise indigestible compounds
Defence against opportunistic pathogens
Contribute to architecture of the gut
11
Q
What is the microbiome?
A
Collective genome of all microbiota
12
Q
What can increase numbers of microbiota?
A
Ingested nutrients
Secreted nutrients
13
Q
What can decrease the numbers of microbiota?
A
Chemical digestive factors leading to bacterial lysis
Peristalsis and defecation
14
Q
What is the bacterial content of the stomach?
A
10^1
HCL, Pepsin and Gastic Lipase
15
Q
What is the bacterial content of the duodenum?
A
10^3
Bile acids from liver
16
Q
What is the bacterial content of the jejunum?
A
10^4
Trypsin, amylase, carboxypeptidase from pancreas
17
Q
What is the bacterial content of the ileum?
A
10^7
Brush border enzymes
18
Q
What is the bacterial content of the colon?
A
10^12
No host digestive factors
19
Q
What is dysbiosis?
A
Altered microbota compsition
20
Q
What are symbionts?
A
Organisms that live with the host without harm or benefit to host or organism
21
Q
What are commnesals?
A
Benefits from host but does not benefit or harm host
22
Q
What are pathobionts?
A
Symbionts that do not normally illicit an inflammatory response
But in certain environments have the potential to cause disregualted inflammation and disease
23
Q
What causes dysbiosis?
A
Infection or inflammation
Xenobiotics
Hygiene
Genetics
24
Q
What is TMAO?
A
Increased deposition of cholesterol in artery walls
25
What is 4-EPS?
Associated with Autism
26
What are SCFAs?
Short chain fatty acids
Decrease associated with IBS
Increase associated with stress
27
What are AHR ligands?
Associated with MS, rheumatoid arthritis and asthma
28
What is NAFLD?
alcoholic fatty liver disease
29
What is NASH?
alcoholic steatohepatitis
| inflammation from fat
30
What comprises the bodies mucosal defence?
```
Anatomical
Epithelial barrier
Peristalsis
Chemical
Enzymes
Acidic pH
```
31
What forms the epithelial barrier?
Mucus layer - Goblet cells
Epithelial monolayer - Tight junctions
Paneth Cells (small intestine)
32
What are the main features of paneth cells?
Bases of crypts of Lieberkühn.
| Secrete antimicrobial peptides (defensins) & lysozyme
33
What are the different types of immunological tissue?
MALT (Mucosa Associated Lymphoid Tissue)
| GALT (Gut Associated Lymphoid Tissue)
34
Where is MALT found?
Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
35
What are they surrounded by?
Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
36
Where is rich in MALT?
Oral cavity
Palatine and lingual tonsils
Pharyngeal tonsisl (Adenoids)
37
What is GALT responsible for?
both adaptive & innate immune responses
38
What comprises GALT?
Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocyt
39
What are the two types of GALT?
Non-organised
| Organised
40
What are the main features of non-organised GALT?
Intra-epithelial lymphocytes
Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells
Lamina propria lymphocytes
41
What are the main features of organised GALT?
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
42
Describe the cells present in non-organised GALT
Stem cells produce enterocytes that rapidly migrate to apex
Apoptotic intra-epithelial cells
Goblet cells at base the migrate north and produce mucus
Paneth cells which produce anti-microbial peptides
Intra-epithelial lymphocytes
Majority of immunological cells found in lamina propia
43
What is the difference between small and large bowel GALT?
No villi just crypts
No paneth cells
Lots of goblet cells
44
What is the main type of organised GALT?
Peyer's patches
45
Where are peyer's patches found?
Found in submucosa small intestine – mainly distal ileum
46
What comprises peyer's patches?
Aggregated lymphoid follicles covered with follicle associated epithelium (FAE).
FAE - no goblet cells, no secretory IgA, no microvilli
47
How are peyer's patches organised?
Sub-epithelial zone - mainly dendritic cells
B-cell follicles
Interfollicular T-cells
All move towards mesenteric lymph nodes
48
What does peyer's patches development require?
Development requires exposure to bacterial microbiota
49
How many peyer's patches are in the body?
50 in last trimester foetus, 250 by teens
50
How do peyer's patches work?
Antigen uptake via M (microfold) cells within FAE
| M cells express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer's patches.
51
What is the route for preventing bacterial invasion separate to M cells?
Via dendritic cells
Open up tight junctions and send dendrites into epithelium to retrieve bacteria from lumen of gut
Bring back and transport to mesenteric lymph nose
They express tight junction proteins so maintain the tight-junction barrier
52
What is the B-cell adaptive response in peyer's patches?
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
Some enter lymphatic system
53
What happens to the immune cells that enter the lymphatics system?
Plasma cells migrate back to enterocytes
Taken up by epithelila cells
Secret IgA
54
What is the function of sIgA?
Up to 90% of gut B-cells secrete IgA
sIgA binds luminal antigen
→ preventing its adhesion and consequent invasion.
55
Summarise lymphocyte honing and circulation
Antigen presents in peyers patch
Activation
Enters mesenteric lymph node - lymphocyte proliferation
Go into circulation via thoracic duct (main duct for return to venous system)
Enters peripheral immune system
56
What comprises peripheral immune system?
Skin
Tonsils
BALT
57
How do lymphocytes return the peyer's patches?
HEV express MAdCAM1 which is as specialised adhesion molecule
MAdCAM1 tethers lymphocytes and arrests them
Transports back to peyers patches
58
Why do enterocytes and goblet cells have such a short lifespan?
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.
59
What is the mechanism of cholera infection?
Cholera -acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
Bacteria reaches small intestine → contact with epithelium & releases cholera enterotoxin.
Gets internalised via retrograde endocytosis into enterocytes activating adenylase cyclase
This increases cAMP
Causes active secretion of salt and fluid via the cystic fibrosis transmembrane conductance regulator (CFTR)
Loss of salt, potassium, chloride, bicarbonate and water
60
How is cholera transmutted?
Transmitted through faecal-oral route
| Spreads via contaminated water & food.
61
What are the symptoms of cholera?
Main symptoms
Severe dehydration & watery diarrhoea
Other symptoms
Vomiting, nausea & abdominal pain.
62
How is cholera diagnosed?
bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available.
63
How is cholera treated?
oral-rehydration is the main management ; up to 80% of cases can be successfully treated.
64
What are the main features of the cholera vaccine?
Dukoral, oral, inactivated.
65
What are the viral causes of diarrhoea?
Rotavirus (children)
| Norovirus “winter vomiting bug”
66
What are the bacterial causes of diarrhoea?
```
Campylobacter jejuni
Escherichia coli
Salmonella
Shigella
Clostridium difficile
```
67
What are the protozoal parasitic causes of diarrhoea?
Giardia lamblia
| Entamoeba histolytica
68
What are rotaviruses?
RNA virus, replicates in enterocytes.
| 5 types A – E, type A most common in human infections.
69
What is the most common cause of diarrhoea in infants and young children?
Rotaviruses
70
What is the vaccine against rotaviruses?
Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013.
71
What is the treatment for rotavirus?
Oral rehydration therapy
Still causes ~ 200,000 deaths/year.
Before vaccine, most individuals had an infection by age 5, repeated infections develop immunity.
72
Describe norovirus
RNA virus
| Incubation period 24-48 hours
73
How is norovirus transmitted?
Faecal-oral transmission.
Individuals may shed infectious virus for up to 2 weeks
Outbreaks often occur in closed communities
74
What are the symptoms of norovirus?
Acute gastroenteritis, recovery 1 – 3 days
No specific treatment - just supportive
75
How is norovirus diagnosed?
Sample PCR
76
How many cases of norovirus are there?
Estimated 685 million cases per year.
77
What are the most common species of curved bacteria?
Campylobacter jejuni Campylobacter coli
78
How are campylobacter transmitted?
```
Undercooked meat (especially poultry), untreated water & unpasteurised milk
Low infective dose, a few bacteria (<500) can cause illness
```
79
What is the treatment for campylobacter?
Not usually required
Azithromycin (macrolide) is standard antibiotic
Resistance to fluoroquinolones is problematic
80
Describe the epidemiology of campylobacter
Estimated 280,000 cases per year in UK, 65,000 confirmed
| Commonest cause of food poisoning in the UK
81
What are the main features of E. coli?
Diverse group of Gram-negative intestinal bacteria
Most harmless
6 ”pathotypes” associated with diarrhoea (diarrhoeagenic):
82
What is the most problematic E. coli pathotype?
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
83
What are the features of Enterotoxigenic E. coli (ETEC)?
Cholera like toxin
| Watery diarrhoea
84
What are the features of Enteroinvasive E. coli (EIEC)?
Shigella like illness
| Bloody diarrhea
85
Why is C diff. called its name?
It is difficult to grow in a lab
86
What often causes c. diff infection?
Long term antibiotics
87
What is weird about C. diff?
Healthy microbiota can contain C. diff
88
When does C. diff become a problem?
Intermediate dysbiotic state caused by a exogenous disturbance e.g. antibiotics
C. diff starts colonising enetrocutes and you get an outgrowth in the distal gut , still not producing toxins
Pathogen induced disturbance creates supportive environment - then starts producing toxin
Causes inflammation of distal gut
89
What is the management in 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
90
What is weird about Metronidazole?
Can cause and treat C. diff
