Immunology of the Gut Flashcards

1
Q

What is the surface area of the GI tract?

A

200m^2

Size of tennis court

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2
Q

What does the gut have to deal with?

A

Massive antigen load

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3
Q

What comprises the massive antigen load of the gut?

A

Resident microbiota 1014 bacteria
Dietary antigens
Exposure to pathogens

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4
Q

What is the permanent state of the gut?

A

“restrained activation”
– Tolerance vs active immune response
– Dual immunological role.

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5
Q

What must the gut develop tolerance towards?

A

Food antigens

Commensal bacteria

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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

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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

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8
Q

What are the 4 major phyla of bacteria?

A

Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria

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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

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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

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11
Q

What is the microbiome?

A

Collective genome of all microbiota

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12
Q

What can increase numbers of microbiota?

A

Ingested nutrients

Secreted nutrients

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13
Q

What can decrease the numbers of microbiota?

A

Chemical digestive factors leading to bacterial lysis

Peristalsis and defecation

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14
Q

What is the bacterial content of the stomach?

A

10^1

HCL, Pepsin and Gastic Lipase

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15
Q

What is the bacterial content of the duodenum?

A

10^3

Bile acids from liver

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16
Q

What is the bacterial content of the jejunum?

A

10^4

Trypsin, amylase, carboxypeptidase from pancreas

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17
Q

What is the bacterial content of the ileum?

A

10^7

Brush border enzymes

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18
Q

What is the bacterial content of the colon?

A

10^12

No host digestive factors

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19
Q

What is dysbiosis?

A

Altered microbota compsition

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20
Q

What are symbionts?

A

Organisms that live with the host without harm or benefit to host or organism

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21
Q

What are commnesals?

A

Benefits from host but does not benefit or harm host

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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

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23
Q

What causes dysbiosis?

A

Infection or inflammation
Xenobiotics
Hygiene
Genetics

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24
Q

What is TMAO?

A

Increased deposition of cholesterol in artery walls

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25
Q

What is 4-EPS?

A

Associated with Autism

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26
Q

What are SCFAs?

A

Short chain fatty acids
Decrease associated with IBS
Increase associated with stress

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27
Q

What are AHR ligands?

A

Associated with MS, rheumatoid arthritis and asthma

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28
Q

What is NAFLD?

A

alcoholic fatty liver disease

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29
Q

What is NASH?

A

alcoholic steatohepatitis

inflammation from fat

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30
Q

What comprises the bodies mucosal defence?

A
Anatomical
Epithelial barrier
Peristalsis
Chemical
Enzymes
Acidic pH
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31
Q

What forms the epithelial barrier?

A

Mucus layer - Goblet cells
Epithelial monolayer - Tight junctions
Paneth Cells (small intestine)

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32
Q

What are the main features of paneth cells?

A

Bases of crypts of Lieberkühn.

Secrete antimicrobial peptides (defensins) & lysozyme

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33
Q

What are the different types of immunological tissue?

A

MALT (Mucosa Associated Lymphoid Tissue)

GALT (Gut Associated Lymphoid Tissue)

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34
Q

Where is MALT found?

A

Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles

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35
Q

What are they surrounded by?

A

Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes

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36
Q

Where is rich in MALT?

A

Oral cavity
Palatine and lingual tonsils
Pharyngeal tonsisl (Adenoids)

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37
Q

What is GALT responsible for?

A

both adaptive & innate immune responses

38
Q

What comprises GALT?

A

Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocyt

39
Q

What are the two types of GALT?

A

Non-organised

Organised

40
Q

What are the main features of non-organised GALT?

A

Intra-epithelial lymphocytes
Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells
Lamina propria lymphocytes

41
Q

What are the main features of organised GALT?

A

Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)

42
Q

Describe the cells present in non-organised GALT

A

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
Q

What is the difference between small and large bowel GALT?

A

No villi just crypts
No paneth cells
Lots of goblet cells

44
Q

What is the main type of organised GALT?

A

Peyer’s patches

45
Q

Where are peyer’s patches found?

A

Found in submucosa small intestine – mainly distal ileum

46
Q

What comprises peyer’s patches?

A

Aggregatedlymphoid follicles covered with follicle associated epithelium (FAE).
FAE - no goblet cells, no secretory IgA, no microvilli

47
Q

How are peyer’s patches organised?

A

Sub-epithelial zone - mainly dendritic cells
B-cell follicles
Interfollicular T-cells
All move towards mesenteric lymph nodes

48
Q

What does peyer’s patches development require?

A

Development requires exposure to bacterial microbiota

49
Q

How many peyer’s patches are in the body?

A

50 in last trimester foetus, 250 by teens

50
Q

How do peyer’s patches work?

A

Antigen uptake via M (microfold) cells within FAE

M cells expressIgA receptors, facilitating transfer of IgA-bacteria complexinto the Peyer’s patches.

51
Q

What is the route for preventing bacterial invasion separate to M cells?

A

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
Q

What is the B-cell adaptive response in peyer’s patches?

A

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
Q

What happens to the immune cells that enter the lymphatics system?

A

Plasma cells migrate back to enterocytes

Taken up by epithelila cells

Secret IgA

54
Q

What is the function of sIgA?

A

Up to 90% of gut B-cells secrete IgA

sIgA binds luminal antigen
→ preventing its adhesion and consequent invasion.

55
Q

Summarise lymphocyte honing and circulation

A

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
Q

What comprises peripheral immune system?

A

Skin
Tonsils
BALT

57
Q

How do lymphocytes return the peyer’s patches?

A

HEV express MAdCAM1 which is as specialised adhesion molecule

MAdCAM1 tethers lymphocytes and arrests them

Transports back to peyers patches

58
Q

Why do enterocytes and goblet cells have such a short lifespan?

A

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
Q

What is the mechanism of cholera infection?

A

Cholera -acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139

Bacteria reaches small intestine → contactwith epithelium & releasescholera 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
Q

How is cholera transmutted?

A

Transmitted through faecal-oral route

Spreads via contaminated water & food.

61
Q

What are the symptoms of cholera?

A

Main symptoms
Severe dehydration & watery diarrhoea

Other symptoms
Vomiting, nausea & abdominal pain.

62
Q

How is cholera diagnosed?

A

bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available.

63
Q

How is cholera treated?

A

oral-rehydration is the main management ; up to 80% of cases can be successfully treated.

64
Q

What are the main features of the cholera vaccine?

A

Dukoral, oral, inactivated.

65
Q

What are the viral causes of diarrhoea?

A

Rotavirus (children)

Norovirus “winter vomiting bug”

66
Q

What are the bacterial causes of diarrhoea?

A
Campylobacter jejuni
Escherichia coli
Salmonella
Shigella
Clostridium difficile
67
Q

What are the protozoal parasitic causes of diarrhoea?

A

Giardia lamblia

Entamoeba histolytica

68
Q

What are rotaviruses?

A

RNA virus, replicates in enterocytes.

5 types A – E, type A most common in human infections.

69
Q

What is the most common cause of diarrhoea in infants and young children?

A

Rotaviruses

70
Q

What is the vaccine against rotaviruses?

A

Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013.

71
Q

What is the treatment for rotavirus?

A

Oral rehydration therapy
Still causes ~ 200,000 deaths/year.
Before vaccine, most individuals had an infection by age 5, repeated infections develop immunity.

72
Q

Describe norovirus

A

RNA virus

Incubation period 24-48 hours

73
Q

How is norovirus transmitted?

A

Faecal-oral transmission.
Individuals may shed infectious virus for up to 2 weeks
Outbreaks often occur in closed communities

74
Q

What are the symptoms of norovirus?

A

Acute gastroenteritis, recovery 1 – 3 days

No specific treatment - just supportive

75
Q

How is norovirus diagnosed?

A

Sample PCR

76
Q

How many cases of norovirus are there?

A

Estimated 685 million cases per year.

77
Q

What are the most common species of curved bacteria?

A

Campylobacter jejuni Campylobacter coli

78
Q

How are campylobacter transmitted?

A
Undercooked meat (especially poultry), untreated water & unpasteurised milk
Low infective dose, a few bacteria (<500) can cause illness
79
Q

What is the treatment for campylobacter?

A

Not usually required
Azithromycin (macrolide) is standard antibiotic
Resistance to fluoroquinolones is problematic

80
Q

Describe the epidemiology of campylobacter

A

Estimated 280,000 cases per year in UK, 65,000 confirmed

Commonest cause of food poisoning in the UK

81
Q

What are the main features of E. coli?

A

Diverse group of Gram-negative intestinal bacteria
Most harmless
6 ”pathotypes” associated with diarrhoea (diarrhoeagenic):

82
Q

What is the most problematic E. coli pathotype?

A

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
Q

What are the features of Enterotoxigenic E. coli (ETEC)?

A

Cholera like toxin

Watery diarrhoea

84
Q

What are the features of Enteroinvasive E. coli (EIEC)?

A

Shigella like illness

Bloody diarrhea

85
Q

Why is C diff. called its name?

A

It is difficult to grow in a lab

86
Q

What often causes c. diff infection?

A

Long term antibiotics

87
Q

What is weird about C. diff?

A

Healthy microbiota can contain C. diff

88
Q

When does C. diff become a problem?

A

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
Q

What is the management in C. diff?

A

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
Q

What is weird about Metronidazole?

A

Can cause and treat C. diff