1b Immunology of the Gut Flashcards

1
Q

Describe the antigen load in the gut?

A

Massive antigen load
- resident microbiota
- dietary antigens
- exposure to pathogens

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2
Q

Why is the GI Tract immune system in a state of ‘restrained activation’?

A

It balances tolerance of food antigens and commensal bacteria vs immunoreactivity against pathogens

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3
Q

What are gnotobiotic mice?

A

These are mice which have been colonized to be germ-free

They are used in experiments to derive the relationship between microbiota and immune system’s response to them

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4
Q

What are the four major phyla of bacteria found in the gut microbiota?

A

Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, as well as viruses and fungi

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5
Q

What factors which the host does leads to bacterial growth?

A

Ingested nutrients
Secreted nutrients

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6
Q

Which factors leads to bacterial lysis and bacterial elimination?

A

Chemical digestive factors
peristalsis, contractions and defecations

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7
Q

In general, explain why bacterial content varies as you pass down the GI tract

A

The chemical digestive factors produced by the host impact viability of the bacteria to survive in different parts of the GI tract

The bacterial content increases as you pass down the GI tract because the factors produced are less hostile to bacterial growth.

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8
Q

List the chemical digestive factors produced by the stomach, liver, pancreas, small intestine and colon respectively

A

Stomach - Pepsin, gastric lipase
Liver - bile salts
Pancreas - trypsin, amylase and carboxypeptidase
Small Intestine - Brush border enzymes
Colon - nothing

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9
Q

What is Dysbiosis?

A

Altered microbiota composition

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10
Q

What is the balance of dysbiosis between?

A

Symbionts = regulation
Commensals
Pathobionts = inflammation

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11
Q

Define the term ‘Symbiont’

A

Lives with a host but no benefit/harm to either

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12
Q

Define commensals?

A

Organism which livs or or in a host and benefits from living there, but does not cause any harm to the host

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13
Q

Define pathobiont?

A

Symbiont that doesn’t naturally produce an immune response but under certain environmental conditions can produce dysregulated inflammation/disease.

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14
Q

Give 5 factors that can either contribute to the maintenance of healthy microbiota or towards dysbiosis

A

1) Infection or inflammation

2) Diet

3) Xenobiotics

4) Hygiene

5) Genetics

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15
Q

Give 5 examples of metabolites and toxins which bacteria produce that can cause damage to body systems

A

TMAO

4-EPS

SCFAs

Bile acids

AHR Ligands

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16
Q

What are the anatomical barriers which contribute to mucosal defense?

A

Epithelial barrier
Peristalsis

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17
Q

What are the chemical barriers which contribute to mucosal defense?

A

Enzymes
Acidic pH

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18
Q

What dysfunction can TMAO cause in the body?

A

TMAO = Trimethylamine N-oxide

Can cause atherosclerosis due to increased cholesterol deposition

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19
Q

What has 4-EPS been associated with?

A

Increased levels of autism

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20
Q

What are decreased numbers of SCFA’s associated with?

A

SCFAs = Short-chained fatty acids

Decreased numbers of SCFAs are associated with Inflammatory bowel disease

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21
Q

What are increased numbers of SCFAs associated with?

A

Neuropsychiatric disorders like stress

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22
Q

What are AHR ligands associated with?

A

cancer

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23
Q

What are the two immunological defense mechanisms following an invasion?

A

MALT (Mucous associated lymphoid tissue)

GALT (Gut associated lymphoid tissue)

-

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24
Q

Where is MALT tissue particularly rich?

A

MALT is particularly rich within the oral cavity ( the three tonsils - palatine, lingual and adenoid)

It is found in the submucosa below the epithelium as a lymphoid mass containing lymphoid follicles

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25
Q

What cells make up the mucus layer?

A

Goblet cells

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26
Q

What are paneth cells and how are they used in mucosal defense?

A

They are cells of the small intestine, found at the bases of the cypts of lieberkuhn and they secrete anti-microbial peptides (defensins) and lysozyme

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27
Q

What is found in the epithelial monolayer?

A

Tight junctions

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28
Q

Where is MALT found?

A

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

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29
Q

What are the lymphoid follicles of MALT surrounded by?

A

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

30
Q

Which tissue is rich in MALT?

A

Oral cavity - palatine tonsils, lingual tonsils, pharyngeal tonsils

31
Q

What is GALT tissue responsible for?

A

Adaptive and innate immune responses

32
Q

What does GALT consist of?

A

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

33
Q

What are the four organised structures of GALT?

A

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

34
Q

What are the two non-organised structures of GALT?

A

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

Lamina propria lymphocytes

35
Q

What are Peyer’s patches?

A

Aggregated lymphoid follicles covered with follicle associated epithelium ( FAE) —> Found in submucosa of small intestine eg. mainly distal ileum

36
Q

What is special about FAE?

A

No goblet cells, No secretory IgA, no microvilli - Therefore no barrier to pathogens so Peyer’s Patches can act accordingly and increase in numbers

37
Q

How does the structure of the large intestine cellular arrangement differ from the small intestine?

A
  1. Large Intestine - Outer mucus layer, inner mucus layer, and shallow crypts
  2. Small Intestine - Lumen, Mucus, larger crypts with microvilli
38
Q

Where are peyer’s patches found?

A

In the submucosa of the small intestine - mainly the distal ileum

39
Q

What are peyer’s patches?

A

Aggregated lymphoid follicles covered in follicle associated epithelium

40
Q

What does the development of Peyer’s Patches require?

A

Development requires exposure to bacterial microbiota

41
Q

How to 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.

42
Q

Describe the growth of the Peyer’s patches from fetus to teenage years

A

Peyer’s patches contain an organized collection of naïve T cells and B cells

Development of it requires previous exposure to bacterial microbiota

Therefore, it grows over time 50 in last trimester as a foetus, 250 by the time you are a teenager.

43
Q

Describe the role trans-epithelial dendritic cells play in the immunological response

A

Dendritic cells can open up tight junction proteins and send dendrites from the outside into the lumen of the intestinal tract where they directly sample bacteria

They can then bring the bacteria back and transport them into mesenteric lymph nodes

44
Q

Describe the B cell adaptive response

A

Pathogen uptake via M cell —> Excreted into pocket found on the inner surface of the enterocyte containing APCs —> APCs engulf pathogen and display on their surface using MHC II —> DCs migrate to Peyers patches —>Mature naive B-cells express IgM in these Peyers patches but on antigen presentation switches to IgA.

  • T-cells and epithelial cells influence B cell maturation via cytokine production
  • B cells further mature to become IgA secreting plasma cells
  • Populate lamina propria
45
Q

Describe the formation of secretory IgA from the submucosa to the lumen

A

Plasma cells in the submucosa release dimeric IgA

This binds to the poly-Ig receptor on the epithelial cells where it is incased in a vesicle

Enzymatic cleavage within vesicle in the epithelial cells converts dimeric IgA into secretory IgA which is then released into the lumen.

46
Q

What is the function of sIgA?

A

Secretory IgA binds to luminal antigen, thereby preventing its adhesion and consequent invasion

47
Q

Describe the cycle of lymphocyte homing and circulation?

A

Mesenteric lymph node -> thoracic duct -> circulation -> lamina propria of gut lumen (containing peyer’s patches where antigen presentation and activation occurs)

48
Q

Describe alpha4beta7/ MADCAM-1 adhesion

A

The lymphocyte express alpha4beta7 integrin and the High Endothelial Venule express MADCAM-1

Chemotactic stimulation of lymphocytes leads to rolling, then activation, then arrest and internalization into tissue fluid from blood, facilitated thorugh alpha4beta7 integrin/MAdCAM-1 adhesion

MAdCAM = on the epithelium of the high endothelial venule

Alpha 4 beta 7 integrin = on the naive t cells to direct them back to the peyes patches

49
Q

Why do enterocytes and goblet cells of the small bowel have such a short life-span (36 hours)?

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

50
Q

What is Cholera and what agents is it caused by?

A

Cholera is an acute bacterial disease caused by vibrio cholerae serogroups O1 and O139

51
Q

How does Cholera cause Watery Diarrhoea?

A
  1. Bacteria reaches the small intestine and releases cholera toxin
  2. Binds to receptor which increased adenylate cyclase activity -> leads to increased cAMP
  3. This increases the activity of the Na+, K+, Cl- and HCO3- channels, which secrete these back into the lumen of the small intestine
  4. Water follows, therefore resulting in watery diarrhoea
52
Q

How is cholera transmitted?

A

Faecal-oral route - spreads through contaminated water and food

53
Q

What are the main symptoms of a cholera infection?

A

Severe dehydration & watery diarrhoea

Other symptoms: vomiting, nausea and abdominal pain

54
Q

How is cholera diagnosed?

A

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

55
Q

What is the treatment for Cholera infection?

A

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

56
Q

What class of viruses are the most common cause of diarrhoea in infants and young children worldwide?

A

Rotaviruses

57
Q

Describe rotaviruses and which one is the most common in humans?

A

RNA Virus, replicates in enterocytes

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

58
Q

What is the treatment for rotaviruses?

A

Oral rehydration therapy

59
Q

Rotavirus vaccine?

A

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

60
Q

What is norovirus?

A

It is an RNA virus with an incubation period (time between exposure and when symptoms apparent) of 24-48 hours

61
Q

What is the transmission of norovirus?

A

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

62
Q

what are the symptoms of norovirus?

A

Acute gastroenteritis, recovery 1 – 3 days

63
Q

How is Norovirus diagnosed?

A

Sample PCR.

64
Q

What is Campylobacter?

A

Curved bateria

65
Q

What is the transmission of campylobacter?

A

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

66
Q

What is the treatment for campylobacter?

A

Azithromycin (macrolide) is standard antibiotic
Resistance to fluoroquinolones is problematic

67
Q

What does Enterotoxigenic E.Coli ( ETEC) do?

A

Cholera like toxin which causes watery diarrhoea

68
Q

Which pathotype of E. Coli is the most harmful?

A

Enterohaemorrhagic or shiga-toxin producing E.Coli ( EHEC/STEC)

69
Q

Which E. Coli Pathotype causes Blood diarrhoea?

A

Enteroinvasive E. coli (EIEC)

70
Q

What is the management of C. Diff. infections?

A

Isolate patient
Stop current antibiotics
Give Metronidazole and Vancomycin

Faecal Microbiota Transplantation -> has a 98% cure rate