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Year 2 - BRS > 6.6 - Immunology of the gut > Flashcards

6.6 - Immunology of the gut Flashcards

1
Q

What is the surface area of the GI tract?

A

200m^2

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2
Q

How big is the antigen load in GI tract and what does it consist of?

A

Massive antigen load consisting of:

  • resident microbiota 10^14 bacteria
  • dietary antigens
  • exposure to pathogens
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3
Q

What does microbiota mean?

A

A mixture of microorganisms that makes up a community within an anatomical niche

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4
Q

What does microbiome mean?

A

Collective genomes of all microbiota in all the different anatomical niches

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5
Q

Immunologically, what state is the GI tract in?

A
  • state of ‘restrained activation’
  • balances tolerance vs active immune response
  • dual immunological role
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6
Q

What does the GI tract need tolerance against? (2)

A
  • food antigens
  • commensal bacteria
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7
Q

What does the GI tract need immunoreactivity against?

A

Pathogens

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8
Q

What is the presence of bacterial microbiota in the gut essential for?

A

Immune homeostasis of the gut and development of a healthy immune system

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9
Q

How do we study the effects of the microbiota on the immune system?

A
  • gnotobiology
  • colonise germ-free mice and give them a particular germ and compare them to normal house mice and look at the microbiota
  • e.g. immunological defect in the development of the small intestine –> Peyer’s patches in germ-free mice will be fewer and less cellular than house mice
  • e.g. immunological defect in expression of angiotensin 4 –> reduced Paneth cells
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10
Q

How many gut bacteria vs cells do we have in the body?

A

10^14 gut bacteria and 10^13 cells in the body –> most densely populated ecosystem on earth

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11
Q

What are the four major phyla of bacteria (4), and what else is also present in the body (2)?

A
  • Bacteroidetes
  • Firmicutes
  • Actinobacteria
  • Proteobacteria
  • viruses
  • fungi
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12
Q

What do the gut microbiota provide for us? (4)

A
  • provide traits we have not had to evolve on our own - genes in gut flora are 100x our own genome
  • metabolise indigestible compounds
  • defence against colonisation by opportunistic pathogens
  • essential nutrients
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13
Q

What host factors stimulate bacterial growth? (2)

A
  • ingested nutrients
  • secreted nutrients
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14
Q

What host factors inhibit bacterial growth? (2)

A
  • chemical digestive factors (bacterial lysis)
  • peristalsis, contractions, defecation (bacterial elimination)
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15
Q

How does bacterial content change as you go along the GI tract?

A
  • stomach has the least due to HCl and pepsin + gastric lipase
  • duodenum has more as it has bile acids
  • by the time we get to the colon, there is a lot of bacteria because there are no host digestive factors
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16
Q

What is dysbiosis?

A

Altered microbiota composition, lack of homeostatic immunological equilibrium

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17
Q

Explain what the immunological equilibrium is.

A
  • one side = symbionts - microbiota and humans live with each other but not with benefit or harm to either, they just live (regulation)
  • middle = commensals - microorganisms that benefit from associating with host, but has no effect on host
  • other side = pathobionts - symbionts that usually do not elicit inflammatory response, but under specific conditions can cause dysregulated inflammatory disease (inflammation)
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18
Q

What happens when something goes wrong and pathobionts begin replicating?

A

Inflammation and disease

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19
Q

What influences GI equilibrium/dysbiosis? (5)

A
  • infection or inflammation
  • diet
  • xenobiotics
  • hygiene
  • genetics
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20
Q

How can dysbiosis negatively affect the rest of the body? (5)

A

Through producing metabolites and toxins e.g:

  • TMAO - increases cholesterol deposition in artery walls to cause atherosclerosis
  • 4-EPS - associated with autism
  • SCFAs (short chain fatty acids) - decreased numbers associated with IBD, increased numbers associated with neuropsychiatric disorders
  • AHR ligands - associated with MS, rheumatoid arthritis, asthma
  • bile acids
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21
Q

What is the first line of defence the body has against pathogens?

A

Mucosal defence

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22
Q

What are the three layers of mucosal defence?

A
  • 1st - physical barriers
  • 2nd - commensal bacteria - occupy an ecological niche and are an ecological barrier
  • 3rd - immunological (lymphoid tissue) - MALT and GALT
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23
Q

What are the two types of physical barriers (mucosal defence)?

A
  • anatomical - epithelial barrier, peristalsis
  • chemical - enzymes, acidic pH
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24
Q

What is the epithelial barrier made up of?

A
  • mucus layer - goblet cells
  • epithelial monolayer with tight junctions
  • Paneth cells (small intestine)
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25
Q

What are Paneth cells and what do they do?

A
  • bases of crypts of Lieberkuhn
  • secrete antimicrobial peptides (defensins) and lysozyme
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26
Q

What types of lymphoid tissue are there? (2)

A
  • MALT (mucosa associated lymphoid tissue)
  • GALT (gut associated lymphoid tissue)
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27
Q

Where is MALT found?

A
  • found in the submucosa below the epithelium, as a lymphoid mass containing lymphoid follicles
  • follicles are surrounded by HEV (high endothelial venule) postcapillary venules, allowing easy passage of lymphocytes
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28
Q

Which specific part of the body is packed full of MALT?

A

Oral cavity is rich in immunological tissue - pharyngeal, palatine and lingual tonsils especially

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29
Q

How big is GALT?

A

Largest mass of lymphoid tissue in body

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30
Q

What types of immune response is GALT responsible for?

A

Responsible for both adaptive and innate immune responses through generations of lymphoid cells and antibodies

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31
Q

What are the two types of GALT?

A
  • non-organised
  • organised
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32
Q

What are non-organised GALT? (2)

A
  • intra-epithelial lymphocytes (sit between enterocytes) - make up 1/5 of intestinal epithelium e.g. T cells, NK cells
  • lamina propria lymphocytes
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33
Q

Describe the important cells in the small intestine villus.

A
  • intestinal epithelial cells migrate up to tip of villus
  • mucus-secreting goblet cells
  • Paneth cells migrate to bottom of crypt (characterised by dense granules containing anti-microbial peptides)
  • lamina propria makes up middle of villus and contains immune cells e.g. T cells, macrophages, DCs
  • intra-epithelial lymphocytes are there between enterocytes
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34
Q

What are organised GALT? (4)

A
  • Peyer’s patches (small intestine)
  • caecal patches (large intestine)
  • isolated lymphoid follicles
  • mesenteric lymph nodes (encapsulated)
35
Q

What do people mistake enlarged mesenteric lymph nodes as being?

A

Pathological even though they are just reactive, and are the largest lymph nodes you find in the body naturally

36
Q

Where are Peyer’s patches found?

A

Submucosa of small intestine - mainly in distal ileum

37
Q

What are Peyer’s patches?

A

Aggregated lymphoid follicles covered with follicle associated epithelium (FAE)

38
Q

What is follicle associated epithelium (FAE)?

A

Made up of specialised enterocytes with the role of transferring things (like bacteria) to Peyer’s patches

39
Q

What cells do FAE lack? (3)

A
  • no goblet cells
  • no secretory IgA
  • lack microvilli
40
Q

What cells are Peyer’s patches made of?

A

Organised collection of naive T cells and B-cells

41
Q

What does the development of Peyer’s patches require?

A

Development requires exposure to bacterial microbiota

42
Q

How many Peyer’s patches do we have from last trimester of foetus to teens?

A
  • 50 in last trimester
  • 250 in teens
43
Q

How does antigen uptake occur in Peyer’s patches?

A
  • via M (microfold) cells within FAE
  • M cells express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer’s patches
44
Q

What do M (microfold) cells have instead of microvilli?

A

Microfolds instead, through which bacteria get taken up

45
Q

What is an alternative route of bacteria uptake other than M (microfold) cells?

A
  • antigen sampling: trans-epithelial dendritic cells
  • trans-epithelial dendritic cells can open up tight junctions and squeeze out and send dendrites into lumen of GI tract and directly sample bacteria
  • brings them back and transports them to mesenteric lymph nodes
46
Q

Describe the B cell adaptive response in the GI tract.

A
  1. M cells take up pathogens
  2. they are excreted into a pocket formed in inner surface of enterocyte
  3. pocket contains APCs (DCs) that engulf antigen and presents them through MHC II
  4. mature naïve B-cells express IgM in Peyer’s patches, and on antigen presentation class switches to IgA
  5. T-cells and epithelial cells influence B-cell maturation via cytokine production
  6. B cells further mature to become IgA secreting plasma cells and populate lamina propria (some APCs escape into lymph to go activate B and T cells in mesenteric lymph nodes, some of these activated cells return to gut tissue to produce antibodies)
47
Q

How do the IgA secreted by B cells get into the lumen?

A
  • the IgA goes into a vesicle in the enterocyte
  • enzymatic cleavage –> secretory IgA –> lumen
  • up to 90% of gut B-cells secrete IgA
48
Q

What does secretory IgA (sIgA) do?

A

Binds luminal antigen to prevent its adhesion and consequent invasion

49
Q

Describe lymphocyte homing and circulation.

A
  1. Peyer’s patch presentation and activation
  2. lymphocytes travel to mesenteric lymph nodes where lymphocyte proliferation occurs
  3. return to circulation through thoracic duct (main lymphatic vessel for return of lymph from GI tract to venous system)
  4. it can now either go to peripheral immune system (skin, tonsils, BALT bronchus associated lymphoid tissue) OR return to intestinal mucosa via vessels in lamina propria

Homing cascade directs circulating naive T cells to Peyer’s patches

50
Q

How do lymphocytes move from blood vessels into lamina propria?

a4B7 integrin/MAdCAM-1 adhesion & gut homing

A
  • HEV expresses MAdCAM1 (mucosal addressin cell adhesion molecule 1; tissue specific)
  • lymphocytes express alpha4beta7 integrin and they adhere to MAdCAM1
  1. lymphocytes roll along HEV wall (rolling)
  2. rolling chemotactically activates T cell = alpha4beta7 integrin and MAdCAM1 interact (activation)
  3. cell gets pulled into lamina propria (arrest)

Homing cascade directs circulating naive T cells to Peyer’s patches

51
Q

Why do enterocytes have such a short life span of 36 hours?

A
  • enterocytes are first line of defence against GI pathogens and 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
  • escalator-like transit of enterocytes (if interrupted through impaired production of new cells e.g. radiation –> severe intestinal dysfunction)
52
Q

What happens if escalator-like transit of enterocytes is interrupted through impaired production of new cells (e.g. radiation)?

A

Severe intestinal dysfunction

53
Q

What is the mechanism of infection of cholera?

A
  • acute bacterial disease caused by Vibrio cholerae serogroups O1 and O139
  • bacteria reaches small intestine –> contact with epithelium and releases cholera enterotoxin
  • enterotoxin gets internalised by retrograde endocytosis
  • this increases adenylate cyclase activity = increased cAMP
  • increases active secretion of salts (Na+, K+, Cl-, HCO3-) via CFTR
  • water follows and leads to diarrhoea
54
Q

How does cholera transmit?

A

Transmitted through faecal-oral route via contaminated water and food

55
Q

What are the main symptoms (2) and other symptoms (3) of cholera?

A

Main:

  • severe dehydration
  • watery diarrhoea

Other:

  • vomiting
  • nausea
  • abdominal pain
56
Q

How do we diagnose cholera?

A
  • bacterial culture from stool sample on selective agar is the gold standard
  • rapid dipstick tests also available
57
Q

How do we treat cholera?

A

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

58
Q

What vaccine is used for cholera?

A
  • Dukoral
  • oral
  • inactivated
59
Q

What is the epidemiology of cholera?

A
  • globally 1.3-4 million cases
  • average 95k deaths a year
60
Q

What are some viral causes of infectious diarrhoea (gastroenteritis)? (2)

A
  • rotavirus (children)
  • norovirus (winter vomiting bug)
61
Q

Describe rotavirus (the virus).

A
  • RNA virus, replicates in enterocytes
  • 5 types A-E, type A most common in human infections
62
Q

What is the epidemiology of rotaviruses?

A

Most common cause of diarrhoea in infants and young children worldwide

63
Q

How do we treat rotaviruses?

A
  • oral rehydration therapy
  • still causes 200k deaths a year
  • before vaccine, most people had infection by age 5 - repeated infections develop immunity
64
Q

What is the vaccination for rotavirus?

A

Live attenuated oral vaccine (Rotarix) against type A introduced in 2013 - very successful

65
Q

Describe norovirus (winter vomiting bug).

A
  • RNA virus
  • incubation period 24-48h
66
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
67
Q

What is the main symptom of norovirus?

A

Acute gastroenteritis, recovery 1-3 days

68
Q

How do we diagnose norovirus?

A

Simple PCR

69
Q

What is the epidemiology of norovirus?

A

Estimated 685 million cases and 200k deaths a year

70
Q

What are some protozoal parasitic causes of infectious diarrhoea? (2)

A
  • Giardia lamblia
  • Entamoeba histolytica
71
Q

What are some bacterial causes of infectious diarrhoea (gastroenteritis)? (6)

A
  • cholera (Vibrio cholerae subgroups O1&O139)
  • Campylobacter jejuni
  • Escherichia coli
  • Salmonella
  • Shigella
  • Clostridium difficile
72
Q

How is Campylobacter (curved bacteria) transmitted?

Most common species: Campylobacter jejuni, Campylobacter coli

A
  • undercooked meat (especially poultry), untreated water and unpasteurised milk
  • low infective dose, a few bacteria (<500) can cause illness
73
Q

What is the treatment for Campylobacter?

A
  • not usually required (excreted in few days)
  • Azithromycin (macrolide) is standard antibiotic
  • resistance to fluoroquinolones is problematic
74
Q

What is the epidemiology of Campylobacter?

A
  • estimated 280k cases per year
  • commonest cause of food poisoning in UK
75
Q

Describe Escherichia coli (E. coli)

A
  • diverse group of gram -ve intestinal bacteria
  • most harmless
76
Q

What are the six pathotypes of E. coli associated with diarrhoea?

A
  • enterotoxic E. coli (ETEC)
  • enteroinvasive E. coli (EIEC)
  • enterohaemorrhagic or Shiga toxin-producing E.coli (EHEC/STEC)
  • enteropathogenic E. coli (EPEC)
  • enteroaggregative E. coli (EAEC)
  • diffuse adherent E. coli (DAEC)
77
Q

What does enterotoxic E. coli (ETEC) cause?

A
  • cholera-like toxin
  • watery diarrhoea
78
Q

What does enteroinvasive E. coli (EIEC) cause?

A
  • Shigella-like illness
  • bloody diarrhoea
79
Q

What does enterohaemorrhagic or Shiga toxin-producing E. coli (EHEC/STEC) cause?

A
  • causes the most problems
  • E. coli O157 serogroup, shigatoxin/verotoxin
  • 5-10% get haemolytic ureamic syndrome - loss of kidney function
80
Q

How does Clostridium difficile cause problems?

A
  • usually lives in GI tract without problem
  • if there is a dysbiosis (usually due to antibiotics) you go into intermediate dysbiotic state where there is more C. diff and more inflammation-tolerant commensals and less disturbance-sensitive commensals
  • still chance for things to go back to normal
  • if not, you get pathogen-induced disturbance (toxin production) and inflammation-derived metabolites
81
Q

How do we manage C. difficile? (3)

A
  • isolate patient (very contagious)
  • stop current antibiotics
  • give vancomycin or metronidazole (odd - can cause C. diff as well as treating it)
82
Q

What are recurrence rates like for C. difficile?

A
  • 15-35% after initial infection
  • increasingly difficult to treat if recurrence occurs
83
Q

How do we cure C. difficile?

A

Faecal Microbiota Transplantation (FMT) - 98% cure

Year 2 - BRS (84 decks)

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