Immunology of the Gut Flashcards
1
Q
What are the implications of the large surface area of the GI tract?
A
exposure to a massive antigen load
2
Q
What does the massive antigen load consist of?
A
- resident microbiota
- dietary antigens
- pathogen exposure
3
Q
What is the impact of this large antigen load?
A
GI tract is in a state of ‘restrained activation’
4
Q
What is a state of ‘restrained activation’
A
- tolerance (food and commensal bacteria) vs active immune response
- dual immunolgoical role
5
Q
What does immune homeostasis and development of a healthy immune system require?
A
the presence of bacterial microbiota
6
Q
What are the 4 major phyla of bacteria?
A
- Bacteroidetes
- Firmicutes
- Actinobacteria
- Proteobacteria
7
Q
What is the benefits of the gut microbiota?
A
- provides traits that we do not have in our genome
- essential nutrients
- metabolism of ingestible compounds
- defence against colonisation of pathogens
8
Q
What is dysbiosis?
A
altered microbiota composition
9
Q
What is the impact of symbionts on the host?
A
- no effect, truly neutral
- for regulation
10
Q
What is the impact of commensals on the host?
A
no effect, but benefit from being part of the host
11
Q
What is the impact of pathobionts on the host?
A
- no effect normally
- can cause dysregulated inflammation and disease
12
Q
What are the important factors of immunological equilibrium in the gut?
A
- symbionts
- commensals
- pathobionts
13
Q
What can cause dysbiosis?
A
- infection
- inflammation
- diet
- xenobiotics
- hygiene
- genetics
14
Q
What happens during dysbiosis?
A
production of bacterial metabolites and toxins
15
Q
What are the 2 primary physical types of barriers?
A
- Anatomical
- Chemical
16
Q
What are the different types of anatomical barriers?
A
- epithelial barriers
- peristalsis
17
Q
What are the different types of chemical barriers?
A
- enzymes
- acidic pH
18
Q
What is involved in the epithelial barrier?
A
- mucus layer (goblet cells)
- epithelial monolayer, tight junctions
- paneth cells (in small intestines)
19
Q
What is the role of Paneth Cells?
A
- bases of crypts of Lieberkuhn
- secrete antimicrobial peptides (defensins) and lysozyme
20
Q
How do commensal bacteria act as barrier?
A
occupy an ecological niche
21
Q
What is involved in the immunological barriers?
A
- MALT (Mucosa Associated Lymphoid Tissue)
- GALT (Gut Associated Lymphoid Tissue)
22
Q
Where is MALT located?
A
- in submucosa below the epithelium
- as lymphoid mass containing lymphoid follicles
- follicles are surrounded by HEV postcapillary venules (easy passage of lymphocytes for a response)
23
Q
What area is rich in immunological tissue?
A
oral cavity
- palatine tonsil
- lingual tonsils
- pharyngeal tonsils (adenoids)
24
Q
What is the role of GALT?
A
adaptive and innate immune response through generations of lymphoid cells and Abs
25
What are the non-organised forms of GALT?
- intra-epithelial lymphocytes (eg: T cells and NK cells)
- Lamina propria lymphocytes
26
What are the organised forms of GALT?
- Peyer's patches
- Caecal patches
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
27
Where are Peyer's patches found?
small intestine
28
Where are Caecal patches found?
large intestine
29
How are non-organised GALT released?
migrate to the tip of the microvilli prior to that as well as absorptive epithelial cells
30
What produces mucus secreting goblet cells?
- stem cells
- crypts
31
Where do Paneth cells migrate to?
the bottom of the crypt of Lieberkuhn
32
Where are intraepithelial lymphocytes?
between entry sites
33
What is found in the mucosa of the microvilli?
- macrophages
- IgA B cells
- dendritic cells
- T cells
34
Where are Peyer's patches?
- submucosa small intestine
- mainly in the distal ileum
35
What are Peyer's patches?
aggregated lymphoid follicles covered with follicle associated epithelium (FAE)
36
What are characteristics of Peyer's patches?
- no goblet cells
- no secretory IgA
- lack microvilli
37
What do Peyer's patches contain?
Organised collection of naïve T cells and B-cells
38
What is required for the development of Peyer's patches?
exposure to bacterial microbiota
39
How are antigens taken up by Peyer's patches?
- via M cells within FAE
- express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer's patches
40
What can trans-epithelial dendritic cells do?
- open up tight junction proteins and send the dendrites outside into the lumen of the intestinal tract to directly sample bacteria
- cells then go to mesenteric lymph nodes
41
What happens in the B cell adaptive response in Peyer's patches?
- mature-naive B cells express IgM in Peyer's patches
- switch to IgA on antigen presentation
- T cells and epithelial cells influence B cell maturation via cytokine production
- B cells mature to become IgA secreting plasma cells
- populate lamina propria
42
How is secretory IgA produced?
- plasma cell produces IgA
- taken from submucosa into enterocyte vesicle
- enzymatic cleavage
- leading to secretory IgA in the lumen
43
What does secretory IgA do?
- bind to antigens in lumen
- prevents adhesion and invasion
(secreted by 90% of gut B cells)
44
What happens in lymphocyte homing and circulation?
- lymphocytes from Peyer's patch move into the mesenteric lymphnode
- proliferate in the lymphnode
- return to circulation via the thoracic duct into the systemic venous system
- can either enter the peripheral immune system or return to the intestinal mucosa via vessels in the lamine propria
45
What is part of the peripheral immune system?
- skin
- tonsils
- BALT (Bronchus Associated Lymphoid Tissue)
46
How does the homing cascade direct circulating naive T cells to Peyer's patches?
- rolling adhesion of T cells to HEV
- activation of T cells via binding of a4b7 integrin on T cell membrane and MAdCAM-1 on HEV walls
- T cell secreted into the lamina propria
47
Why do enterocytes and goblet cells have a rapid turnover?
- first line of defense and may be directly affected by toxicity
- may have impacts on function, metabolic rate
- shorten the effect of lesions
48
What happens if enterocyte and goblet cell turnover is interrupted?
severe intestinal dysfunction
49
What is the mechanism behind cholera infections?
- Vibrio cholerae serogroups O1 and O139
- bacteria reaches small intestine, contact with epithelium triggers the release of cholera enterotoxin
- cholera toxin enters cell via retrograde endocytosis
- increased adenylate cyclase acitvity
- increased cAMP
- cAMP activates ion channels which secrete Na+, K+, Cl- and HCO3- into the intestinal lumen
- water follows ions leading to osmotic diarrhoea
50
How is cholera transmitted?
- faecal-oral route (contaminated water and food)
51
What are the main symptoms of cholera?
- severe dehydration
- watery diarrhoea
- vomiting
- nausea
- abdominal pain
52
How do you diagnose cholera?
- bacterial culture from stool sample on selective agar (gold standard)
- rapid dipstick tests
53
How do you treat cholera?
oral rehydration
54
How do you vaccinate against cholera?
- Dukoral vaccine
- oral and inactivated
55
What are the possible viral causes of infectious diarrhoea/gastroenteritis?
- Rotavirus (children)
- Norovirus
56
What are the possible bacterial causes of infectious diarrhoea/gastroenteritis?
- Campylobacter jejuni
- E. coli
- Salmonella
- Shigella
- C. difficile
57
What are the possible protozoal parasitic causes of infectious diarrhoea/gastroenteritis?
- Giardia lamblia
- Entamoeba histolytica
58
What are rotaviruses?
- RNA virus
- replicates in enterocytes
- 5 types (A-E)
- A most common in human infection
59
How common are rotaviruses?
most common cause of diarrhoea in children and infants
60
How do you treat rotaviruses?
- oral rehydration therapy
- Rotarix vaccination (live, attenuated against type A)
61
What is Norovirus?
- RNA virus
- incubation: 24-48hours
62
How are Noroviruses transmitted?
- faecal-oral transmission
- may shed virus for up to 2 weeks
- outbreaks in closed communities common
63
What are the symptoms of Norovirus?
- acute gastroenteritis
- recovery in 1-3 days
64
How do you diagnose Norovirus?
Sample PCR
65
What are the causes of food poisoning?
- Campylobacter jejuni
- Campylobacter coli
66
How is Campylobacter transmitted?
- undercooked meat
- untreated water
- un-pasturised milk
- low infective dose
67
How do you treat for Campylobacter?
- not usually required
- Azithromycin is standard ABx
- Resistance to fluoroquinolones is problematic
68
What are the pathotypes of E. coli?
gram negative bacteria
- Enterotoxic E. coli
- Enterohaemorrhagic/Shiga toxin-producing E. coli
- Enteroinvasive E. coli
- Enteropathogenic E. coli
- Enteroaggregative E. coli
- Diffusely adherent E. coli
69
What symptoms is Enterotoxic E. coli associated with?
- cholera like toxin
- water diarrhoea
70
What symptoms is Enterohaemorrhagic/Shiga toxin-producing E. coli associated with?
- 5-10% haemolytic uraemic syndrome
- loss of kidney function
71
What symptoms is Enteroinvasive E. coli associated with?
- shigella like illness
- bloody diarrhoea
72
How does Clostridium difficile infect the body?
- always present in the gut
- exogenous disturbance e.g. antibiotics leads to dysbiosis
- intermediate dysbiotic state
- pathogen induced disturbance and toxin induction leads to diseased state
73
How do you manage Clostridium difficile?
- isolation
- stop current ABx
- Metronidazole (can also trigger infection)
- Vancomycin
- reccurence rate 15-35%, increasingly more difficult to treat
- faecal microbiota transplant
74
What symptoms would indicate a C. difficile infection?
- raised WCC and CRP
- new onset diarrhoea
- generalised tenderness
- signs of dehydration (AKI and dry mucous membranes)
75
How do you diagnose a C. difficile infection?
- stool sample for C. difficile toxin
- stool cultures
- Imaging (AXR)
