Immunology of the Gut Flashcards
(115 cards)
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 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
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 can no evolve on our own
8
Q
What factors stimulate bacterial growth/cell numbers?
A
- ingested nutrients
- secreted nutrients
9
Q
What factors inhibit bacterial growth/cell numbers?
A
- chemical digestive factors
= bacterial lysis - peristalsis, contractions and defecation
= bacterial elimination
10
Q
What chemical digestive factors are produced in the stomach?
A
- HCl
- Pepsin
- Gastric lipase
11
Q
What chemical digestive factors are produced in the liver?
A
- Bile acids
12
Q
What chemical digestive factors are produced in the pancreas?
A
- Trypsin
- Amylase
- Carboxypeptidase
13
Q
What chemical digestive factors are produced in the small intestine?
A
- brush border enzymes
14
Q
What chemical digestive factors are produced in the colon?
A
no host digestive factors
15
Q
What is the general relationship between the toxicity of chemical digestive factors and the bacterial content?
A
the more toxic the digestive factors, the smaller the bacterial content
16
Q
What is dysbiosis?
A
altered microbiota composition
17
Q
What is the impact of symbionts on the host?
A
no effect, truly neutral
18
Q
What is the impact of commensals on the host?
A
no effect, but benefit from being part of the host
19
Q
What is the impact of pathobionts on the host?
A
no effect (normally) can cause dysregulated inflammation and disease
20
Q
What are the important factors of immunological equilibrium in the gut?
A
- symbionts
- commensals
- pathobionts
21
Q
What can cause dysbiosis?
A
- infection
- inflammation
- diet
- drugs/glutens
- hygiene
- genetics
22
Q
What happens during dysbiosis?
A
production of bacterial metabolites and toxins
23
Q
What are some examples of bacterial metabolites and toxins?
A
- TMAO
- SCFAs
- 4 - EPS
- bile acids
- AHR ligands
24
Q
What is the effect of TMAO?
A
encourages the deposition of cholesterol in vessel walls leading to atherosclerosis
25
What is the effect of 4-EPS?
autism
26
What is the effect of SCFA's?
decreased: IBD
increased: stress
27
What is the effect of AHR ligands?
- MS
- rheumatoid athritis
- asthms
28
What are the 2 primary physical types of barriers?
- Anatomical
| - Chemical
29
What are the different types of anatomical barriers?
- epithelial barriers
| - peristalsis
30
What are the different types of chemical barriers?
- enzymes
| - acidic pH
31
What is involved in the epithelial barrier?
- mucus layer (goblet cells)
- epithelial monolayer, tight junctions
- paneth cells (in small intestines)
32
What is the role of Paneth Cells?
- bases of crypts of Lieberkuhn
| - secrete antimicrobial peptides (defensins) and lysozyme
33
How do commensal bacteria act as barrier?
- occupy an ecological niche
| - act as an ecological barrier
34
What is involved in the immunological barriers?
- MALT (Mucosa Associated Lymphoid Tissue)
| - GALT (Gut Associated Lymphoid Tissue)
35
Where is MALT located?
- 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)
36
What area is rich in immunological tissue?
oral cavity
- palatine tonsil lingual tonsils
- pharyngeal tonsils (adenoids)
37
What is the role of GALT?
responsible for both adaptive and innate immune response through generations of lymphoid cells and Abs
38
What type of response is mounted by GALT?
both adaptive and innate immune response
39
What are the non-organised forms of GALT?
- intra-epithelial lymphocytes (in between entry points) (eg: T cells and NK cells)
- Lamina propria lymphocytes
40
What are the organised forms of GALT?
- Peyer's patches
- Caecal patches
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
41
Where are Peyer's patches found?
small intestine
42
Where are Caecal patches found?
large intestine
43
How are non-organised GALT released?
migrate to the tip of the microvilli prior to that as well as absorptive epithelial cells
44
What produces mucus secreting goblet cells?
- stem cells
| - crypts
45
Where do Paneth cells migrate to?
the bottom of the crypt
46
How do you characterise Paneth cells?
- presence of dense granules that anti-microbial peptides
| - appropriate lamina
47
Where are intraepithelial lymphocytes?
between entry sites
48
What is found in the mucosa of the microvilli?
- macrophage
- IgA B cells
- DC
- I cell
49
Where are Peyer's patches?
- submucosa small intestine
| - mainly in the distal ileum
50
What are Peyer's patches?
aggregated lymphoid follicles covered with follicle associated epithelium (FAE)
51
What are characteristics of Peyer's patches?
- no goblet cells
- no secretory IgA
- lack microvilli
52
What are the causes of infectious diarrhoea?
- Clostridium difficile
- Klebsiella oxytoca
- Clostridium perfringens
- Salmonella spp
(can cause bloody diarrhoea)
53
What are the causes of non-infectious diarrhoea?
- antibiotics side effect
- post-infectious IBS
- IBD
- Microscopic colitis
- Ischaemic colitis
- Coeliac disease
- Haemorrhoids
54
How do you manage C. difficile?
- Infection control (side room)
- Discontinue inciting antibiotic agents
- Management of fluids, nutrition and diarrhoea
55
What would classify a non-severe infection?
- WCC < 15
| - Creatinine < 150
56
What would classify a severe infection?
- WCC > 15
| - Creatinine > 150
57
What fulminant colitis?
- hypotension
- shock
- ileus
- toxic megacolon
58
How do you treat non-severe C. difficile infections?
- ABx with oral vancomycin/fidaxomicin/metronidazole
| - role of Faecal Microbiota Transplantation (FMT)
59
How do you treat severe/fulminant colitis C. difficile infections?
- ABx
- supportive care
- close monitoring
- early surgical consultation
60
What is the first line treatment of fulminant colitis and toxic megacolon?
- Medical therapy with antibiotics and supportive management
| - IV fluid resuscitation and inotropic support
61
What are the indications for surgery?
- Colonic perforation
- Necrosis/Full-thickness ischaemia
- Intra-abdominal hypertension
- Abdominal compartment syndrome
- Clinical signs of peritonitis
- Worsening abdominal exams
- End-organ failure
62
What is pseudomembranous colitis?
- manifestation of severe colonic disease
| - characteristic yellow-white plaques that form pseudomembranes on the mucosa
63
What tends to cause pseudomembranous colitis?
C. difficile
64
How do you confirm pseudomembranous colitis?
- endoscopy
| - biopsy
65
What does chronic inflammation with no granulomas on a colonoscopy indicate?
Ulcerative colitis
66
What do Peyer's patches consist of?
- dome area filled with dendritic cells
- B cell follicles
- interfollicular T cells
67
What does the development of the naive T and B cells require?
exposure to bacterial microbiota
68
How does antigen uptake to Peyer's patches occur?
```
via M (microfold) cells in FAE
- express IgA receptors facilitating the transfer of IgA-bacteria complexes into the Peyer's patches.
```
69
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
- mesenteric lymph nodes
70
What happens in the B cell adaptive response?
- mature naive B cells express IgM in Peyer's patches
- on antigen presentation switch to IgA
- T cells and epithelial cells influence B cell maturation via cytokine production
- B cells mature to become IgA secreting plasma cells
- in lamina propria
71
How is secretory IgA produced?
- plasma cell produces IgA
- taken into enterocyte vesicle
- enzymatic cleavage
- leading to secretory IgA in the lumen
72
What does secretory IgA do?
- bind luminal antigen
- prevents adhesion and invasion
(secreted by 90% of gut B cells)
73
What happens in lymphocyte homing and circulation?
- lymphocytes from Peyer's patch move into the mesenteric lymphnode
- in the lymphnode they proliferate
- 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
74
What is part of the peripheral immune system?
- skin
- tonsils
- BALT (Bronchus Associated Lymphoid Tissue)
75
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
76
What happens if enterocyte and goblet cell turnover is interrupted?
severe intestinal dysfunction
77
What is the mechanism behind cholera infections?
- Vibrio cholerae serogroups 01 and 0139
- bacteria reaches small intestine, contact with epithelium triggers the release of cholera enterotoxin
- internalised via retrograde endocytosis
- increased adenylate cyclase acitvity
- increased cAMP
- secretion of salts and water follows by CFTR
78
How is cholera transmitted?
- faecal-oral route (contaminated water and food)
79
What are the main symptoms of cholera?
- severe dehydration
- water diarrhoea
- vomiting
- nausea
- abdominal pain
80
What does CFTR stand for
Cystic fibrosis transmembrane conductance regulator
81
How do you diagnose cholera?
- bacterial culture from stool sample on selective agar (GS)
| - rapid dipstick tests
82
How do you treat cholera?
- oral rehydration
83
How do you vaccinate against cholera?
- Dukoral
- oral
- inactivated
84
What are the possible viral causes of infectious diarrhoea/gastroenteritis?
- Rotavirus (children)
| - Norovirus
85
What are the possible bacterial causes of infectious diarrhoea/gastroenteritis?
- Campylobacter jejuni
- E. coli
- Salmonella
- Shigella
- C. difficile
- Cholera
86
What are the possible protozoal parasitic causes of infectious diarrhoea/gastroenteritis?
- Giardia lamblia
| - Entamoeba histolytica
87
What are rotaviruses?
- RNA virus
- replicates in enterocytes
- 5 types (A-E)
88
How common are rotaviruses?
most common cause of diarrhoea in children and infants
89
How do you treat rotaviruses?
- oral rehydration therapy
| - vaccination (live, attenuated against type A)
90
What is Norovirus?
- RNA virus
| - incubation: 24-48hours
91
How are Noroviruses transmitted?
- faecal-oral transmission
- may shed for up to 2 weeks
- outbreaks in closed communities common
92
What are the symptoms of Norovirus?
- acute gastroenteritis
| - recovery in 1-3 days
93
How do you diagnose Norovirus?
Sample PCR
94
What are the causes of food poisoning?
Campylobacter
- Campylobacter jejuni
- Campylobacter coli
95
How is Campylobacter transmitted?
- undercooked meat
- untreated water
- un-pasturised milk
- low infective dose
96
How do you treat for Campylobacter?
- not usually required
- Azithromycin is standard ABx
- Resistance to fluoroquinolones is problematic
97
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
98
What symptoms is Enterotoxic E. coli associated with?
- cholera like toxin
| - water diarrhoea
99
What symptoms is Enterohaemorrhagic/Shiga toxin-producing E. coli associated with?
5-10% loss kidney function
| haemolytic uraemic syndrome
100
What symptoms is Enteroinvasive E. coli associated with?
- shigella like illness
| - bloody diarrhoea
101
How does Clostridium difficile infect the body?
- always present in the gut
- dysbiosis - intermediate dysbiotic state
- pathogen induced disturbance and toxin induction
102
How do you manage Clostridium difficile?
- isolation
- stop ABx
- Metronidazole (can also trigger infection)
- Vancomycin
- reccurence rate 15-35%, increasingly more difficult to treat
- faecal microbiota transplant
103
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)
104
How do you diagnose a C. difficile infection?
- stool sample for C. difficile toxin
- stool cultures
- Imaging (AXR)
105
What would cause dilation of the large intestine (transverse) secondary to a C. difficile infection?
toxic megacolon
106
What clinical features suggest toxic megacolon?
- dilation of bowel
| - septic features of the patient
107
What investigations would you do for suspected IBD?
- Stool culture for C. diff infections
- Stool culture (calprotectin)
- Endoscopy
108
What are the management options for UC?
- steroids
- 5 ASA
- immune suppressants (azathioprine and methotreaxate)
- biologic therapy
- diet
- FMT
- ABx,PBx
109
What would classify UC as mild?
- 4 BM/day
- no systemic toxicity
- normal ESR/CRP
- mild symptoms
110
What would classify UC as moderate?
- more than 4BM/day
- mild anaemia
- mild symptoms
- minimal systemic toxicity
- nutrition maintained
- no weight loss
111
What would classify UC as severe?
- more than 6 BM/day
- severe symptoms
- systemic toxicity
- significant anaemia
- increased ESR/CRP
- weight loss
112
What can azathioprine cause?
reactivation of diseases like:
- Hep B/C
- HIV
- TB
113
What must be tested when prescribing azathioprine to prevent toxicity?
thiopurine methotransferase (TPMT)
114
What is the last line medical treatment for presistant UC?
Infliximab with Azathioprine
115
What are the side effects of Infliximab?
- demyelinating disease
- autoimmunity
- congestive heart failure
- hepatoxicity
- malignancy
- infection/bone marrow suppression
- infusion reactions
