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BRS Phase 1b > Gut Immunology > Flashcards

Gut Immunology Flashcards

1
Q

What is the surface area of the GI tract?

A

200m2

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2
Q

What makes up the antigen load that the GI Tract is exposed to ?

A

Resident microbiota 1014 bacteria
Dietary antigens
Exposure to pathogens

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3
Q

What state describes the GI tract’s immunological activation?

A

State of “restrained activation”
– Tolerance vs active immune response
– Dual immunological role. Immune homeostasis of gut & development of healthy immune system requires presence of bacterial microbiota

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4
Q

What makes up the Gut Microbiota?

A

1014 gut bacteria and 1013 cells in body - most densely populated “ecosystem” on Earth.
4 major phyla of bacteria (Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria), also viruses & fungi.
Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome.

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5
Q

Which chemical digestive factors produced by the host affect bacteria?

A

Stomach - HCl pH-14, pepsin, gastric lipase.
Liver - bile acids.
Pancreas - trypsin, amylase, carboxypeptidase
Small intestine - brush border enzymes
Colon - No host digestive factors

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6
Q

Define Symbionts, Commensals, Pathbionts.

A

Symbionts - no benefit or disbenefit.
Commensals - benefit from the host but do not cause harm.
Pathbionts - benefit host but have potenitial to cause disease

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7
Q

What happens in an immunological dysequilibrium?

A

Increased pathobiont replication

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8
Q

Which factors cause and influence Dysbiosis?

A 
Infection
Diet
Xenobiotics
Hygiene
Genetics
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9
Q

What are some examples of Bacteial metabolites and toxins?

A

TMAO, 4-EPS, SCFAs, bile acids, AHR ligands.

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10
Q

What are the Mucosal Defence Barriers?

A 
Physical barriers
Anatomical;
Epithelial barrier
Peristalsis
Chemical;
Enzymes
Acidic pH
Commensal bacteria
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11
Q

What makes up the Epithelial barrier?

A 
Mucus layer - Goblet cells
Epithelial monolayer - Tight junctions
Paneth Cells (small intestine)
Bases of crypts of Lieberkühn.
Secrete antimicrobial peptides (defensins) & lysozyme.
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12
Q

What are the Immunological barriers?

A

MALT (Mucosa Associated Lymphoid Tissue)

GALT (Gut Associated Lymphoid Tissue)

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13
Q

Describe the role of Mucosa Associated Lymphoid tissue MALT in immunological defence?

A

Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes

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14
Q

Give an example of somewhere rich in immunological tissue?

A

Oral cavity

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15
Q

Describe the role of Gut associated lymphoid tissue in immunological GULT defence?

A

Responsible for both adaptive and innate immune responses through generations of lymphoid cells & Antibodies. Two main types Organised & Non-organised.
Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes

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16
Q

Where would you find Non-organised GALT’s?

A

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

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17
Q

Where would you find organized GALT’s?

A

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

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18
Q

What characterises paneth cells?

A

Presence of dense granules that contain antimicrobial peptides

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19
Q

Where do you find the majority of the immuno-intestinal cells?

A

Lamina propria

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20
Q

Describe the role of Peyer’s Patches in gut immunology?

A

Immune sensorFound in submucosa small intestine – mainly distal ileum
Aggregatedlymphoid follicles covered with follicle associated epithelium (FAE).
FAE - no goblet cells, no secretory IgA, no microvilliOrganised collection of naïve T cells & B-cells
Development requires exposure to bacterial microbiota
50 in last trimester foetus, 250 by teens

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21
Q

How does Antigen uptake take place in Peyer’s patches?

A

Antigen uptake via M (microfold) cells within FAE

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

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22
Q

What is the role of Trans-epithelial Dendritic cells?

A

Antigen sampling
Open tight junction proteins and send their dendrites into GI lumen to sample bacteria, then send them to Mesenteric Lymph node.

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23
Q

Explain the adaptive response?

A

Pathogens taken up by M cells, excreted into pocket formed on the inner surface of enterocytes. Pocket contains Antigen presenting cells, these engulf the antigens and present them via MHC2 expression, dendritic cells then migrate to the peyers patch where the APC, t cells, bcells all form an organised lymphoid molecule. some antigen presenting cells escape via lymph nodes that develop in the Mesenteric lymph node.

24
Q

Describe the adaptive response?

A

Mature naïve B-cells express IgM in Peyer’s Patches
On antigen presentation class switches to IgAT-cells & epithelial cells influence B cell maturation via cytokine production
B cells further mature to become IgA secreting plasma cells.
Populate lamina propria

25
Q

How is Secretory IgA produced?

A

The plasma cell produces IgA which is taken into the enterocyte via a vesicle where there is enzymatic cleavage, Producing secretory IgA which is secreted into the lumen.

26
Q

Which cells secrete IgA

A

Up to 90% of gut B-cells secrete IgA

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

27
Q

How does Lymphocyte

A

Lymphocytes travel to Mesenteric lymph nodes for Lymphocyte proliferation following Activation & presentation in Peyer’s Patch, return to circulation via thoracic duct. It can then either enter toncils, skin, Brochus associated lymphoid tissue BALT. It can also return to intestinal mucosa via Lamina propria.

28
Q

What is important for chemotaxis of lymphocytes in the High Endothelial venule?

A

𝝰4β7 Integrin/MAdCAM-1 Adhesion & Gut Homing

29
Q

Why is rapid turnover of Enterocytes important?

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.

30
Q

What is the mechanism of action of Cholera infection?

A

Cholera -acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
Bacteria reaches small intestine → contactwith epithelium & releasescholera enterotoxin.

31
Q

Why do you get diarrhoea in cholera?

A

Cholera endotoxin gets internalised via retrograde endocytosis, once inside you get increased adenylate cyclase activity. Increased cAMP, causes secretion of salts and water follows it.

Activation of CFTR, allows salt secretion.

32
Q

What are the main symptoms of Cholera infection?

A 
Transmitted through faecal-oral route 
Spreads via contaminated water & food.
Main symptoms 
Severe dehydration & watery diarrhoea
Other symptoms
Vomiting, nausea & abdominal pain.
33
Q

How do you diagnose Cholera infection?

A

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

34
Q

How do you treat Cholera?

A

Treatment: oral-rehydration is the main management ; up to 80% of cases can be successfully treated.
Vaccine: Dukoral, oral, inactivated.
Globally 1.3 - 4 million cases, avg. 95,000 deaths/year (last indigenous UK case 1893: 2017 - 13 cases).

35
Q

What are some other causes of Infectious diarrhoea - Gastroenteritis?

A 
Viral - Rotavirus, Norovirus
Bacterial -
Campylobacter jejuni
Escherichia coli
Salmonella
Shigella
Clostridium difficile
Protozoa Parasitic - Giardia lamblia, Entamoeba histolytica
36
Q

Describe Rotaviruses

A

RNA virus, replicates in enterocytes.

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

37
Q

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

A

Rotavirus

38
Q

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

39
Q

Describe Norovirus

A

RNA virus

Incubation period 24-48 hours

40
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

41
Q

What are the symptoms of Norovirus?

A

Acute gastroenteritis, recovery 1 – 3 days

42
Q

How do you diagnose Norovirus?

A

PCR, no treatment necessary

43
Q

How is Campylobacter transmitted?

A 
Undercooked meat (especially poultry), untreated water & unpasteurised milk
Low infective dose, a few bacteria (<500) can cause illness
44
Q

What are the most common species of Campylobacter?

A

Campylobacter jejuni, Campylobacter coli

45
Q

What is the treatment for Campylobacter?

A

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

46
Q

Is Campylobacter still common?

A

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

Commonest cause of food poisoning in the UK

47
Q

What are the Pathotypes of E. coli

A

Gram negative intestinal bacteria.
Enterotoxigenic E. coli (ETEC)
Cholera like toxin
Watery diarrhoea

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

Enteroinvasive E. coli (EIEC)
Shigella like illness
Bloody diarrhea

Enteropathogenic E. coli (EPEC)
Enteroaggregative E. coli (EAEC)
Diffusely adherent E. coli (DAEC)

48
Q

How do you get C Diff?

A

C Diff exists normally in the gut, however when there is a dysbiosis, usually caused by antibiotic treatmen, then you can develop a diseased state where there is a supportive environment for toxin production

49
Q

How do you manage C Diff?

A

Isolate patient (very contagious)
Stop current antibiotics
Metronidazole (can give you it, but it also causes it), Vancomycin
Recurrence rate 15-35% after initial infection, increasingly difficult to treat.
Faecal Microbiota Transplantation (FMT) – 98% cure rate

50
Q

How do you define the severity of C Diff infection?

A

Non-severe infection
WCC<15, Creat <150

Severe infection
WCC>15, Creat >150

Fulminant colitis
Hypotension or shock, ileus, toxic megacolon

51
Q

What is the first line treatment for fulminant colitis with toxis megacolon?

A

Medical therapy with antibiotics and supportive management

52
Q

What are indications for surgery following C Diff infection?

A

Colonic perforation

Necrosis or full-thickness ischaemia

Intra-abdominal hypertension or abdominal compartment syndrome

Clinical signs of peritonitis or worsening abdominal exam despite adequate medical therapy

End-organ failure

53
Q

What is Pseudomembranous colitis?

A

Most often associated with C. difficile infection
Manifestation of severe colonic disease
Characteristic yellow-white plaques that form pseudomembranes on the mucosa
Confirmed on endoscopy +/- bio

54
Q

What are the management options for ulcerative colitis?

A

Steroids

5 ASA

Immune suppressants
Azathioprine
Methotreaxate

Biologic therapy

Others –diet, FMT, antibiotics, probiotics, novel agents

55
Q

How do you define severity of Ulcerative colitis?

A

Different scopes including clinical disease activity index, Montreal classification and Trulov & Witt scores.
Mild
4 x BMs/day, no systemic toxicity, normal ESR/CRP, mild symptoms.
Moderate
> 4x BMs/day, mild anaemia, mild symptoms, minimal systemic toxicity, nutrition maintained and no weight loss.
Severe
> 6 BMs/day, severe symptoms, systemic toxicity, significant anaemia, increased ESR/CRP and weight loss.

BRS Phase 1b (80 decks)

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