Immunology of the Gut Flashcards
What is the definition of gut microbiota?
- A community of commensal organisms that are found within the gastrointestinal tract
What are the 4 major phyla of commensal bacteria?
- Bacteroidetes
- Firmicutes
- Actinobacteria
- Proteobacteria
Which region of the GI tract has the greatest bacterial content?
- Colon - due to the absence of digestive host factors (pancreatic enzymes, bile acids and acid)
Why is there restricted bacterial load in the stomach (3)?
- Due to acidic pH (1-4)
- Pepsin - digestive enzymes
- Gastric lipase
Which digestive factor is produced by the liver, reducing the bacterial load in the duodenum?
Bile acids
What is dysbiosis?
- A reduction in microbial diversity, especially in the incumbent commensal organisms that colonise the gastrointestinal tract, and a rise in pathobionts – there is an imbalance in the immunological equilibrium
What is a pathobiont?
- Symbiotic bacteria that have become pathogenic under specific conditions
What is a symbiont?
- An organism that interacts with the host such that there is a mutual benefit
What are the main causes of dysbiosis (5)?
- Infection or inflammation
- Diet
- Xenobiotics
- Hygiene
- Genetics
Which junctions hold the epithelial monolayer together?
- Tight junctions - minimising the available space to which toxins can pass through
Which cells secrete mucin, forming a protective mucous layer, in the gut?
- Goblet cells
What function is performed by goblet cells in the gut, in terms of immunology?
- Secrete mucin forming a protective mucous layer that promotes immunological clearance to limit inflammation and infection
What happens to the distribution of goblet cells within the small intestine?
- Progressively increase
Which part of the small bowel has the greatest proportion of goblet cells?
- Ileum
Where do Paneth cells reside?
- Reside within the base of the crypts of Lieberkühn and secrete antimicrobial peptides (defensins) & lysozyme
What function is performed by Paneth cells?
- Secrete anti-microbrial peptides (defensins) & lysozyme
What is MALT?
- Mucosa Associated Lymphoid Tissue (MALT)
Found within the submucosa below the epithelium, as a lymphoid mass that contains lymphoid follicles.
Which types of venules surround lymphoid follicles?
- HEV postcapillary venules - allowing for the easy passage of lymphocyte migration into the tissue
What are pharyngeal tonsils?
- A collection of lymphoid tissue within the mucosa of the roof to the nasopharynx (referred to adenoids when enlarged) -> Forms Waldeyer ring
Which zones are located within MALT?
- Distinct B & T-cell zones
Which lymphoid structures are the first line of defence for pathogens entering the nasopharynx or oropharynx?
- Pharyngeal tonsils (palatine and lingual)
What are secondary lymphoid organs?
- Sites at which lymphocytes interact with antigen-presenting cells (dendritic cells) bearing antigens from peripheral tissues and differentiating into effector and memory cells that eliminate antigen
Outline the process of antigen sampling (2 / 1) and the process of that takes place in Peyer’s patch (2)
Antigen sampling:
1. Transepithelial Dendritic cells interfere with tight junction proteins in order to gain access to the lumen
2. Dendrites interact with antigens and (become APCs and are transported to peyers patch so present to naive b and t cells in peyers patch) and are transported to the mesenteric lymph node to activate B and T cell lymphocytes
Another way in which antigen sampling happens:
1. M (micro-fold) cells, within FAE, express IgA receptors and they facilitate the transfer of IgA - bacteria complex into Peyer’s patches
In peyers patch:
1. AFTER ANTIGEN PRESENTATION
B cells undergo antibody affinity maturation in Peyer’s patches (igm to iga) that generate dimeric IgA gut specific secreting plasma cells (in lamina propria)
2. Dimeric IgA which binds to poly-Ig receptors on the basolateral surface on epithelial cells and are internalised and enzymatically cleaved within the cells in vesicles before being secreted as secretory IgA - this bind to luminal antigen preventing its adhesion + invasion
Which lymphoid structures are classified as GALT?
- Peyer’s patches
Where are Peyer’s patches predominantly found?
- Within the small bowel
Which immune cells are associated with Peyer’s patches (5)?
- B lymphocytes
- T lymphocytes
- Macrophages
- Dendritic cells
- Intra-epithelial lymphocytes
What are intra-epithelial lymphocytes?
- NK cells analogues
What happens in germinal centres within Peyer’s patches?
- B-cells undergo mutation and selection - generating high affinity antibodies by somatic hypermutation and class-switch recombination
Which immune cell forms 20% of the intestinal epithelium?
Intra-epithelial lymphocytes
Which organised GALT centres are found in the small intestine?
- Peyer’s patches
Which organised GALT centres are found within the large intestine?
- Caecal patches
What are the two main differences, immunologically between the small and large intestine?
- Absence of villi & paneth cells within the large bowel in comparison to the small bowel.
- There is a greater distribution of Intra-epithelial lymphocytes (IEL) and goblet cells in the large bowel
Which epithelial cells are associated with Peyer’s patches?
- Follicle associated epithelium (FAE)
What is essential for the development of functional Peyer’s patches?
- Development requires exposure to bacterial microbiota (50 in last trimester foetus, 250 by teens)
How do B-cells undergo antibody affinity maturation in Peyer’s patches?
- Exposed to antigens presented by dendritic cells to generate IgA gut-specific secreting plasma cells
Which type of gut-specific secreting plasmas cells are produced by Peyer’s patches?
IgA
How are antigens taken up into Peyer’s patches?
- M (micro-fold) cells within FAE, which express IgA receptors
Which type of receptor is expressed by M-cells?
IgA
What function is performed by M-cells (3 steps)?
- Antigen uptake via M (microfold) cells within FAE
- Express IgA receptors
- Facilitating the transfer of IgA - bacteria complex into Peyer’s patches
What are FAE?
- Specialised epithelial cells surrounding Peyer’s patches – absent of goblet cells, no secretory IgA or microvilli
What class switch occurs upon the interaction between antigen-presenting cells and B cells?
IgM to IgA
What type of IgA is secreted from plasma cells?
- Dimeric IgA which binds to poly-Ig receptors on the basal surface on epithelial cells and are internalised and proceeded within the cells before being secreted as secretory IgA
How do dendritic cells gain access to the gastrointestinal lumen?
- Interfere with tight junction proteins in order to gain access to the lumen, dendrites interact with antigens - transported to the mesenteric lymph node to activate B and T cell lymphocytes
How are activated lymphocytes transported into mesenteric lymph nodes?
-
Mucosal addressin cell adhesion molecule 1 (MAdCAM1) is tissue specific and is presented by endothelial cells within the high endothelial venule
- MAdCAM1 interacts with 𝝰4β7 integrins expressed by lymphocytes
- Adhesion to the endothelium elicits transmigration into the lamina propria
Which tissue-specific molecule supports lymphocyte homing?
MAdCAM1
How do cholera enterotoxins cause toxicity (4 steps)?
- Binds to GM-1 receptors that irreversibly stimulates the intracellular enzyme adenylate cyclase, potentiating the action at which ADP decomposes into cAMP - an intracellular molecule
- Increased chloride secretion and inhibition of sodium chloride resorption increases intestinal lumen solute concentrations – promotes release of water into the lumen (movement of water along a water potential gradient).
- Serogroups O1 & O139
- Enterotoxins are released when the bacteria reach contact with the epithelium.
How is cholera transmitted?
- Transmitted through faecal-oral route – and spreads via contaminated water & food
What are the symptoms of cholera (4)?
- Severe watery diarrhoea
- Vomiting
- Nausea
- Abdominal pain
How is a cholera diagnosis made?
- Bacterial culture from stool sample, grown on selective agar – rapid dipstick tests are also available, although a stool sample is first line.
What is the main treatment for cholera?
- Oral rehydration solution for diarrhoea associated symptoms
What type of virus is rotavirus?
- RNA viruses that lyrically replicates within enterocytes existing as 5 serotypes (A-E), with type A rotavirus being most prevalent in human infections
How many serotypes are there for rotavirus?
5 serotypes (A-E)
Which serotype of rotavirus is most prevalent?
Type A rotavirus
What is the treatment for rotavirus?
- Oral rehydration therapy
What type of vaccine is administered as prophylaxis for rotavirus?
Live attenuated oral vaccine (Rotarix) against type A introduced in July 2013 – saw a significant reduction in cases within the UK
What type of virus is norovirus?
An RNA virus with an incubation of 24-48 hours
What is the transmission of norovirus?
-
Faecal-oral transmission
- Individuals may shed infectious virus for up to 2 weeks
- Outbreaks are common within closed communities
What is the symptom of norovirus?
- Acute gastroenteritis – recovery 1-3 days
How is a diagnosis made for norovirus?
Sample PCR
How is campylobacter transmitted (3)?
-
Undercooked meat (especially poultry), untreated water & unpasteurised milk
- Low infective dose, a few bacteria (< 500) can cause illness
Which standard antibiotic is administered to patients with a campylobacter infection?
Azithromycine (Macrolide)
What is the number of pathotypes that exist for e.coli?
6
What is the risk of E.coli 0157?
Haemolytic uraemic syndrome
How is a Clostridium difficile (C. Diff.) infection managed?
- Isolate patient (very contagious)
- Stop current antibiotics
- Treat with:
- Metronidazole
- Vancomycin
- Faecal Microbiota Transplantation (FMT) – 98% cure rate
Recurrence rate 15-35% after initial infection, increasingly difficult to treat
