Gut Immunology (Complete) Flashcards
How large is the surface area of the GI tract and what consequence does this play in relation to antigens?
Surace area is 200m2
Therefore has a massive antigen load (exposed to a large amount of antigens)
List 3 examples of things that contribute to the antigen load of the GI tract
Resident microbiota bacteria
Dietary antigens
Pathogen antigens
The GI tract is in a state of restrained activation. Explain what this means and how the GI tract achieves this.
GI tract plays a dual immunological role and has to balance between tolerance and active immune response
Example of tolerance includes: Food antigens and Commensal bacteria
Active immune response: Immunoreactivity to pathogens
Give 2 examples of tolerance displayed in the GI tract
Tolerance to food antigens
Tolerance to commensal bacteria
Immune homeostasis of gut & development of healthy immune system requires on what important factor?
Presence of bacterial microbiota
The gut bacteria is considered a ‘virtual organ’ due to the fact that?
1014 gut bacteria versus 1013 cells in body
Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome.
What are the main types of organisms that contribute to the gut microbiota?
Viruses
Fungi
Bacteria (Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria),
List the 4 main phyla of bacteria that are present in the gut microbiota
Bacteroidetes
Firmicutes
Actinobacteria
Proteobacteria
Which region of the GI tracts contain the highest and lowest bacterial content?
Highest: Colon
Lowest: Stomach
List 2 host factors that can increases bacteria cell numbers and 2 factors that can decrease cell numbers and explain why it affects numbers.
Increase: Ingested nutrients and Secreted nutrients (Promotes bacterial growth)
Decrease: (Lead to cell lysis and bacterial elimination)
Chemical digestive factors (Lysis)
Peristalsis contractions (Eliminiation)
Defecation (Elimination)
Suggest a reason why the colon has the highest bacterial cell numbers in the GI tract.
Due to lack of secretion of chemical digestive factors in this region versus various other GI tract regions.
List 3 examples of chemical factors released from the stomach which can influence bacterial cell numbers
HCL
Pepsin
Gastric lipase
List an example of a chemical factor released from the liver which can influence bacterial cell numbers in the duodenum.
Bile acid
List an example of a chemical factor released from the small intestine which can influence bacterial cell numbers
Brush border enzymes
List 3 examples of chemical factors released from the pancreas which can influence bacterial cell numbers in the jejunum
Tripsin
Amylase
Carboxypeptidase
Define symbiont
Organism that lives with the host and neither benefit or harm the other
Define commensal bacteria
Bacteria that benefits from the host but does not help or harm the host
Define pathobiont
An initially non-harming symbiont that becomes pahogenic under certain (usually enviornmental) conditions
Define dysbiosis
Altered microbiota composition
List 5 factors that can influence dysbiosis
Infection or inflammation
Diet
Xenobiotics (chemical foreign to the body or substances e.g. drugs)
Hygeine
Genetics
Dysbiosis can have multiple effects on the body due to?
Production of harmful bacterial toxins and metabolites
Dysbiosis can have multiple effects on the body. List 3 examples of effects it can have on the brain
Stress
Autism
Multiple sclerosis
Dysbiosis can have multiple effects on the body. Give an example of its effects on the lung?
Asthma
Dysbiosis can have multiple effects on the body. Give 2 examples of a consequence of its effects on the Liver.
Nonalcoholic fatty liver disease (NAFLD) [Range of liver diseases that occur in people who dont drink]
Non-alcoholic steatohepatitis (NASH) [type of NAFLD caused by buildup of fat leading to hepatitis]
Dysbiosis can have multiple effects on the body. Give 2 examples of a consequence of its effects on the adipsoe tissue
Obesity
Metabolic diseases
Dysbiosis can have multiple effects on the body. Give 2 examples of a consequence of its effects on the intestine.
IBD (inflammatory bowel disease)
Coeliac disease
Dysbiosis can have multiple effects on the body. Give 2 examples of systemic consequences.
T1DM
Atherosclerosis
Rheumatoid arthiritis
What is the first, second and last line of mucosal defense in the GI tract?
1st line: Physical barrier
2nd line: Commensal bacteria
3rd line: immunological response
Mucosal defense involves which two types of physical barriers? Give 2 examples for each type of physical barrier
Anatomical physical barriers (e.g. epthielial barriers and peristalsis)
Chemical physical barriers (e.g. enzymes and pH)
In which three ways does the epithelial barrier provide protection in the GI tract?
Mucus layer (produced by goblet cells)
Epithelial monolayer (has tight junctions)
Paneth Cells of small intestine (Secrete antimicrobial peptides (defensins) & lysozyme)
Where are paneth cells located and how do they provide protection within the GI tract?
Located in the small intestine within the bases of crypts of Lieberkühn.
Secrete antimicrobial peptides (called defensins) and lysozymes
Which two types of tissues provide immunological mucosal defense within the GI tract?
MALT: Mucosal associated lymphoid tissue
GALT: Gut Associated Lymphoid Tissue
Where is MALT located?
Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles.
The oral cavity is rich in immunological tissue.
Where is MALT located and briefly describe its structure which enables it to perform its imunological functions
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
Name the venules which sorround the lymphoid follicles of MALT.
HEV (high endothelial venule) postcapillary venules
Give 3 examples of regions of the oral cavity which contains high amount of lymphoid tissue (MALT)
Paletine tonsil
Lingual tonsil
Pharyngeal tonsil
GALT is responsible for which types of immunological responses?
Both active and innate immunological responses
List 6 cellular components which make up the GALT.
B lymphocytes
T lymphocytes
Macrophages
APC (dendritic cells)
Epithelial lymphocytes
Intra-epithelial lymphocytes
What is the role GALT plays in the active and innate immunological response? (2)
Producing lymphoid cells and antibodies
GALT can be considered as non-organised and organised. What are 2 examples of non-organised GALT?
Intra-epithelial lymphocytes (e.g. T-cells, NK cells) [Makes up 1/5th of intestinal epithelium)
Lamina propria lymphocytes
GALT can be considered as non-organised and organised. What are 4 examples of organised GALT?
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
Diagram showing differences between large and small intestine
Where are Peyer’s patches located?
Found in submucosa small intestine (mainly distal ileum)
Briefly describe the structure of Peyer’s patches
Aggregated lymphoid follicles covered with follicle associated epithelium (FAE).
Contains an organised collection of naïve T cells, B-cells and a subethilial dome containing dendritic cells
How does follicle associated epithelium (FAE) differ from normal epithelium of the intestinal tract? (3)
No goblet cells
No secretory IgA
No microvilli
The development of naive T-cells and B-cells of the Peyer’s patches requires exposure to?
Requires exposure to bacterial microbiota
How does the amount of Peyer’s patches differ between the last trimester of pregnancy up until teenage years?
50 in last trimester foetus, 250 by teens
What component of the FAE (Follicle associated epithelial cells) plays a role in antigen uptake and transfer to Peyer’s patches?
Microfold cells (AKA M cells)
Briefly describe the role of M cells
M cells play a role in antigen uptake for peyer’s patches
M cells express IgA receptors, facilitating transfer of IgA-bacteria complex into the Peyer’s patches
What 2 cells of the GI tract play an important role in antigen sampling?
Microfold cells (M cells)
Dendritic cells
Briefly explain how dendritic cells play a role in antigen sampling
Dendritic proccesses can pass through the tight junction of the epithilial cells, enabling them to sample antigens present within the lumen.
They the trnasfer the anrtigens sampled and deliver them to mesenteric lymph nodes
Explain how the B-cell adaptive response occurs within the Peyer’s patches.
Mature naïve B-cells express IgM in Peyer’s Patches
On antigen presentation class switches to IgA
T-cells & epithelial cells influence B cell maturation via cytokine production
B cells further mature to become IgA secreting plasma cells and populate lamina propria
Mature niave B-cells express which type of antibodies in peyer’s patches? How does this change when presented with an antigen?
Mature naïve B-cells express IgM in Peyer’s Patches
On antigen presentation class switches to IgA
T-cells & epithelial cells influence B cell maturation via?
Cytokine production
Up to 90% of gut B-cells produces which type of antibody?
IgA
Explain how secretory IgA is secreted into the gut lumen.
Activated plasma cells produce and secrete dimeric IgA in the submucosa
IgA binds to poly-ig receptors and is taken into the epithelial cells.
Enzymatic cleavage between the IgA and receptor occurs and secretory IgA is released into the lumen to perform its function
Explain the role of secretory IgA in the gut lumen
sIgA binds luminal antigen preventing its adhesion and consequent invasion.
Briefly explain what occurs during lymphocytic homing and circulation
Antigens from gut lumen taken in and presented to Peyer’s patches for antigen presentation and activation.
Activated lymphocytes then travel to mesenteric lymph nodes where lymphocyte proliferation occurs.
Lymphocytes then return to the circulation via thoracic duct.
Once it enters circulation it can travel to the peripheral immune system (e.g. skin, tonsils BALT [Bronchus-associated lymphoid tissue])
An alternative route would involve exiting the peripheral immune system and entering the intestinal mucosa via vessels in the lamia propria
Enterocytes & goblet cells of small bowel have a short life span (about 36 hrs) versus other types of epithelial cells. Suggest 3 reasons why rapid turnover of enterocytes occurs.
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.
What is a consequence of impairment of rapid turnover of enterocytes?
Severe intestinal dysfunction will occur
Give an example of a cause of rapid enterocyte cell turnover dysfunction
Radiation
Cholera is a acute bacterial disease caused by which bacteria and its serotypes?
Vibrio cholerae serogroups O1 & O139
Explain how vibrio cholerae leads to development of cholera
Bacteria reaches small intestine → contact with epithelium & releases cholera enterotoxin.
Once inside the epithelial cells, it activated adenylate cyclase activity, increasing cAMP levels.
This results in increased secretion of Na+, K+, Cl- and HCO3-, leading to osmotic movement of water into the lumen of the intestinewhich results in presentation of diarrhea
Cholera infection is transmitted via which route and how does it spread?
Transmitted via Faecal-oral route
Spreads via contaminated water & food.
What are the two main symptoms of cholera?
List 3 other common symptoms of cholera
Severe dehydration
Watery diarrhoea
Vomiting
Nausea
Abdominal pain.
What is the gold-standard diagnostic investigation for a patient suspected of having cholera?
What is an alternative investigation that can be used?
Gold standard: bacterial culture from stool sample on selective agar
Rapid dipstick tests also available
What is the main treatment option for a patient with cholera?
oral-rehydration is the main management (up to 80% of cases can be successfully treated)
What is a medical preventative measure against cholera infections?
Vaccine: Dukoral (oral inactivated vaccine)
How common are cholera cases globally versus in the UK?
Globally 1.3 - 4 million cases, avg. 95,000 deaths/year
Uk around 2017 - 13 cases (with last indigenous case being in 1893) [Check travel history]
Define gastroenteritis
Inflammation of the stomach and intestines, typically resulting from bacterial toxins or viral infection and causing vomiting and diarrhoea (aka stomach bug)
List 2 viral causes of infectious diarrhoea (gastroenteritis)
Rotavirus (Children)
Norovirus (Winter vomitting bug)
Which gastroenteritis causing virus is most common in children?
Rotavirus
The ‘winter vomitting bug’ is caused by which type of virus?
Norovirus
List 2 parasitic causes of infectious diarrhoea (gastroenteritis)
Giardia lamblia
Entamoeba histolytica
List 6 bacterial causes of infectious diarrhoea (gastroenteritis)
Vibrio cholerae
Campylobacter jejuni
Escherichia coli
Salmonella
Shigella
Clostridium difficile
What type of virus is the rotavirus and where does it replicate?
RNA virus
Replicates in enterocytes
What are the 5 types of rotaviruses and which one is most common in human infections?
Type A-E
Rotavirus type A most common in human infections
What pathogen is the most common cause of diarrhoea in children and infants worldwide?
Rotavirus
What is the main treatment option for gastroentertisis in children caused by rotavirus?
Oral rehydration therapy
Before the vaccine was introduced, most individuals had a rotavirus infection by which age? What was the consequence of this?
Individuals had an infection by age 5, repeated infections develop immunity.
Name the vaccine introduced in the UK to fight against rotavirus type A. What type of vaccine is it?
Rotarix (Live attenuated oral vaccine)
What type of virus are noroviruses and what is their incubation period?
RNA Virus
24-48 hour incubation period (until symptoms appear)
How does norovirus transmit itself? How long can a person be contagous and what communites tend to be affected by the virus?
Faeco-oral route transmission
Can shed the virus for up to 2 weeks
Outbreaks often occur in closed communities (e.g. on cruise ships
What is the main symptom of noroviruses and how long would a person usually be symptomatic for?
Acute gastroenteritis
Symptomatic for 1-3 days
What species of norovirus is the most common cause of acute gastroenteriris symptoms?
Norwalk virus
What is the main diagnostic investigation for norovirus and what is the treatment option
Sample PCR
Ussually no treatment option required
How many cases of norovirus occur each year?
685 million per year
What are the two most common species of campylobacter?
Campylobacter jejuni
Campylobacter coli
What are the 3 most common ways campylobacter is transmitted?
Undercooked meat (especially poultry)
Untreated water
Unpasteurised milk
Suggest a reason why campylobacter can easily cause illness after infection.
Low infective dose, a few bacteria (<500) can cause illness
What is the main treatment option for a patient infected with campylobacter.
Treatment not usually required (unless extremely unwell)
If so Azithromycin (macrolide) is the standard antibiotic
What is the most commonest cause of food poisoning in the UK?
Campylobacter
How many cases of campylobacter infections in the UK per year?
Estimated 280,000 cases per year in UK, 65,000 confirmed
Name the diverse group of Gram-negative intestinal bacteria present in humans.
Escherichia coli (E. coli)
E. coli is a diverse group of gram-negative bacteria in the GI tract and are mostly harmless. How many of these types of E coli are pathogenic and are associated with diarrhoea (diarrhoeagenic)?
6 pathotypes of E.coli considered diarrhoeagenic
Is E.coli gram positive or gram negative?
Gram negative
Name the 6 pathogenic types of E.coli
Enterotoxigenic E. coli (ETEC)
Enteroinvasive E. coli (EIEC)
Enterohaemorrhagic or Shiga toxin-producing E. coli (EHEC/STEC)
Enteropathogenic E. coli (EPEC)
Enteroaggregative E. coli (EAEC)
Diffusely adherent E. coli (DAEC)
Name the type of E.coli responsible for causing watery diarrhoea and briefly describe how it causes this.
Enterotoxigenic E. coli (ETEC)
Produces a cholera-like toxin
Name the type of E.coli responsible for causing bloody diarrhoea which is typical of a shigella like illness.
Enteroinvasive E. coli (EIEC)
Which type of E.coli is considered to cause the most serious medical complications and why?
Enterohaemorrhagic or Shiga toxin-producing E. coli (EHEC/STEC)
Produces a shigatoxin/verotoxin which can result in development of haemolytic uraemic syndrome (loss of kidney function) in around 5-10% of cases.
What is haemolytic uraemic syndrome?
condition that can occur when the small blood vessels in your kidneys become damaged and inflamed, resulting in blood clots that can lead to kindey failure
Name a type of bacteria that is known to be particularly problematic in hospital settings due to being highly contagious
Clostridium difficile (C. diff)
Explain why clostridium difficile tends to emerge in hospital settings.
C.diff exists normally in the gut and does not cause problems when a patient is in a normal healthy state.
If a patient is being treated with therapeutics (e.g. antibiots, probitoics, faecal microbiotic transplantations (FMT), this places their gut in a intermediate dysbiotic state due to reducing numbers of distubrance-sesnitive commensal bacteria.
This has a chance of progressing into a diseased state in which the environment is supportive for C. diff to thrive.
What is the step by step management plan for a patient who has a C.diff infection?
Isolate the patient
Stop current antibiotics
Give Metronidazole or Vancomycin
May consider Faecal Microbiota Transplantation (FMT) (98% cure rate)
What is the reccurence rate of a patient with C.diff becoming reinfected after intial infection and what is the consequence of this?
Recurrence rate 15-35% after initial infection, increasingly difficult to treat.
What treatment option has been show to be particularly effective in treating C.diff infections?
Faecal Microbiota Transplantation (FMT) – 98% cure rate
