Gut Immunology Flashcards
What is the surface area of the GI tract?
200m^2
What is the state of the GI tract?
State of “restrained activation”
Why is bacterial microbiota important?
Immune homeostasis of gut & development of healthy immune system requires presence of bacterial microbiota
What is tolerance?
- food antigens
- commensal bacteria
What is the massive antigen load that the GI tract needs to deal with?
- Resident microbiota 1014 bacteria
- Dietary antigens
- Exposure to pathogens
What is immunoreactivity?
pathogens
What is involved in GI tract immunology?
– Tolerance vs active immune response
– Dual immunological role
How many gut bacteria and cells are there?
10^14 gut bacteria and 10^13 cells in the body
What are the 4 major phyla of bacteria?
- Bacteriodetes
- Firmicutes
- Actinobacteria
- Proteobacteria
- also viruses and fungi
Why do we need the gut microbiota?
provide traits we have not had to evolve on our own, genes in. gut flora 100 times our own genome
What is dysbiosis?
altered microbiota composition
What is all balanced in immunological equilibrium?
- Symbionts (regulation): live with host no benefits/harm
- Commensals: benefits from host but no affect on host
- Pathobionts (inflammation): can cause inflammation and disease in certain circumstance but usually symbionts
Which bacterial metabolites and toxins can be produced by pathobiomes in dysbiosis?
- TMAO
- 4-EPS
- SCFAs
- bile acids
- AHR ligand
What are the brain diseases that can develop from dysbiosis?
- Stress
- Autism
- Multiple sclerosis
What are the lung diseases that can develop from dysbiosis?
asthma
What are the liver diseases that can develop from dysbiosis?
- NAFLD
2. NASH
What are the adipose tissue diseases that can develop from dysbiosis?
- Obesity
2. Metabolic disease
What are the intestine diseases that can develop from dysbiosis?
- IBD
2. Coeliac disease
What are the systemic diseases that can develop from dysbiosis?
- T1 diabetes
- Atheroscelerosis
- Rhematoid arthritis
What aspects can contribute to both healthy microbiota and dysbiosis?
- Infection or inflammation
- Diet
- Xenobiotics
- Hygiene
- Genetics
What are the anatomical physcial barriers to muscosal defence?
- Epithelial barrier
* Peristalsis
What are the chemical physcial barriers to muscosal defence?
- Enzymes
* Acidic pH
What are commensal bacteria?
occupy “ecological niche”
What is an immunological response to invasion?
following invasion
•MALT (Mucosa Associated Lymphoid Tissue)
•GALT (Gut Associated Lymphoid Tissue)
What is the epithelial barrier made up of?
- Mucus layer - Goblet cells
- Epithelial monolayer - Tight junctions
- Paneth Cells (small intestine)
What are Paneth Cells? Where are they?
-small intestine
•Bases of crypts of Lieberkühn
•Secrete antimicrobial peptides (defensins) & lysozyme
Where is MALT found?
in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
What are the follicles in MALT surrounded by?
surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
What is the oral cavity rich in?
immunological tissue
What is GALT responsible for?
adaptive and innate immune system
What does GALT consist of?
- B and T lymphocytes
- Macrophages
- APC (dendritic cells)
- Specific epithelial and intra epithelial lymphocytes
What is the non organised section of GALT?
- Intra-epithelial lymphocytes
•Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells - Lamina propria lymphocytes
What is the organised section of GALT?
- Peyer’s patches (small intestine)
- Caecal patches (large intestine)
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
Where are peyer’s patches found?
in submucosa small intestine – mainly distal ileum
What are stimulatory factors for microbiota?
- Ingested nutrients
- Secreted nutrients
- lead to bacterial growth
What are inhibitory factors for microbiota?
- Chemical digestive factors (bacterial lysis)
2. Peristalsis, contractions and defecation (bacterial elimination)
What is dysbiosis?
- immunological dysequilbrium
- Altered microbiota composition
What are the aggregated lymphoid follicles covered with in peyers patches?
with follicle associated epithelium (FAE)
What is FAE?
no goblet cells, no secretory IgA, no microvilli
What is Peyer’s Patches?
Organised collection of naïve T cells & B-cells
What is needed for the development of Peyer’s Patches?
-requires exposure to bacterial microbiota
•50 in last trimester foetus, 250 by teens
What are M cells in Peyer’s patches?
- Antigen uptake via M (microfold) cells within FAE
* M cells expressIgA receptors, facilitating transfer of IgA-bacteria complexinto the Peyer’s patches.
What do mature naive B cells express in Peyer’s patches?
IgM
What happens to the IgM on antigen presentation?
class switches to IgA
What influences B cell maturation? What do they populate?
- T-cells & epithelial cells influence B cell maturation via cytokine production
- B cells further mature to become IgA secreting plasma cells.
- Populate lamina propria
What is the formation of IgA?
Up to 90% of gut B-cells secrete IgA
Where does sIgA bind (secretory IgA)?
- sIgA binds luminal antigen
* → preventing its adhesion and consequent invasion.
Why if enterocytes & goblet cells of small bowel have a short life span (about 36 hrs)
and rapid turnover contrasts with lifespan of weeks/months for other epithelial cell types (e.g. lung, blood vessels)?
- 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 the mechanism of cholera infection?
- Cholera -acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
- Bacteria reaches small intestine → contactwith epithelium & releasescholera enterotoxin
How is cholera transmitted?
- Transmitted through faecal-oral route
* Spreads via contaminated water & food
What are the symptoms of cholera?
- Main symptoms
•Severe dehydration & watery diarrhoea - Other symptoms
Vomiting, nausea & abdominal pain
What does the diagnosis of cholera involve?
bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available
What does the treatment of cholera involve?
oral-rehydration is the main management ; up to 80% of cases can be successfully treated
Is there a vaccine for cholera?
Dukoral, oral, inactivated
What is the epidemiology of cholera?
Globally 1.3 - 4 million cases, avg. 95,000 deaths/year (last indigenous UK case 1893: 2017 - 13 cases)
What are the viral causes of infectious diarrhoea?
- Rotavirus (children)
* Norovirus “winter vomiting bug”
What are the protozoal parasitic causes of infectious diarrhoea?
- Giardia lamblia
- Entamoeba histolytica
What are the bacterial causes of infectious diarrhoea?
- Campylobacter jejuni
- Escherichia coli
- Salmonella
- Shigella
- Clostridium difficile
What is rotavirus?
- RNA virus, replicates in enterocytes.
* 5 types A – E, type A most common in human infections.
What is the epidemiology of rotaviruses?
Most common cause of diarrhoea in infants & young children worldwide
What is the treatment of rotaviruses?
- Oral rehydration therapy
- Still causes ~ 200,000 deaths/year.
- Before vaccine, most individuals had an infection by age 5, repeated infections develop immunity.
Is there a vaccination for rotaviruses?
Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013
What is norovirus?
- RNA virus
* Incubation period 24-48 hours
What is the transmisstion of norovirus?
- Faecal-oral transmission.
- Individuals may shed infectious virus for up to 2 weeks
- Outbreaks often occur in closed communities
What are the symptoms of norovirus?
•Acute gastroenteritis, recovery 1 – 3 days
What is the treatment of norovirus?
•Not usually required
What is the diagnosis of norovirus?
•Sample PCR.
What is the epideimiology of norovirus?
•Estimated 685 million cases per year.
What is the most common species of campylobacter?
•Campylobacter jejuni, Campylobacter coli
What is the transmission of campylobacter?
- Undercooked meat (especially poultry), untreated water & unpasteurised milk
- Low infective dose, a few bacteria (<500) can cause illness
What is the treatment of campylobacter?
- Not usually required
- Azithromycin (macrolide) is standard antibiotic
- Resistance to fluoroquinolones is problematic
What is the epidemiology of campylobacter?
- Estimated 280,000 cases per year in UK, 65,000 confirmed
* Commonest cause of food poisoning in the UK
What is E.Coli?
•Diverse group of Gram-negative intestinal bacteria
•Most harmless
6 ”pathotypes” associated with diarrhoea (diarrhoeagenic)
What is Enterotoxigenic E. coli (ETEC)?
- Cholera like toxin
* Watery diarrhoea
What is 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
What is Enteroinvasive E. coli (EIEC)?
- Shigella like illness
* Bloody diarrhea
What are other pathotypes of E coli?
•Enteropathogenic E. coli (EPEC)
•Enteroaggregative E. coli (EAEC)
-Diffusely adherent E. coli (DAEC
What is the management of Clostridium Difficile?
- Isolate patient (very contagious)
- Stop current antibiotics
- Metronidazole, Vancomycin
- Recurrence rate 15-35% after initial infection, increasingly difficult to treat.
- Faecal Microbiota Transplantation (FMT) – 98% cure rate
