Immunology Of The Gut Flashcards
GI tract
- surface area of 200m squared
- Massive antigen load
- 10^14 resident bacteria in the microbiota
- State of restrained activation
Dual immunological role - tolerance vs active immune response (tolerance would be food antigens and commensal bacteria) (immune reactivity would be pathogens)
What did germ free mice show
maldevelopment of small intestine
- fewer Peyer’s patches
- angiogenin 4 expressed less
4 Major phyla of bacteria
Bacteroidetes, firmicutes, actinobacteria, proteobacteria
Provide traits we have not had to evolve individually
Genes in gut flora 100 times our own genome
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Dysbiosis
Symbionts regulate
Pathobionts cause inflammation
Commensals do not effect the equilibrium
Xenobiotics - small chemical compounds that enter unnaturally - drugs, pollutants
Dysbiosis is related to a multitude of disorders, including autism (4-EPS), cancers (short chain fatty acids), pancreatic diseases (bile acids)
Cancer development may also include overgrowth of certain biota - so cancer patients may be given probiotics
Mucosal defenses physical barrier
- Epithelial barrier
- Mucus layer - goblet cells
- Epithelial monolayer - tight junctions
- Paneth cells (in small intestine)
- At the base of the crypts of Lieberkuhn
- Secrete antimicrobial peptides (defensins) & lysozyme
- Peristalsis
Chemical mucosal defense
Enzymes
Ph
Commensal bacteria occupy an ecological niche
Immunological barriers
MALT (Mucosa Associated Lymphoid Tissue)
GALT (Gut Associated Lymphoid Tissue)
MALT (Mucosa Associated Lymphoid Tissue)
- Found in submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
- Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
- Oral cavity rich in this tissue
HEVs are found in lymph nodes and other secondary lymphoid organs but not in the spleen
GALT (Gut Associated Lymphoid Tissue)
- Responsible for both adaptive and innate immune responses through generations of lymphoid cells and Abs
1. Non organised - Intra-epithelial lymphocytes - make up 20% of intestinal epithelium, such as T cells and NK cells
- Lamina propria lymphocytes
- Less surface area in large intestine so more Ig-A secretion
2. Organised - Peyer’s patches (small intestine)
- Caecal patches (large intestine)
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
Peyer’s patches:
Act as immune sensors
Mainly found in the distal ileum
Aggregated lymphoid follicles covered with follicle associated epithelium (FAE)
FAE - no goblet cells. no secretory IgA, lack microvilli
Organised collection of naive T and B cells
Development requires exposure to bacterial microbiota
- 50 in last trimester of pregnancy, 250 by teens
Antigen uptake via M (microfold) cells within the FAE
- M cells express IgA receptors, and facilitate transfer of IgA bacteria complex into the Peyer’s patches
specialised nodules in ileum
massed together in intestinal wall adj. to mesenteric attachment
Antigen sampling
Trans-epithelial dendritic cells capture an antigen from beyond the epithelial barrier, and then relocate to the mesenteric lymph nodes
B cell Adaptive Response
- Mature naive B cells express IgM
- This switches to IgA on antigen presentation
- T-cells and epithelial cells secrete cytokines which influence B cell maturation
- B cells further mature and become IgA secreting plasma cells
- These populate the lamina propria
Formation of Secretory IgA (sIgA)
- Up to 90% of gut B cells secrete IgA
- sIgA binds the luminal antigen to prevent adhesion and therefore invasion
Lymphocyte homing and circulation
Peyer’s patches - antigen presented and activated
Travels to mesenteric lymph node (lymphocyte proliferation)
This goes to the thoracic duct, into circulation
It can then go back to lamina propria, or skin, tonsils, or BALT
Tight junctions formed of a4b7 integrins where T cells bind causing cytokine release and MAdCAM-1s which causes cell adhesion . Directs circulating T cells to peyers patch to mount response
What is the life span of enterocytes and goblet cells of the small bowel?
36 hours
- Enterocytes are the first line of defence against GI pathogens, may be directly affected by toxins
- This means diminishing the effects of agents which interfere with cell function
Any lesions will be short-lived.
If escalator-like transit of enterocytes is interrupted through impaired production of new cells (e.g. radiation) severe intestinal dysfunction will occur
Cholera
Caused by Vibrio cholerae serogroups O1 and O139
Releases cholera enterotoxin on contact with small intestine epithelium which causes increased adnelytate cyclase activity this increased water pump activity
Transmitter via faecal oral route, contaminated food and water
Main symptoms - diarrhoea, dehydration, vomiting, abdominal pain
Diagnosis: Bacterial culture taken from faecal sample on selective agar, or dipstick test may be performed
Treatment: Oral rehydration
Dukoral - oral, inactivated vaccine against the pathogen - useful where there is a lack of clean water
Gastroenteritis
- ViralRotavirus (children)Norovirus (Winter vomiting bug)
- Protozoal parasiticGiardia lambliaEntamoeba histolytica
- BacterialCampylobacter jejuniEscherichia coliSalmonellaShigellaClostridium difficile
Rotaviruses
RNA virus, replicating in enterocytes
Types A-E, with A causing most human infections
Most common cause of diarrhoea in infants and young children
Still causes around 200,000 deaths per year
Treated with oral rehydration therapy
Rotarix - attenuated oral vaccine against type A, intoduced in UK in July 2013
Norovirus
RNA virus
Incubation period of 24 to 48 hours
Faecal-oral transmission
Individuals may shed infectious virus for up to 2 weeks
Diagnose via sample pcr
Outbreaks often occur in closed communities - especially cruise ships
Symptoms - Acute gastroenteritis, recovery in 1-3 days
685 million cases per year, 200,000 deaths
Campylobacter
- Campylocbacter jejuni / coli most common
- Transmitted via undercooked meat, untreated water & unpasteurised milk
- Low infective dose, less than 500 can cause illness
- Treatment usually isn’t necessary, azithromycin may be used as a standard antibiotic resistance to fluoroquinolones problematic
- Estimated 280,000 causes per year in UK
- Commonest cause of food poisoning in UK
Escherichia coli
- Mostly harmless
- 6 “pathotypes” associated with diarrhoea
-Enterotoxigenic E coli - causes watery diarrhoea
-Enterohaemorrhagic or Shiga toxin-producing E. Coli (EHEC/STEC) - 5-10% get haemolytic - uraemic syndrome, loss of kidney function
-Enteroinvasive E. coli (EIEC) - causes bloody diarrhoea
-Enteropathogenic E. coli (EPEC)
-Enteroaggregative E. coli (EAEC)
-Diffusely adherent E. coli (DAEC)
Clostridium difficile
Management:
- Isolate patient
- Stop current Abs
- Metronidazole, vancomycin
- Recurrence rate of 15-35% after initial infection, gets increasingly difficult to treat
- Faecal Microbiota Transplantation (FMT) - 98% cure rate
Toxin by-products (inflammatory metabolites) may be used to help determine C dif
Clinical assessment
- When did it start?
-may suggest contaminated food (S. aureus, Salmonella, E. coli, Bacillus cereus toxin, norovirus) - What does it look like?
-Amount, consistency, frequency
-Blood, mucus, pus suggests severe inflammatory or infectious cause
-Mucus and pus indicate a chronic inflammatory cause - How do you feel?
-Pain, bloating, nausea, vomiting, fever, tenesmus
-Thirsty, no appetite - Where have you been recently?
-Recent travel or consumption of food (meat, eggs, dairy, seafood) indicates infection
-Exposure to pets or cattle indicates infection
-Working in day care centres, hospitals or care homes indicates infection
-Social history, including sexual practice, alcohol or drug use
-IBD, coeliac, IBS
What does ingested nutrients,secreted nutrients, chemical digestive factors and peristalsis/contraction cause
Ingested and secreted nutrients contribute to bacterial growth causing an increase in cell numbers
Chemical digestive factors and peristalsis contractions/defecation eliminate bacteria thus decreasing cell numbers Chemical
Symbionts
Organism that loves with a history without benefit or harm to either
Commensalism
A microorganism that benefits from association but has no known effects on host
Pathobiont
Symbiont that doesn’t normally elicit an inflammatory response but under particular conditions (usually environmental) has potential to cause dysrefllated inflammation and disease
Gnotobiology
Selective colonization of germ free animals
Importance of HEV
Immune surveillance allowing to identify foreign invaders such as neoantigens in cancer
Lymphocyte recirculation so supports high levels of lymphocyte extravasation from the blood
And helps initiate and maintain immune response in lymph nodes
symbiosis symbionts commensals and pathobionts
Symbiosis: living together, doesn’t imply either partner benefits
Symbionts: organism that lives with a host without benefit or harm to either
Commensals: a microorganism which benefits from association but has no known effects on host
Pathobionts – symbiont that doesn’t normally elicit an inflammatory response BUT under particular conditions (usually environmental) has the POTENTIAL to cause dysregulated inflammation & disease
