Immunology of the gut Flashcards
(33 cards)
What is the role of the GI in the immune system?
Large most complex immune system: SA of 200m2
- The GI tract has dual immunological role:
1. Tolerance to:
- resident microbiota 10 to the 14 bacteria (commensal bacteria)
- dietary antigens
(the GI tract has tolerance to both food antigens and commensal bacteria)
2. Active immune response against:
- pathogens
(however, it remains in a state of “restrained activation”)
What is the importance of the gut bacterial microbiota?
Immune homeostasis of gut & development of healthy immune system requires presence of bacterial microbiota.
Describe what is the gut microbiota
a “virtual organ”
- 10 to the 14 gut bacteria 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.
How do we allow for bacterial growth in microbiota and ALSO prevent excess bacterial growth in the gut microbiota?
(to increase bacterial growth for the microbiota)
- host ingests nutrients
- secretes nutrients
BUT also has mechanisms to prevent excess (decrease bacterial growth)
- chemical digestive factors (lead to bacterial lysis)
- peristalsis, contractions defecation (lead to bacterial elimination)
NOTE: the higher up in the GI tract the more bacteria killed
What is “Dysbiosis”?
“an “imbalance” in the gut microbial community that is associated with disease”/ altered microbiota composition
The three types of dysbiosis are:
1) Loss of beneficial bacteria (commensal)
2) Overgrowth of potentially pathogenic bacteria (pathobionts)
3) Loss of overall bacterial diversity.
Describe the immunological equilibrium of gut bacteria
There is a balance between 3 types of bacteria:
1. Symbionts (bacteria that live in the bowel causing no harm and have no advantage)
2. Commensals (bacteria the live the body, also causing no harm but has an advantage “beneficial bacteria”
3. Pathobionts (bacteria that also INITIALLY causes no harm but has the potential to “tip over” and become harmful”
What are the causes of Dysbiosis?
- Infection or inflammation
- Diet
- Xenobiotics (introduced unnaturally)
- Hygiene (poor)
- Genetics
(turn healthy microbiota into dysbiosis)
How do the bacteria cause disease in Dysbiosis?
Bacteria now produce bacterial metabolites and toxins:
- TMAO (causes atherosclerosis)
- 4-EPS (autism)
- SCFSs (IBD/ Stress)
- bile acids
- AHR ligands (multiple sclerosis, autism, rheumatoid arthritis)
What diseases can develop from Dysbiosis?
Brain:
- stress
- Autism
- Multiple sclerosis
Lung:
- Asthma
Liver:
- NAFLD
- NASH
Adipose tissue:
- Obesity
- Metabolic disease
Intestine:
- IBD
- Coeliac disease
Systemic diseases:
- Type I diabetes
- Atherosclerosis
- Rheumatoid arthritis
What are the different immunological defense mechanisms in the GI tract?
a) Physical barriers:
1. Anatomical:
- epithelial barrier
- Peristalsis
2. Chemical:
- enzymes
- acidic pH
b) Commensal bacteria occupy “ecological niche” (out-compete harmful bacteria)
c) Immunological
1. MALT (mucosa associated lymphoid tissue)
2. GALT (gut associated lymphoid tissue)
How does the epithelial barrier protect the body from pathogens?
mechanical protection:
- Mucus layer (goblet cells)
- epithelial monolayer (tight junctions)
Chemical protection:
- Paneth cells: bases of crypts of Lieberkühn: Secrete antimicrobial peptides (defensins) & lysozyme.
What are MALT’s ?
“Mucosa Associated Lymphoid Tissue”:
- Found in the submucosa below the epithelium of immunological tissue, as lymphoid mass containing lymphoid follicles
- Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
- The oral cavity is rich in immunological tissue: palatine tonsil, lingual tonsils, pharyngeal tonsil (adenoid)
What are GALT’s ?
“Gut Associated Lymphoid Tissue”:
- Responsible for both adaptive & innate immune responses
- Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes
- There are 2 types of GALT:
1. Non- organised:
- Intraepithelial lymphocytes (Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells)
2. Organised:
- Peyer’s patches (small intestine)
- Caecal patches (large intestine)
- Isolated lymphoid follicles
- Mesenteric lymph nodes (encapsulated)
What is the role of Peyer’s patches?
“Immune sensors”
lump of lymphoid tissue that take antigens from the lumen of the small intestine to be processed (allows them to encounter white blood cells to stimulate immune response)
- Found in submucosa small intestine – mainly distal ileum
- Aggregatedlymphoid follicles covered with follicle associated epithelium (FAE).
- FAE - no goblet cells, no secretory IgA, no microvilli
- Organised collection of naïve T cells & B-cells
- Development requires exposure to bacterial microbiota (50 in last trimester foetus, 250 by teens)
Describe how Peyer’s patches process antigens and produce antibodies against these antigens
- Follicle associated epithelium FAE of Peyer’s patch (PP) have specialised M (microfold) cells
- M cells express IgA receptors- uptake and transfer IgA- bacteria complexes (antigens) into the Peyer’s patch
- Peyer’s patches also have sub-epthelial dome containing dendritic cells: able to get past the FAE and “grab” antigens from the lumen also
- On antigen presentation, mature naïve B-cells that first express IgM in PP, class switch to IgA
- T-cells & epithelial cells influence further B cell maturation via cytokine production: become IgA secreting plasma cells (AB against gut bacteria)
- Populate lamina propria: Up to 90% of gut B-cells secrete IgA
- secretory IgA binds luminal antigen preventing its adhesion and consequent invasion.
What is meant by “Lymphocyte homing”?
Adhesion of the circulating lymphocytes in blood to specialized endothelial cells within lymphoid organs:
- Free lymphocytes constantly recirculate in blood after their re-entry from lymphoid tissue, via mesenteric lymp nodes and thoracic ducts.
- Circulate to the gut lumen, skin, tonsils, BALT (bronchus- associated lymphoid tissue)
- Circulating lymphocytes adhere to the lamina propria/ high endothelial venule of the peyer’s patch via 𝝰4β7 Integrin binding to the MAdCAM-1 of HEV
- High endothelial venules (HEVs) are cells found in secondary lymphoid organs that express large quantities of cell adhesion molecules, enabling undifferentiated lymphocytes to bind.
- After entering lymph nodes and Peyer’s patches via HEVs, naive T and B cells are exposed to antigen circulating in lymph and differentiate to contribute to the adaptive immune response.
Why do erythrocytes of the small bowel turnover so rapidly- in contrast to other epithelial cell types
- 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
- if escalator-like transit of enterocytes is interrupted through impaired production of new cells (e.g. radiation) severe intestinal dysfunction will occur
Describe the mechanism for infection of Cholera
- Cholera -acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139
- Bacteria reaches small intestine → contactwith epithelium & releasescholera enterotoxin.
- Transmitted through faecal-oral route
- Spreads via contaminated water & food
What are the symptoms of Cholera infection?
Main symptoms:
Severe dehydration & watery diarrhoea
Other symptoms:
Vomiting, nausea & abdominal pain.
How do you diagnose suspected cholera infection?
bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available.
How is Cholera infection treated?
- oral-rehydration is the main management ; up to 80% of cases can be successfully treated.
- Vaccine: Dukoral, oral, inactivated.
What are some other causes of infectious diarrhoea/ gastroenteritis?
- VIRAL:
- Rotavirus (children)
- Norovirus “winter vomiting bug” - BACTERIAL:
- Campylobacter jejuni
- Escherichia coli
- Salmonella
- Shigella
- Clostridium difficile - Protozoal parasitic:
- Giardia lamblia
- Entamoeba histolytica
What are rotaviruses?
- RNA virus, replicates in enterocytes.
- 5 types A – E, type A most common in human infections
- Most common cause of diarrhoea in infants & young children worldwide.
How are rotaviruses treated?
- 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.
