immunology of the gut Flashcards
what does a state of “restrained activation” mean in terms of the guts immunology?
Surface area of GI tract 200 m2, so it gets a massive antigen load:
Resident microbiota 1014 bacteria
Dietary antigens
Exposure to pathogens
State of “restrained activation”
– Tolerance vs active immune response
– Dual immunological role.
Tolerance:
Food antigens
Commensal bacteria
immunoreactivity:
pathogens
Immune homeostasis of gut & development of healthy immune system requires presence of bacterial microbiota.
what is the gut microbiota?
10^14 gut bacteria and 10^13 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.
the bacterial content increases along the GI tract.
fewest in the stomach, then duodenum, jejunum, ileum, and most in the colon
how is the micriobiota maintained at the normal level?
host ingested and secreted nutrients -> bacterial growth -> increased cell numbers
host chemical digestive factors -> bacterial lysis -> decreased cell numbers
peristalsis, contraction and defecation -> bacterial elimination -> decreased cell numbers
what is dysbiosis?
altered micriobiota composition
like a weighing scale with symbionts on one end and pathobionts on the other (commensals in the middle, they benefit off us be we dont from them)
an increase in the number of pathobionts (that have the potential to cause harm) will lead to inflammation. it may also be driven by the entrance of pathogens
the role of the symbionts (which we live in harmony with) is to regulate this
what are possible causes and disease development of dysbiosis?
causes: diet hygiene infection/inflammation xenobiotics (drugs or pollutants) genetics
healthy micriobiota –> dysbiosis
this can then have negative effects on the:
brain (autism, MS)
lung (asthma)
adipose tissue (obesity)
liver (NAFLD)
intestine (IBD, coeliac)
systemic diseases (T1D, rheumatoid arthritis)
what are the main types of defense mechanisms of the mucosa?
Physical:
anatomical - Epithelial barrier, Peristalsis
chemical - enyzymes, acidic pH
Commensal bacteria:
occupy “ecological niche”
“Immunological”: following invasion MALT (Mucosa Associated Lymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) (this is the final port of call, last resort)
what is the function of the epithelial barrier in defense?
Mucus layer - Goblet cells
Epithelial monolayer - Tight junctions
Paneth Cells (small intestine): Bases of crypts of Lieberkühn. Secrete antimicrobial peptides (defensins) & lysozyme
what does MALT mean?
Mucosa Associated Lymphoid Tissue
Found in the submucosa below the epithelium, as lymphoid mass containing lymphoid follicles
Follicles are surrounded by HEV (high endothelial vessels) postcapillary venules, allowing easy passage of lymphocytes
The oral cavity is rich in immunological tissue. – tonsils and adenoids
what does GALT mean?
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
Non-organised:
Intra-epithelial lymphocytes - Make up 1/5th of intestinal epithelium, e.g. T-cells, NK cells
Lamina propria lymphocytes
Organised Peyer’s patches (small intestine) Caecal patches (large intestine) Isolated lymphoid follicles Mesenteric lymph nodes (encapsulated) (paneth cells (migrate down from stem cells into the crypt of leiberkhun)?
what are Peyers patches?
“immune sensors”
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 (at sides) & B-cells (in middle)
Development requires exposure to bacterial microbiota
50 in last trimester foetus, 250 by teens
dendritic cells at front
Antigen uptake via M (microfold) cells within FAE
M cells expressIgA receptors, facilitating transfer of IgA-bacteria complexinto the Peyer’s patches.
what is the role of dendritic cells in peyers patches?
Antigen Sampling: Trans-epithelial Dendritic Cells
Open tight junctions
Extend dendrites
Directly sample lumen bacteria and bring it back in
what is the adaptive response of B cells in peyers 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.
Populate lamina propria
this is the formation of secretory IgA (sIgA):
Up to 90% of gut B-cells secrete IgA
sIgA binds luminal antigen
→ preventing its adhesion and consequent invasion.
what happens to lymph from peyers patches?
primary goes to mesenteric lymph nodes
then via the thoracic duct into the systemic circulation
then either back to the gut lumen, or the skin, tonsils and BALT (bronchus associated lymphoid tissue)
what is the turnover of enterocytes and why?
Enterocytes & goblet cells of small bowel have a short life span
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.
