Gut Immunology Flashcards
GI tract balance
State of ‘restrained activation’
- tolerance vs active immune response
- dual immunological role
‘Virtual’ organ
Microbiota
Factors that stimulate bacterial growth
Ingested nutrients
Secreted nutrients
Factors that stimulate bacterial lysis or elimination
Chemical digestive factors
Peristalsis, contractions, defecation
Chemical digestive factors in stomach
HCl
Pepsin
Gastric lipase
Chemical digestive factors in liver
Bile acid
Chemical digestive factors in pancreas
Trypsin
Amylase
Carboxypeptidase
Chemical digestive factors in small intestine
Brush border enzymes
Chemical digestive factors in colon
None
Bacterial content in stomach
10^1
Bacterial content in duodenum
10^3
Bacterial content in jejunum
10^4
Bacterial content in ileum
10^7
Bacterial content in colon
10^12
Immunological equilibrium
Symbionts, commensals, pathobionts
Balance tips to inflammation when pathogens are involved with pathobionts - dysbiosis
Factors that may cause dysbiosis
Infection or inflammation Diet Xenobiotics Hygiene Genetics
Mucosal defense - physical barrier
Anatomical - epithelial barrier and peristalsis
Chemical - enzymes and acidic pH
Epithelial barrier
Mucus layer made by goblet cells
Epithelial monolayer by tight junctions
Paneth cells
- bases of crypts of Lieberkühn
- secrete antimicrobial peptides (defensins) and lysozyme
Mucosal defense - other barrier
Commensal bacteria - occupy ‘ecological niche’
Mucosal defense - immunological
Following invasion
MALT - mucosa associated lymphoid tissue
GALT - gut associated lymphoid tissue
MALT
Found in submucosa below epithelium. Exist as lymphoid mass containing lymphoid follicles.
Follicles are surrounded by HEV postcapillary venules, allowing easy passage of lymphocytes
Oral cavity is rich in immunological tissue
- palatine tonsil
- lingual tonsil
- pharyngeal tonsils (adenoids)
GALT
Responsible for both adaptive and innate immune responses
Consist of B and T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial and intra-epithelial lymphocytes
Non organised GALT
Intra-epithelial lymphocytes
-make up 1/5 of intestinal epithelium - T-cells, NK cells etc.
Lamina propria lymphocytes
Organised GALT
Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)
Stem cell of intestine location
In crypts
Commonest cells of intestine
Enterocytes (intestinal epithelial cells)
Migrate towards tip of villi
Goblet cells
Mucus secreting
Cell of intestine
Paneth cells
Migrate to bottom of crypt
Characterised by presence of dense granules and antimicrobial peptides
Lamina propria lymphocytes
Central part of villus
T cell, macrophages, dendritic cells, IgA B cells
Intraepithelial lymphocytes
Dotted between enterocytes
Peyer’s patches
Found in submucosa small intestine - mainly distal ileum
Aggregated lymph’s follicles covered with follicle associated epithelium (FAE - no goblet cells, no secretory IgA, lack microvilli)
Organised collection of naive T cells and B cells, and subepithelial dome of dendritic cells
Development requires exposure to bacterial microbiota - 50 in last trimester fetus, 250 by teens
Antigen uptake via M (microfold) cells within FAE
M cells express IgA receptors, facilitating transfer of IgA bacteria complex into Peyer’s patches
Antigen sampling
M cells
Dendritic cells - open up tight junctions to send dendrites into lumen to sample bacteria and bring back to transport to mesenteric lymph nodes
B cell adaptive response
Pathogen taken up by M cells
Excreted into pocket formed in inner surface of enterocytes which contains antigen presenting cells such as dendritic cells
Antigen engulfed and presented to MHC II molecules on surface
Dendritic cells then migrate to Peyer’s patch
DC, T and B cells all aggregate in patch and form an organised lymphoid follicle
Other antigen loaded dendritic cells escape and migrate through lymphatic system where they activate B cells, T cells, other plasma cells in mesenteric lymph nodes
Some activated cells then return to GALT tissue effector sites and produce antibodies secreted from intestinal lumen
B cell maturation
Mature naive B cells express IgM in Peyer’s patches On antigen presentation class switched to IgA
T cells and epithelial cells influence B cell maturation via cytokine production
B cells further mature to become IgA secreting plasma cells
Populate lamina propria
Secretory IgA
Up to 90% of gut B cells secrete IgA
sIgA binds luminal antigen - preventing adhesion and consequent invasion
Lymphocyte homing and circulation
Lymphocytes travel to mesenteric lymph nodes - lymphocyte proliferation - return to circulation via thoracic duct
Either enter peripheral immune system (skin, tonsils, bronchus associated lymphoid tissue) or exit peripheral immune system and return to intestinal mucosa via vessels in lamina propria
Cholera mechanism
Acute bacterial disease caused by vibrio cholerae serogroupd O1 and O139
Bacteria reaches small intestine - contact with epithelium and releases cholera enterotoxin via retrograde endocytosis
Once inside it increases adenylate cyclase activity - increased cAMP - active secretion of salt, potassium, chloride, bicarbonate - water follows
Cholera transmission
Faecal oral - spreads via contaminated water and food
Cholera symptoms
Severe dehydration and watery diarrhoea
Vomiting, nausea, and abdominal pain
Cholera diagnosis
Bacterial culture from stool sample, selective agar is standard, rapid dipstick also available
Cholera treatment
Oral rehydration is main management
Up to 80% get better by itself
Vaccine
Other causes of infectious diarrhoea (gastroenteritis)
Viral
- Rotavirus (children)
- norovirus
Bacterial
- salmonella
- shigella
- c.diff
Rotavirus
RNA virus, replicates in enterocytes
Five types A-E, A most common in Human infections
Rotavirus treatment
Oral rehydration therapy
Vaccine - live attenuated oral vaccine (Rotarix) against type A
Norovirus Norwalk virus
RNA virus
Incubation 24-48 hours
Norovirus Norwalk transmission
Faecal oral
May shed infectious virus for up to 2 weeks
Outbreaks often in closed communities
Norovirus Norwalk symptoms
Acute gastroenteritis, recovery 1-3 dats
Norovirus Norwalk treatment
Not required
Norovirus Norwalk diagnosis
Sample PCR
Campylobacter
Curved bacteria
Jejuni or coli
Campylobacter transmission
Undercooked meat, untreated water and unpasteurised milk
Low ineffective dose, a few bacteria can cause illness
Campylobacter treatment
Not required
Azithromycin standard antibiotic
E. Coli
Diverse group of gram negative intestinal bacteria Most harmless 6 pathotypes associated with diarrhoea EHEC/STEC most problematic ETEC EIEC EPEC EAEC DAEC
C. Diff
More C. Diff than normal leads gut from health stable state to intermediate dysbiotic state
Could either go back to recovery or diseased state where pathogen induced disturbance (toxin production) create supportive environment
C. Diff management
Isolate patient - very contagious
Stop current antibiotic - caused by antibiotics
Metronidazole or vancomycin
Recurrence rate 15-35% after initial infection, increasingly difficult to treat
Faecal microbiota transplantation (FMT) 98% cure rate
