What is the GIT immunology status?
Massive antigen load - resident microbiota, dietary antigens, exposure to pathogens State of restrained activation
What does immune homeostasis require?
Presence of bacterial microbiota
What are the 4 major phyla in the gut microbiota?
Bacteriodetes, Firmicutes, actinobacteria, proteobacteria
What are the abnormalities present in 'germ-free' animals - with no gut microbiota?
Immune function (oral tolerance) Metabolic function (altered enzymes) Physiological function (altered motility) Trophic function (altered cell turnover)
What are 4 infections of the GIT?
Oral candidiasis Helicobacter pylori Infective diarrhoea (bacterial, viral, amoebic) Clostridium difficile
What is oral canidiasis?
Yeast/fungal infection by Candida albicans Carried in 50% of individuals - asymptomatically usually
What patients are affected by oral candidiasis?
How is oral candidiasis treated?
With oral anti-fungals or IV antifungals is immunocompromised
What is helicobacter pylori?
GNB, microaerophilic rod
What are the symptoms of H. pylori?
Gastritis/ gastric or duodenal ulcers/ gastric carcinoma BUT 80% infected individuals are asymptomatic
How is H. pylori investigated and treated?
Investigated: Blood Ab, stool Ag, urea breath test, biopsy ureases test Treatment: 1 week eradication therapy with proton pump inhibitor and clarithromycin/amoxicillum
What are the main causes of traveller's diarrhoea?
Escherichia coli (E coli) Shigella Salmonella Cholera Rotavirus Norovirus Giardia
What are the symptoms and transmission of Norovirus?
Acute gastroenteritis for less than 3 days with incubation of 24-48hrs Faeco-oral transmission Infectious for up to 2 weeks
What are the 4 strains of E. coli and what do they cause?
Enterotoxigenic - cholera-like toxin causing watery diarrhoea Enterhaemorrhagic - verotoxin/shigatoxin causing haemolytic uraemic syndrome Enteropathogenic - occurs in nurseries Enteroinvasive - shigella-like illness, bloody diarrhoea, megacolon
How does C. difficile colonise the colon?
What disease does C. difficile cause?
Pseudomembranous colitis (AB-associated colitis) A and B toxin
How is a C. difficile infection treated?
Isolate, stop current antibiotics and treat with metronidazole and vancomycin Then undergo faecal microbiota transplation
What is the success of faecal transplantation in C. difficile?
Cure rate of 98% - stool resembles donor stool in 2 weeks
How does the gut's mucosal layer provide defense?
Physical barrier - epithelial and peristalsis, chemical (enzymes and pH) Commensal bacteria Immunological after invasion - MALT/GALT
How does the epithelial layer act as a barrier?
Mucus layer (goblet cells) Epithelial monolayer (tight junctions, antimicrobial peptides and transports IgA) Paneth cells (bases of crypts and have defensins and lysozymes)
Where are MALT most present?
In the oral cavity - the palatine tonsil, lingual tonsils and pharyngeal tonsil
What is GALT and what are the 2 types?
Gut-associated lymphoid tissue - not organised OR organised
What are some not organised GALT?
Intra-epithelial lymphocytes and lamina propria lymphocytes
What are some organised GALT?
Cryptopatches, peyer's patches, isolated lymphoid follicles, mesenteric lymph nodes
What does GALT do?
Generates lymphoid cells and antibodies -> IgA (secretory and interstitial), IgG, IgM and cell mediated immunity
What are peyer's patches and where are they located?
Small intestine - mainly distal ileum (similar elsewhere in GIT) Covered by follicle associated epithelium (no goblet cells, secretory IgA, lack microvilli and infiltrated by T/B cells, macrophages and dendritic cells) Organised collection of naive T and B cells
How do peyer's patches develop?
Requires exposure to bacterial microbiota
What is the structure of Peyer's patches? FITB
What is the function of peyer's patches?
Antigen sampling by M cells Transport to APC in subepithelial dome, where DC's take up Ag and process it They then present to naive B/T cells in Peyer's patch or transport to lymph nodes - results in development on gut homing markers They then transfer to mesenteric lymph node to proliferate
What is the B-cell adaptive response?
Naive B cells expressing IgM in peyer's patches, which upon presentation switch to IgA, under influence from T cells and epithelium Then further maturation to become IgA secreting plasma cells, populating lamina propria
What are intraepithelial lymphocytes?
Make up 1/5th of intestinal epithelium Made from: conventional T cells (lamina propria) - migrated from other tissue; unconventional T cells (innate) - resident, express unusual combinations of CD4/8 gamma/delta TCR Other innate immune cells - resident NK cells
How is the T cell adaptive response activated and what does it lead to?
3 signals: presentation of Ag within MHC, co-stimulatory signals on DC and secretion of cytokines by DC Leads to: cell mediated immunity, normal gut response, inflammatory disease, tolerance
What are the different types of T cells that can be formed from different IL stimulations?
What is gut homing?
Lymphocytes proliferate in MLN and enter lymphatics to thoracic duct where they enter circulation, selectively home to sites similar to initial priming - Ag presentation in GALT favours gut homing characteristics (intergrins/chemokine receptors) Integrins act as a postcode marker so that the lymphocytes know to return to that site
Why does the gut have a dual immunological role?
Immunoreactivity to pathogens BUT tolerance to food Ag and commensal bacteria
What is immune tolerance?
Suppression of immune responses towards Ag via deletion of responding lymphocyte, anergy or TReg cells
What may loss of tolerance underlie?
Inflammatory bowel disease Coeliac disease Food allergy
What are some common food allegies?
Nuts Hen egg white Cows milk Wheat Sesame seeds Soya Shell fish
What causes inflammatory bowel disease?
Genetic background, immune system and/or environmental factor With some factors like: smoking (sometimes the removal can cause bloody diarrhoea), stress, diet and vitamin D affecting
What alleviates or worsens Crohn's disease?
Faecal stream diversion alleviates but reanastomosis triggers recurrence Infusion of luminal contents into excluded normal bowel reduces inflammation
Which gut flora are associated with certain symptoms of crohn's disease?
Fusobacteriaceae - biomarker, progression of colorectal cancer Pastueurellacaea, Veillonellaceae, pathogenic E coli - linked with ulcer formation
What does microaerophilic mean?
Needs a little bit of oxygen to survive
How do dendritic cells sample the gut bacteria?
They stick their dendrites into epithelial barrier, so they can sample the lumen on the other side. It then takes the antigens to the MNL
What is coeliac disease?
40-50% and most patients can be asymptomatic and others have bloating/abdominal pain, dermatitis
How does coeliac disease present histologically?
Villus atrophy and many infiltration of intraepithelial lymphocytes