Infection and immunology of the gut Flashcards
1
Q
Why are there so many bacteria in the gut?
A
Massive antigen load:
- external pathogens
- dietary antigens
2
Q
What state is the gut immune system in?
A
The gut immune system is in a restrained state - tolerance vs active immunity
3
Q
What are the most prevalent bacteria in the gut, especially the colon?
A
bacteroidetes
4
Q
What are the functions of the microbiota?
A
- oral tolerance
- enzyme alteration
- motility alteration
- alteration of cell turnover
5
Q
What are some features of the microbiome?
A
- 10,000 different types of organisms
- diverse types between humans
- diet, host genetics and early microbial exposure affect repertoire
- different body site have unique communities
- at particular sites microbe have similar genes/functions
6
Q
Describe the distribution of microbiota in GI tract
A
- Loads in the mouth is because we put lots of dirty things into it, including food, fluid, cutlery, air etc.
- Into the stomach, the low pH kills lots of bacterial populations so near 0 (except H. pylori)
- The number is kept low in the duodenum, jejunum and proximal ileum because of paneth cells and Peyer’s patches
- Beyond the ileocaecal valve the number of microorganisms increases markedly
7
Q
Helicobacter pylori: what is it , what does it cause and treatment?
A
- gram negative, rod
- in response to H.Pylori excess acid production which causes the damage
- in chronic cases, atrophy of stomach wall and malignant growths
- causes: gastritis, gastric or duodenal ulcers, gastric carcinoma
- investigations include blood antibodies, stool antigen, urea test, breath test
- treatment is 1 week with proton pump inhibitor and amoxicillin
8
Q
Traveller’s diarrhoea
A
Bacterial, viral and ameobic
- bacteria: E.coli, shigella, salmonella and cholera
- viral: rotavirus, norovirus (most common are viruses)
- ameobic: giardia
9
Q
Norovirus, incubation period and length of infectiousness
A
causes acute gastroenteritis in less than 3 days, in 24-48 hrs incubation and infectious for up to 2 weeks
10
Q
What are the types of diarrhoea caused by different E.coli types?
A
enterotoxigenic E. coli (watery)
enterohaemorrhagic
enteropathogenic
enteroevasive (bloody)e
11
Q
Clostridium difficile
A
- antibiotics kill commensals and this is able to produce toxins causing mucosal injury
- then neutrophils and RBC leak into the gut
- Produces toxins A and B
- results in pseudomembranous colitis
- treatment include isolating, stopping AB, vanocmycin, faecomicrobiota transplantation
12
Q
Mucosal defence - 3 types?
A
- physical (anatomical: epithelial layer, peristalsis and chemical: pH, enzymes)
- commensal bacteria
- immunological (MALT, GALT)
13
Q
The structure and function of the epithelial barrier
A
- mucus secreted by goblet cells, maintained by glycocalyx
- monolayer has tight junctions, antimicrobial peptides and IgA
- paneth cells in crypts secrete lysozymes and defensins
14
Q
Organisation of GALT
A
seperated into organised and non organised:
Organised: cryptopatches, peyer’s patches (SI), isolated lymphoid follicles (colon), mesenteric lymph nodes
Non organised: floats randomly in sub epithelial e.g. intra epithelial lymphocytes and lamina propria lymphocytes
15
Q
What is the function of GALT?
A
generate lymphoid cells and antibodies and cell mediated immunity
16
Q
GALT - Peyer's patch where is it when does it develop what does it consist of what is present and not
A
- found in distal ileum
- develops throughout life into teens
- has B cell and T cells areas
- covered by follicle associated epithelium
- has no goblet cells, IgA, microvilli
- infiltrated by T/B cells, macrophages and dendritic cells
- antigen taken up by M cell on epithelium
- similar found in colon
17
Q
What do mature naive B cells express in PP?
A
IgM and class switch to IgA They populate lamina propria
18
Q
IgA antibody
A
- upto 90% of gut B cells make this
- dimeric at mucosa
- prevents invasion, adherence and does not activate complement or Tc cells
19
Q
T cells adaptive response - 3 signals
A
Determined by 3 signals:
- presentation of antigen MHC by DC
- costimulatory signal from DC
- secretion of cytokines by DC
20
Q
Give examples of some types of T cells
A
th1 - cellular, automimmunity
th2 - humoural e.g asthma
th17 - inflammation, autoimmunity
iTreg
21
Q
Pathway of lymphocytes after activation
A
proliferate in mesenteric lymph node -> thoracic duct -> circulation -> go to sites similar to where they were activated
22
Q
What regulates T cell homing (know where they are from and can return)
A
- T cells exhibits alpha4beta7 intergin
- gut epithelium exhibits MAdCAM -1
- Interaction between the two means t cells specific to gut
23
Q
What may loss of tolerance cause?
A
- inflammatory bowel disease
- coeliac disease
- food allergies
24
Q
Coeliac disease histology
A
- villus atrophy so less absorption
- large infiltrate of intra epithelial lymphocytes
25
Pathogenesis of coeliac disease
- MHC has two hit model of mutation in DQ2 or DQ8
- grains like gluten stimulate AP cells to activate CD4 t cells and macrophages with IL-15 which causes epithelial remodelling and atrophy
26
Presentation of coeliac disease and treatment
- anaemia
- malnourished
- diarrhoea
- bloating
- scurvy/osteoporosis
- steatorrhoea
```
treatment:
diet restriction (gluten free)
```
27
Inflammatory bowel disease- Chron's and ulcerative colitis, what is it?
- inappropriate chronic immune response against gut microbes
28
Incidence and trends in ulcerative colitis and Chron's
- UC has higher incidence but Chron's incidence is increasing more
- Incidence increasing in young and non western countries
29
Which 4 factors contribute to the effects of IBD?
- smoking (smoking cessation worsens UC and smoking worsens Chron's)
- stress
- diet
- vitamin D
30
What are some changes occurring in Chron's disease?
- dysbiosis - reduction in diversity, anterobacteriacea and reminococcus gnavus rise and drop in clostridium types
- rise in fusobacteriacea which can progress to colorectal cancer
- rise in pastuerellacaea, veillonellaceae and pathogenic E coli
31
What are some changes occurring in UC?
decreases in faecalibacacterium praunsnitzii and reseburai hominus
32
What are the overall changes in the microbiome in IBD (not organisms)?
- change in oxidative stress pathways
- decreased carbohydrate metabolism
- decreased amino acid synthesis
- in ilieal Chron's increase in virulence and secretion pathways
33
Virome in IBD?
Expansion of caudovirales and bacteriophages
34
Fungal microbiota in IBD?
there is some
35
Treatment for IBD
immune targets
- CAM inhibitors
- TNF alpha inhibitos
- JaK3 inhibitors
36
What is the function and importance of M cells?
- FAE contains specialized enterocytes or M cells
- The main function of M cells is to perform transcytosis of luminal bacteria, antigens and proteins
- M cells express IgA receptors, facilitating transfer of IgA-bacteria compex into the peyer's patches
- Antigen uptake is a combined effort by specialised M-cells and dendritic cells
37
IgA dimer secretion
- SIgA is a dimeric form of IgA - In the plasma cell, two IgA molecules are bound together by a J-chain, and secreted into the interstitial space.
- The dimer binds to a special receptor on the external basolateral surface of enterocytes
- This receptor becomes the secretory component and binds to the length of the IgA dimer, becoming SIgA
- SIgA is then endocytosed into the epithelial cell and actively transported within a vesicle to the apical membrane, where it is exocytosed into the gut lumen.
- The secretory component protects the antibody dimer from enzymatic and acidic degradation
38
How do lymphocytes exit circulation?
- L-selectin is expressed on the surface of lymphocytes and mediates the low adhesive interactions that enable leukocytes to roll in postcapillary venules and HEVs
- In HEVs, L-selectin binds to (MAdCAM-1)
- In addition to the HEVs of Peyer’s patches and mesenteric lymph nodes, MAdCAM-1 is expressed on the endothelial cells localised in the lamina propria of the small and large intestine and enables lymphocyte recruitment
39
Where can MAdCAM-1 be found?
HEVs of Peyer’s patches and mesenteric lymph nodes
| On endothelial cells localised in the lamina propria of the small and large intestine
40
What are some symptoms of irritable bowel syndrome?
- Recurrent abdominal pain
- Abnormal bowel motility
- Constipation and/or diarrhea
41
What are the treatments for IBS?
Diet modification - Avoiding certain foods such as apples, beans, cauliflowers
Treatment of constipation - soluble fiber, stool softeners and osmotic laxatives
Treatment of spasms and pain - anti-diarrheals, anti-muscarinic
Management of stress, anxiety, depression
42
What are some triggers for IBS?
Acute gastreoenteritis, stress
43
What causes pain in IBS and diarrhoea?
Short chain carbohydrates trigger symptoms - maybe unabsorbed ones act as solutes leading to diarrhoea. They are metabolised by bacteria causing gas.
44
Mechanism behind coeliac disease
- Gliadin (component of gluten) is not broken down in the stomach, reaches the small intestine, and binds to the secretory IgA in the mucosal membrane.
- Gliadin-secretory IgA complex binds to the Transferrin receptor (TFR) and are transferred to the lamina propria.
- Enzyme tissue transglutaminase (tTG) cuts off amide group from the protein.
- Deamidated gliadin is phagocytosed by the macrophages, and presented by MHC II molecules.
- This leads to activation of immune system causing destruction of epithelial cells.
45
How is coeliac disease diagnosed?
- Antibody blood tests (anti-gliadin, anti-tTg, anti-endomysial)
- Biopsy test of duodenum
46
What is thought to be responsible for chron's disease?
Frame-shift mutation in NOD2 gene
Immune-related disorder - triggered by pathogens such as mycobacterium paratuberculosis, pseudomonas, and listeria
Unregulated immune response causing the destruction of cells in the GI tract.
47
Treatment for Chron's
- anti inflammatory drugs, antibiotics
- immunosuppressants
- remove tissue
- liquid diet
- food intolerance tests
48
Mechanism of UC?
Autoimmune disorder - T cells destroy the cells lining the walls of large intestine
Secondary cause - Diet and stress
49
Treatment for UC?
- anti inflammatory drugs
- immunosuppressant
- colectomy
- diet changes
- pre/probiotcs
- drink fluids and nutritional drinks for diarrhoea
50
Cholera: symptoms, mechanism, diagnosis and treatment
symptoms:
- vomiting
- abdominal pain
- diarrhoea
mechanism:
- The bacteria reaches the small intestine from the stomach, where the flagellum propels it towards the epithelial cell.
- On making close contact it releases cholera toxin.
- Cholera toxin on entering the epithelial cell, starts a series of biochemical reactions resulting in exit of ions such as Na+, K+, Cl- and water from the epithelial cell.
diagnosis:
stool test
treatment:
- Drink a lot of fluids.
- Antibiotics?
- Vaccination for cholera is also available.
