Immunology of the gut Flashcards
1
Q
How do most infectious agents invade the body?
A
Mucosal Surfaces
2
Q
- Describe mucosal surfaces?
2. Describe the physiological functions of mucosal surfaces?
A
- Thin and permeable barrier
2. Gas exchange (lungs), food absorption (gut), sensory activities (nose and mouth)
3
Q
What are the barriers to the pathogens of the skin;
- Mechanical barrier
- Chemical barriers
- microbiological barriers?
A
- epithelial cells with tight junctions, longitudinal flow of air or fluid
- Fatty acids, antibacterial peptides
- Normal flora
4
Q
What are the barriers in the gut
- Mechanical
- Chemical
- microbiological
A
- Epithelial cells with tight junctions, longitudinal flow of air or fluid
- Low pH, enzymes (pepsin), antibacterial peptides,
- Normal flora
5
Q
What are the barriers in the lung
- Mechanical
- Chemical
A
- Epithelial cells with tight junctions, Movement of mucus by cilia
- Antibacterial peptides
6
Q
What are the barriers of the eye/nose?
- Mechanical
- Chemical
A
- Epithelial cells with tight junctions, Tears, nasal cilia
2. Enzymes in tears (lysozyme)
7
Q
Describe the intestinal epithelial cell barrier?
A
Tight junctions
Goblet cells secrete mucin
Planets cells secrete anti-microbial peptides
8
Q
Name some of the aspects of the innate immune system (4)?
A
Dendritic cells
Macrophages
Monocytes
Granulocytes (neutrophils, eosinophils, basophils)
9
Q
Name examples of adaptive immune response (3)?
A
CD4+ T cells
CD8+ T cytotoxic cells
B cells
10
Q
How are antigens recognised
- innate recognition
- Adaptive recognition
A
- Pattern recognition receptors (toll like receptors, NODs/CARDs) recognise patterns and motifs eg peptidoglycan, LPS, dsRNA
- Antigen specific receptors (T cell receptors, B cell receptor recognise antigens (T cells recognise antigen peptide/MHC complex, B cells recognise 3D structure of antigen)
11
Q
Name the effector subtypes of CD4+ T cells?
A
These help fight against pathogens
TH1-IFN gamma
TH2-IL4 IL5
TH17- IL-17
12
Q
What are the regulator subtypes of CD4+ T cells?
A
TR1: IL-10
Th3: TGF-beta
CD25+: IL-10, TGF beta
[IL-10 and TGF-beta are cytokines which dampen down the immune system]
13
Q
What is the role of Th1?
A
IFN-gamma
Beneficial against intracellular pathogens eg toxoplasma
Involved in chronic inflammation, autoimmunity
14
Q
What is the role of the effector subtypes of CD4+?
A
Help fight against pathogens
15
Q
What is the role of regulatory subtypes of CD4+?
A
Regulates/dampens effectors
16
Q
What is the role of Th2?
A
IL-4, IL-5
Beneficial against extracellular pathogens such as helminths
Involved in allergy and asthma
IL-4 drives IgE immune response
17
Q
What is the role of TH17
A
IL-17
Beneficial against extracellular bacteria and fungi such as klebsiella, candida
Involved in chronic inflammation, autoimmunity (RA, MS, psoriasis, IBD)
18
Q
What are the different tyes of MALT?
A
Nasal associated lymphoid tissue
Bronchus associated lymphoid tissue
Gut associated lymphoid tissue
19
Q
What is the role of the mucosal immune system?
A
Ignore harmless antigens (proteins in food, commensalism bacteria
Mount protective immune responses to pathogens
20
Q
Give 2 examples of where mucosal immune system goes wrong
A
Celiac disease
Inappropriate response to wheat protein gluten
Inflammatory bowel disease-inappropriate response to intestinal bacteria
Immune cells infiltrate the Tissue leading to inflammation, necrosis, perforations etc
21
Q
What makes up the organised tissue in GALT?
A
Peyer’s patches (in small intestine)
Isolated lymphoid follicles (in small and large intestine)
Mesenteric lymph nodes (largest lymph node in body, drains intestinal tract)
22
Q
What are the scattered lymphoid cells in GALT
A
Lamina propria leukocytes
Intraepithelial lymphocytes
23
Q
- What are M cells?
- Where are similar follicles found?
- How do M cells work?
- What pathogens target M cells to gain access to subepithelial space?
A
- Specialised cells that transport antigens from the gut lumen into Peyer’s patches
- Similar follicles are found in BALT and NALT
- Take up antigen by endocytosis or phagocytosis and transport across the barrier to dendritic cells which migrate to T cell areas of PP and via draining lymphatics to mesenteric lymph nodes and activate T cells
- Poliovirus, reovirus, some retroviruses, salmonella, shigella, yersinia
24
Q
Describe antigen capture?
A
Macrophages extend processes across epithelia to capture antigens from gut lumen
They are handed over to dendritic cells in lamina propria
The loaded DCs migrate via draining lymphatics to mesenteric lymph nodes where they activate T cells
25
How do intestinal epithelial cells regulate immune cell function?
Immune cells are condition by the environment due to signalling from epithelia acting on dendritic cells
Conditioning of DC in healthy intestine favour induction of T-reg response
Microbial metabolites control gut inflammatory response and condition DCs eg short chain fatty acids (butyrate, acetate, propionate)
26
Describe intestinal homeostasis and what may go wrong?
Balance between effector T cells (Th1, Th2, Th17) and regulatory T cells (TR1, Th3, CD25+)
If there are too many effector cells=intestinal inflammation
Regulatory cell defect=intestinal inflammation
27
1. What is the dominant antibody in the mucosal immune system
2. What is the difference between this in the blood and in the mucosal tissue
1. IgA
2. Blood=monomeric IgA
Mucosal tissue=dimeric IgA (2 IgA joined by J chain)
28
1. What mediates transcytosis of IgA across the epithelium?
| 2. How does it do this?
1. Poly-Ig receptor
2. Poly-IgR has high affinity for J-chain (dimeric IgA), the antibody is transported to luminal surface of epithelium where it is released by cleavage of poly-IgR, part of the cleaved receptor remains associate with IgA and is known as the secretory component and the resulting antibody is known as secretory IgA
29
What are the functions of IgA?
Bind to mucus layer coating the epithelial surface via carbohydrate determinants in secretory component
Prevent adherence of microorganism
Neutralise toxins and enzymes
Neutralise bacterial LPS that has penetrated epithelia Cells
Little capacity to activate the classical pathway of complement or act as poisonings (unlike IgM and IgG) so it cannot induce inflammation
Limit access of pathogens to mucosa surfaces without risking inflammatory damage to tissue
Important role in symbiotic relationship between an individual and their commensalism bacteria-help restrict these organisms to gut lumen
30
What can replace IgA in deficienct patients?
Secretory IgM (pentamer, 5 IgM stuck together with J chain
31
1. How does the number of commensalism bacteria change as you go down the GI tract
2. What % cells in the body are bacteria
3. What is the role of commensalism bacteria
1. Concentration/number increases (conditions more anaerobic so commensals are anaerobic)
2. 55-60%
3. Good to help breakdown components of diet that we lack
32
What is the important task of the mucosal immune system?
Ignore harmless antigens
| Mount protective immune response to pathogens
33
Why are there normally no adverse response against food antigens?
The default response to oral administration of a protein antigen (e.g. food antigens)
is the development of specific peripheral unresponsiveness 'oral tolerance
Antigen-specific effector T cells are turned off or deleted, antigen-specific T-reg cells
are generated
34
Why are there normally no adverse response against commensal flora?
Induce IgA and T-reg cells in the intestine
Ignored by the systemic immune system – antigens normally don’t reach rest of
body (you see a response localised to the Payer’s patch or lymph nodes)
35
How does the immune system mount a response when exposed to pathogens?
```
DCs become fully activated -> induce CD4+ T cells -> become effectors
Immune cells (e.g. DCs) are activated through pattern-recognition receptors (PPRs)
```
Localization of PRRs-TLR4 (toll-like receptor 4) expression in epithelial cells at the crypt base, Basolateral TLR5 expression in epithelial cells, = pathogens invading tissues can trigger TLR activation
Virulence factors in pathogens-Salmonella type III secretion system = activation of intracellular inflammasome (via flagellin)
Commensals avoid PRR activation-Changes in flagelling sequence= TLR5 hyporesponsiveness
DC activation/maturation-Up-regulation of MHC and co-stimulatory molecules (CD40, CD80, CD86) o Cytokine production (e.g. IL-6, IL-12, IL-23)
36
Give examples of conditions in which things go wrong immunological in the intestinal tract
celiac disease – gluten free diet
Inappropriate immune response to intestinal bacteria leads to inflammatory bowel disease - ulcerative colitis or Crohn's disease- Genetic factors (Mutations in NOD2,Mutations in IL-23) Gut microbiota, Environmental exposures, Immune system abnormalities
37
1. Where is NOD2 expressed?
| 2. What does stimulation lead to?
1. Paneth cells
2. Stimulation through NOD2 leads to production of anti-microbial peptides (NOD2 is also expressed in innate immune cells)
38
What anti inflammatory drugs treat IBD?
Aminosalicylates
Corticosteroids
Immunosuppressants
Biologicals
39
What are aminosalicylates?
Dampen inflammatory process
Sulphasalazine
Mesalazine
40
What are corticosteroids?
Block substances that trigger inflammation
Prednisolone
Prednisone
Hydrocortisone
41
What are immunosuppressants?
Suppress the immune system
Azathioprine
Methotrexate
42
What are biologicals?
Target specific component of the immune system
Infliximab (anti-TNF alpha monoclonal antibody)
Adalimumab (anti TNF alpha monoclonal antibody)
43
What is the mechanism, location and examples of non inflammatory GI infections?
```
Enterotoxins (pre-formed in food thats ingested), mucosal adherence
In Proximal small bowel
Vibrio Chlolerae
Bacillus cereus
Enterotoxigenic E-coli
```
44
What is the mechanism, location and examples of inflammatory GI infections?
```
Invasion of mucosa production of cytotoxins
In colon
Shigella sp.
salmonella sp.
campylobacter jejune
Enterohaemorrhagic/enteroinvasive E.coli
```
45
What is the mechanism, location and examples of penetrating GI infections?
```
Induced phagocytosis, invades cells of immune system and disseminate beyond gut
In distal small bowel
Salmonella typhoon
Yersinia enterocolitica
Listeria monocytogenes
```
46
Give examples of sensory host defences?
Smell
| Taste
47
Give examples of behavioural host defences?
Pooing in toilet away from food, sewer system keeps it away from drinking water
Washing hands after going to the toilet
48
What are the physiological defences in the GI tract
Gastric pH - 1.5-3.5pH, achieved mostly by HCl
Bile salts and acids - in proximal small bowel, attacks bugs which get through
gastric acid
Peristalsis - maintains movement to prevent time for microorganisms to settle on
epithelium and start an infectious process
Mucus - gut epithelia produces mucus which is a physical barrier and is full of
antimicrobials (e.g. lysozyme) - mucus can also be upregulated by signalling molecules if there is an infection to create more of a barrier to prevent more tissue damage
49
What are the immune system defences against GI infection?
Humoral (antibody-mediated) immunity with secretory IgA - binds to bacteria in gut
preventing them from accessing the epithelial cells (immune exclusion)
Cell-mediated immunity - involves patrolling macrophages and cell signalling
processes
GALT (gut associated lymphoid tissue) - acts as a focus for lymphocytes and
immune cells, aiding in recruitment if there is infection
50
How does Normal gut flora defend against GI infection
Colonization resistance - occupies space, produces antibiotic-like substances (bacteriocins), end products of metabolism may be toxic
Stimulate local immune system
51
Describe the numbers of regional GI flora (Excluding mouth)?
Small numbers in stomach, duodenum and jejunum
Very large numbers in colon (1012 organisms/gram faeces)
>400 known species in the colon, possible 1500
Anaerobes outnumber others by 1000:1
52
What is the microbiome?
Sum of all species in the bowel
2-5kg
40-60% stool is bacteria
53
What are the functions of the microbiome?
Synergistic
Synthetic – forms folate, biotin, vitamin K, vitamin B
Promotes release of nutrients from foods – Fe2+, Ca2+, amino acids
Removes toxins from the breakdown of metabolism – alkaloyds, hydrogen,
heterocyclic amines from cooking
Out competes pathogens – colonisation resistance, prevents pathogen
establishment
Releases energy from carbohydrates by breaking them into sugars
54
What can GI regional flora cause if it gets into the rest of the body?
Peritonitis
| Urinary tract infections
55
What is the appendix?
What surrounds the appendix?
What does the appendix store?
Vestigial remnant
surrounded by lots of lymphoid tissue MALT which aids immune response to gut infection
The appendix stores a copy of your gut flora, so following an infection (e.g. cholera, C. difficile) where the diarrhoea flushes out the majority of your gut flora, the store can repopulate the gut with the healthy gut flora
Hence, patients who lack an appendix are much more prone to recurrences of C. difficile infection because it takes much longer for them to repopulate their gut flora
56
What type of bacteria causes most bacteria overgrowth
Gram positive (lactobacilli, enterococci)
57
What are the symptoms of bacterial overgrowth
```
Diarrhoea
Bloating
Abdominal pain
Flatulence
Steatorrhoea – fatty stools o Weight loss
```
58
What disease can result from bacterial overgrowth?
Fe deficiency – microcytic anaemia
B12/folate deficiency – macrocytic anaemia
Ca2+ deficiency – tetany
Vitamin A deficiency – visual acuity o Selenium – dermatitis
Protein – weight loss, cachexia
Fats – haemorrhagic stroke
59
How do you make a diagnosis and teat bacterial overgrowth?
Diagnosis
Hydrogen breath test, Increase in total flora (1010 organisms/ml diagnostic)
Treatment
Treat underlying condition – e.g. due to PPIs, needs to be reduced Rifaximin
60
What is bacterial overgrowth syndrome and its management?
Malabsorption (Steatorrhea, Diarrhoea)
Deficiency of fat-soluble vitamins
Macrocytic anaemia
Diagnosis (>105 bacteria/ml in a proximal small bowel aspirate,14C-D-xylose breath test)
Management
Correct underlying condition
Nutritional supplements
Suppressive antimicrobial therapy
61
Name some gut flora associated diseases?
Autism – C. botiae
Asthma/atopy - decreased bifidobacteria, increased clostridia
Obesity – decreased bacteroides, increased actinobacteria
62
1. Are antibiotics used in treating gastroenteritis, why?
2. Is gastroenteritis infectious?
3. Where can gastroenteritis come from?
1. Antibiotics-Rarely help, hence rarely prescribed o Make E. coli O157 worse, Cause diarrhoea
2. Yes-Needs barrier nursing
3. Travel/contact history, Occupation, Pets
63
Describe C. Difficile infection?
Overgrowth or colonisation
Inflammatory gastroenteritis
Gr+ and forms spores – enable to survive well outside host
Mild diarrhoea to perforation and toxic megacolon (result of huge amounts of inflammation
produces as an immune response against the toxin), malnutrition
Diarrhoea, fever, not bloody, vomiting
64
What antibiotics typically cause C.diff?
Clindamycin
Cephalosporins
Ciprofloxacin (and other fluoroquinolones)
Co-amoxiclav
65
Describe the pathogenesis of C.diff infection?
Imbalance of regional flora caused by antibiotics
Acquisition of C. difficile
Increase in number of C. difficile in patients already colonised
Production of mucosa-damaging toxins (A and B)
66
How is C.diff diagnosed?
Toxin detection
| Stool culture doesn’t establish the diagnosis as asymptomatic carriage in the elderly is common
67
How is C.diff managed?
Stop inciting antibiotics (if possible
Isolate patient - prevents environment becoming contaminated with C. difficile
spores and other patients becoming affected
Specific anti-C. difficile antimicrobials (Oral metronidazole - 1st choice, anaerobic activity, Oral vancomycin, Oral fidaxomicin, For 10-14days)
Probiotics (e.g. Saccharomyces cerevisiae) – used to try and repopulate healthy gut
flora
Faecal flora transplant – as a last resort to restore healthy gut flora, requires donor to donate some faeces which is then tested to ensure correct microbiome is introduced
68
What are prebiotics?
chemicals that alter the structure of the microbiome by promoting growth of specific types of bacteria
PI (prebiotic index) = (Bif/Total) – (Bac/Total) + (Lac/Total) – (Clos/Total)
PI allows you to calculate the effectiveness of a specific chemical on the altering of
the gut flora
You want to promote bifidobacteria and lactobacilli, you want to supress
bacteroides and clostridium
69
What are probiotics?
live cultures of organisms to repopulate gut flora after infection
Prevention of infections (Direct effects on invading pathogens, Indirect by stimulating immune function – e.g. sIgA production
Treatment of established infection
Use in conditions with a non-infective aetiology – e.g. chronic inflammatory bowel disease
