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Unit 10 lectures > Balance and Regulation in the Gut > Flashcards

Balance and Regulation in the Gut Flashcards

1
Q

What can be found in the mucosal immune system?

A
  • intraepithelial dendritic cell
  • CD4 and CD8 T cells
  • IgA secreting plasma cell
  • Paneth cells (secrete defensins)
  • macrophages
  • goblet cell
  • mast cells
  • Peyers patches:

(which are clusters of B and T cells, follicular DCs and macrophages to form germinal centres):
→ B cells
→ T cells
→ follicular DCs
→ macrophages
→ germinal centre (5x more B cells than T)

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2
Q

Features of microbiota

A
  • generally non-pathogenic
  • constantly proliferating and being passed out of gut
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3
Q

Features of Outer and Inner Mucus layers mucus layers in the gut

A

Outer mucus layer:
- non-sterile
- degrading mucus
- microbes utilise mucin carbs

Inner mucus layer:
- sterile
- rich in antimicrobial peptides
- Paneth cells produce α-defensins in small bowel and β-defensins in colon

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4
Q

What is IgA in the gut secreted for?

A

commensal bacteria in health gut

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5
Q

What do Paneth cells in the gut produce?

A

Defensins
- alpha-defensins in small bowel
- beta-defensins in colon

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6
Q

What do microbiota do in the gut? (4)

A
  • produce vitamins such as vitamin K (needed for clotting factor)
  • breakdown non-digestable carbs into short chain fatty acids
    (acetate,propionate, butyrate)
  • degrade toxins into harmless components
  • outcompete pathogenic bacteria
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7
Q

What does high levels of SCFAs mean?

A

lower risk diet obesity and insulin resistance and are absorbed and reach the liver and peripheral organs used for gluconeogenesis and lipogenesis

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8
Q

How does the GI tract maintain an anti-inflammatory environment?

TH17 cytokines

A

→ secrete IL-22 and IL-17

→ induce defensin expression by endothelial cells

→ Clostridiatermed segmented filamentous bacteria (SFB) are essential to the development of Th17 cells in the mouse gut

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9
Q

How does the GI tract maintain an anti-inflammatory environment?

T regs

A

→ present in large numbers

→ control the population of effector T cells

→ TH2 cells are relatively abundant in the intestinal epithelium but TH1 are kept at low numbers (an increase is seen in IBD)

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10
Q

How does the GI tract maintain an anti-inflammatory environment?

Intraepithelial Leukocytes

A

→ predominantly CD8+ these survey and remove infected/damaged cells

→ virally infected cells are detected through MHCI antigen presentation

→ Stressed cells (e.g. toxin exposure) up-regulate MIC-A and MIC-B and release IL-15 which targets them for killing

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11
Q

How does the GI tract maintain an anti-inflammatory environment?

TLR down-regulation

A

→ TLRs are down-regulated on the apical surface of the epithelium and present in the cytosol and basal surface

→ NOD can trigger inflammatory cytokine release and autophagy to remove bacteria

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12
Q

How do Dendritic cells sample the gut? (4)

A
  • DC’s in Peyers patches produce IL-10 in response to antigen uptake to promote T-reg activation and IgA production
  • Antibodies on FC receptors transcytose antigens to DC in lamina propria
  • Apoptotic cells with bacteria phagocytosed by DCs
  • DCs send processes between epithelial cells to sample gut
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13
Q

What happens if pathogen breaks through barrier?

A

Dendritic Cells rapidly recruited and release:

  • IL-12
  • which activates Th1
  • which releases IFNγ to enhance macrophage killing
  • IL-21 and 6
  • which activates Th17 to release IL-17 and 22
  • which induce defensins release and recruits neutrophils
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14
Q

When sampled, the Microbiota cause an anti-inflammatory defensive response…

A

COMMENSAL RESPONSE

1) epithelial cells secrete TGF-B and TSLP (thymic stromal lymphopoietin)

2) DCs + TLRs and macrophages produce IL-10

3) Foxp3 T regs in mesenteric lymph nodes - inhibit TH1 and TH17

4) IgA produced by B cells

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15
Q

If bacteria enter through other means an inflammatory reaction occurs…

A

PATHOGENIC RESPONSE

1) pathogens damage and break through the barrier

2) M cells are exploited and penetrate through destroying them and breaking barrier

3) DC cells recruited

4) IL-12 → TH1 → IFNy → enhance macrophage killing

5) IL-6 and IL-21 → TH17 → IL 17 → neutrophil recruitment

IL- 22 → induce defnesin expression

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16
Q

Changes in Microbiota

A

foetus is exposed to microbes in the uterus

  • colonisation continues after birth and influenced by mode of deliver, diet, hygiene and antibiotic exposure
  • bifidobacterium longum is present in breast milk

→ breakdown oligosaccharides in breast milk
→ produces lactic acid to reduce pathogenic colonisation

  • adult like microbiota by 3 years old
17
Q

How does imbalance in microbiota lead to opportunistic infections?

A

Broad spectrum antibiotics → clostridium difficile

1) healthy colon is colonised by large numbers of commensal bacteria

2) broad spectrum antibiotic treatment may kill off many of the commensals

3) clostridium difficile gains a foothold and produces toxins which cause injury

4) neutrophils and RBCs leak into the gut in-between epithelial cels

18
Q

What is Ulcerative Colitis?

A

inflammation of the colon and rectum

  • ulcers develop in the colon lining
  • continuous inflammation along the length without gaps
  • only mucosal layer affected
  • no granulomas
  • pseudopolyps in mucosa
19
Q

Symptoms of Ulcerative Colitis

A
  • recurring diarrhoea
  • abdominal pain
  • need to empty bowels frequently
  • fatigue
  • loss of appetite
  • weight loss

flare ups
- painful joints
- mouth ulcers
- red and swollen skin

20
Q

What is Crohn’s disease?

A
  • immune response to our own commensal bacteria
  • barrier defences are disrupted which increase risk of commensal bacteria reaching the epithelial layer → inflammatory response
  • affects epithelium, lamina propria and other layers of the bowel
  • can affect any part (common at end of ileum or colon)
  • inflammation is patchy-skip lesions
  • non-caseating granulomas are present
  • mucosa appear cobblestone-like
21
Q

Symptoms of Crohn’s disease

A
  • rectal bleeding
  • abdominal pain
  • diarrhoea
  • tiredness and fatigue
  • feeling generally unwell or feverish
  • mouth ulcers
  • loss of appetite
  • weight loss
  • anaemia
22
Q

Genetics and Crohn’s disease

A

ATG16L1
→ forms auto-phagocytic vesicles
→ low level of defensins from paneth cells

IRGM
→ forms auto-phagocytic vesicles
→ low levels of defensins from paneth cells

IL-23R
→ Th17 response
→ high levels of Th17 and granulomatous inflammation

NOD2
→ intracellular recognition of bacteria → defective recognition of bacteria

MUC1
→ reduced mucus secretions
→ insufficient mucosal barrier

23
Q

Crohn’s disease:

What is the role of ATG16L1?

A
  • formation of autophagocytic vesicle
  • low levels of defensins from paneth cells
24
Q

Crohn’s disease:

What is the role of IRGM?

A
  • formation of autophagocytic vesicle
  • low levels of defensins from paneth cells
25
Q

Crohn’s disease:

What is the role of IL-23R?

A
  • TH17 response
  • high levels of TH17 cells in granulomatous inflammation
26
Q

Crohn’s disease:

What is the role of NOD2?

A
  • intracellular recognition of bacteria (PRR)
  • defective recognition of bacteria
27
Q

Crohn’s disease:

What is the role of MUC1?

A
  • reduced mucus secretion
  • insufficient mucosal barrier
28
Q

Mechanism of crohn’s disease (5)

A

1) commensal bacteria

2) ↓ mucous secretion and defensive expression
→ weakened junctions between cells inc permeability
→ defective NOD2 protein dec autophagy

3) bacteria are detected and initiate an inflammatory response
→ TLR- macrophages phagocytose and secrete IL-12, Il-6, IL1-B and TNFa

4) dendritic cells release IL-12, IL-23, IL-16, IL-21
→ IL-12 recruits TH1 cells and promote inflammation and macrophage activation (INFy)

5) IL-21 and IL-16 recruits TH17 cells and inc inflammation
→ release IL-17 and IL-22 → granulocytes enter tissue causing damage

29
Q

Immunology of genetically mutated mucosal barrier

A
  1. Barrier Dysfunction:
    → reduced mucus layer
    → reduced defensin expression
    → weakened junction between epithelial cells (increase permeability)
    → Defective NOD2 protein (decrease autophagy)
  2. Bacteria detected by DCs causing inflammatory response:
    → DCs release IL-12 and 23
    → recruit Th1 cells
    → which release TNFα and IFNγ (activates macrophages)
    → DCs release IL-21 and 6 to activate Th17 and granulocytes
30
Q

What are the treatments for Crohn’s Disease

A

Steroids and Immunosuppressants:
→ Prednisolone - glucocorticoid to reduce inflammatory cytokine and T cell proliferation
→ Azathioprine - reduce T and B cell proliferation and T cell apoptosis
→ Mercaptopurine - antimetabolite to reduce T cell proliferation

Biologicals:
→ Adalimumab - binds to TNFα
→ Inflixumab - binds to TNFα
→ Vedolizumab - binds to adhesion molecule to reducing leukocyte recruitment

31
Q

Steroid immunosuppressants treatment for Crohn’s disease (3)

A

→ focuses on reducing inflammation
→ to relieve symptoms and trigger remission

Steroids and immunosuppressants:

Prednisolone:
→ glucocorticoid reduce inflammatory cytokines and T cell proliferation

Azathiorprine
→ reduce T and B cell proliferation and stimulate T c ell apoptosis

Mercaptopurine
→ antimetabolite to reduce T cell proliferation

32
Q

Biological treatments for Crohn’s disease (4)

A

Adalimumbab
→ bind to TNFa

Infliximab
→ bind to TNFa to inhibit

Vedolizumab
→ binds to adhesion molecule a4B7 intern reducing leukocyte recruitment

Ustekinumab
→ binds to p-40 subunit present in IL-12 and IL-23

33
Q

Surgical treatment of Crohn’s disease

A

Surgery to remove inflamed sections

→ not curate as underlying risks still exist and recurrence is relatively common lesions can occur at resected bowel site

34
Q

Oral Tolerance

A
  • GI tract is major entry to body for pathogenic and non-pathogenic molecules
  • in order to survive the immune system needs to detect the difference

1) soluble proteins and macromolecules are taken up through M cells
→ as they have entered via oral route no antibodies have been previously produced

2) dendritic cells present antigen alongside IL-10
→ no innate immune activation
→ teaches immune system that not pathogenic molecule

3) high levels of antigen can induce anergy in effector T cells

35
Q

What is coeliac disease?

A

Immune mediated inflammatory disease directed towards gluten

→ HLA DQ2 or HLA DQ8 allows DCs to present the gluten antigen responsible

→ tissue Transglutaminase (TTG) amplify peptide fragments
(peptides produced of gluten digestion)

→ leading to greater targets for autoantibodies

→ causing general malabsorption by destroying villi of small intestine

→ reducing SA for absorption

36
Q

How to diagnose Coeliac disease?

A

Assay for anti-tissue transglutaminase antibodies

(patient tested for IgA antibodies to anti-TTG)

37
Q

Symptoms of Coeliac disease (6)

A
  • diarrhoea
  • malabsorption
  • weight loss
  • anaemia
  • Irritability
  • muscular wastage
38
Q

Mechanism of Coeliac Disease

A

1) unknown trigger results in breakdown of oral tolerance and gluten enters epithelium

2) tissue transglutaminase can break gluten into antigenic peptides → Gliadin

3) epithelial cells become stressed by Gliadin peptides:
- up-regulating MIC-A and MIC-B
- and secreting IL-1B and IL-15
→ CD8+ targets and kills stressed cells

4) DCs present Gliadin peptide and promote TH1 cells
→ release of TNFa and IFN-y
→ promotion of B cell activation

5) B cells can have receptors of TTG and present Gliadin and TTG components
→ T cell recognises the gliding and stimulates B cell
→ which secretes anti TTG antibodies

Unit 10 lectures (14 decks)

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