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I&I WC1 > Organ-specific immunity: GUT - Innate-and adaptive immunity > Flashcards

Organ-specific immunity: GUT - Innate-and adaptive immunity Flashcards

This deck contains the lectures about innate- and adaptive mechanisms in the gut

1
Q

Why do we need microbiota in the intestine?

A

They help digest our food and prime our immune system

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2
Q

Advantages of host-microbial symbiosis in the GI-tract for the host (3)

A
  • Bacteria facilitate digestion and absorption of nutrients
  • Bacteria-derived signals needed for normal intestinal physiology
  • Commensal bacteria limit pathogen colonization
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3
Q

What is an advantage for bacteria considering host-microbial symbiosis in the GI-tract?

A

Host provides a protected and nutrient-rich environment

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4
Q

When in life do we get colonized mostly and why?

A

Directly after birth. Intestine is most permeable at that time.

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5
Q

Which two factors define mucosal immune homeostasis?

A
  • Hyporesponsiveness to harmless substances
  • Protection against harmful substances
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6
Q

Which two factors shape the gut immune system?

A
  • Microbiota/microbiome
  • Food
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7
Q

What is the first structure we have in terms of the gut immune system? Made up by?

A

Intestinal barrier made up by innate immune cells

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8
Q

Name five factors important for epithelial barrier function

A
  • Microvillar extensions
  • Epithelial-cell tight junctions
  • Secreted mucins by goblet cells
  • Epithelial transcytosis of IgA
  • Antimicrobial peptides
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9
Q

Which layer is made by the goblet cells?

A

A polysaccharide layer called the lumen

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10
Q

Of what does the lumen consist in the small intestine?

A

Single thin mucus layer

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11
Q

Of what does the lumen consist in the colon?

A

Inner and outer mucus layer

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12
Q

What is the difference between the inner- and outer lumen layer when considering bacterial colonization?

A

There are generally less bacteria living close to the epithelium

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13
Q

What is MUC2?

A

A major mucin of the colon mucus

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14
Q

What do mice lacking MUC2 suffer from? Why?

A

Intestinal inflammation. They are unable to maintain the relatively bacteria-free zone in the crypt.

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15
Q

Which immunoglobulin is mostly produced in the intestine?

A

IgA

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16
Q

Why is IgA the most prominent immunoglobulin in the intestine?

A

This allows for certain bacteria to stay in the intestine

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17
Q

What is the function of antimicrobial peptides produced by paneth cells?

A

Keeping microbiota under control

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18
Q

What does a lack of paneth cells result in?

A

Increased bacterial translocation

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19
Q

What are the three ways of antigen-uptake across the epithelium?

A
  • Passive diffusion
  • Transcellular transport by M cells
  • Macrophage uptake
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20
Q

Explain the transcellular transport by M cells

A

M cells are equipped with PRR molecules + epithelial cells next to dome area have more PRRs. Allows for selective fragments of microbiota or entire bacteria to be taken up.

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21
Q

Why are DCs in the majority in the Peyer’s Patch?

A

They are very good presenters

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22
Q

What is the function of the macrophage uptake across the epithelium?

A

Needed in case there is still an entire bug that needs to be digested

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23
Q

Which substances will pass via passive diffusion?

A

Many solubles in food

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24
Q

Example of soluble in food that will pass through passive diffusion

A

Ovalbumin

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25
Explain the 'macrophage uptake' way of antigen-uptake
Macrophages very close to the epithelium can transiently break tight junctions and put their cytoplasm into the lumen.
26
What are the differences in epithelial barrier and antigen sampling in the small intestine vs. the colon? (4)
- Presence vs. absence of M cells - Thin vs. thick mucus layer - Presence vs. absence of paneth cells - Peyer's Patches vs. isolated lymphoid follicles
27
Why is sensing by PRRs in the gut required?
To discern harmless from harmful
28
What determines the cocktail of inflammatory mediators in the gut?
The combination of receptor activation
29
What is the function of NFkB in the regulation of intestinal homeostasis? (2)
- Maintains mucosal barrier integrity - Activates innate immune cells
30
What is needed for NFkB to become activated and move into the nucleus?
Phosphorylation, ubiquitylation and proteasomal degradation of IkB
31
What is meant with the 'dual function' of NFkB?
It causes transcription and translation of pro-inflammatory AND anti-apoptotic proteins
32
What does a loss of NFkB function result in?
Apoptosis of epithelial cells leading to intestinal inflammation
33
What kind of response occurs on the apical surface?
Homeostatic, anti-inflammatory response
34
What kind of response occurs on the basolateral surface?
Invasive bacteria elicit a pro-inflammatory response
35
Where do you see TLRs on the apical side?
Near the Peyer's Patch
36
What facilitates the difference in anti-microbial response between the small intestine and colon?
Small intestine and colon do not have the same base-line expression of the same type of PRRs
37
Why do the small intestine and colon not have the same base-line expression of the same type of PRRs?
Different microbial composition
38
How is balanced epithelial responsiveness ensured?
Repetitive microbial interaction elicits desensitization of the epithelium leading to hyporesponsiveness
39
What is an example of an inhibitor expressed by epithelial cells?
A20 or SLPI
40
Name the three main messages that are important when considering microbial sensing in the gut
- NFkB functions differ depending on cell type - TLR have patterned expression - TLR signaling can induce regulatory (inhibitory) responses
41
What molecules are most effective for losing innate tolerance?
Cytokines
42
What are the homeostatic functions of macrophages in the intestine? (4)
- Eliminating invading commensal bacteria - Phagocytosis of senescent/apoptotic epithelial cells - Maintenance of regulatory T cells - Transfer of antigens to migratory DCs
43
What are the functions of macrophages during intestinal inflammation? (3)
- Increased phagocytosis - Production of pro-inflammatory cyto- and chemokines - Maintenance of pro-inflammatory effector T cells
44
What is the default response to harmless antigens?
Tolerance
45
What kind of defense would you ideally want if you have a mucosal infection?
Mucosal defense at the mucosa sight
46
Why is it extremely hard to vaccinate via a mucosal route/induce mucosal defense at the mucosa sight?
Predominance of tolerance in these areas normally
47
Which antigen-presenting cells are the most important in the intestine?
DCs and macrophages
48
Describe the difference in drainage between intestinal DCs and macrophages
DCs generally drain more. Macrophages drain less, because they mostly stay locally
49
What are CD103+ lamina propria DCs?
Truely DCs, because they stem from a DC precursor
50
What are CX3CR1+CD103- cells?
Macrophages, because they stem from a monocyte precursor
51
What is meant with division of labour between DCs and macrophages in the intestine?
- DCs sample + migrate + go to mesenteric lymph node --> show what's out there - Macrophages digest, spit out what they've digested - DCs can home back to the intestine
52
Why do CD103+ lamina propria DCs and CX3CR1+CD103- cells reside in different locations?
They have a different function
53
What is the difference in location between CD103+ lamina propria DCs and CX3CR1+CD103- cells?
CX3CR1+CD103- cells extend their dendrites and sit much closer to the epithelium
54
What happens with naive T cells after antigen-presentation in a lymphocytic site in the intestine?
Differentiation
55
What are the inflammatory Th subsets and their cytokines?
Th1: IFN-y Th2: IL-4, IL-5 IL-13 Th17: IL-17, IL-21, IL-22
56
What are the regulatory Th subsets and their cytokines?
Tr1: IL-10 FoxP3 Treg (iTreg and nTreg_)
57
What is the lamina propria/outside of the mucosa associated lymphoid tissue populated by?
Effector memory cells
58
Which two DCs present antigen in the mucosa-draining lymph node and what kind of antigens do they present?
- Migrated DCs: bacterial-derived antigens - Resident DCs: antigens of diffused proteins/leak with lymphatics
59
How is the T cell response mounted in the case of migrated DCs?
- PP: inductive site - In mesenteric LN --> DCs really need to drain to the mesenteric LN with the lymph in order to present - Induction of Th1, 2, 17 response
60
How is the T cell response mounted in the case of resident DCs?
- Subcapsular macrophages are the first to sieve --> pick up macromolecules that have not been picked up - Macrophages digest and transfer this antigen to resident DCs - Resident DCs sit in the mesenteric LN
61
How is the T cell response imprinted to go back to the intestine after differentiation?
Migration dependent imprinting is dependent on: - Chemokine receptors + chemokines (CCR9/CCL25) - Adhesion molecules (alpha4beta7)
62
What is alpha4beta7?
Adhesion molecule that allows cells that express the molecule to enter the intestinal tissue
63
Describe the principle of oral tolerance in the intestine (first encounter with antigen after mucosal injection)
Intestinal immune system not only makes tolerance at the intestinal site, but also suppresses any systemic encounter with that antigen
64
What happens when we eat a soluble protein?
We see it with our immune system and within that timeframe we make tolerogenic cells
65
Where do functionally suppressive mucosal Treg differentiate? (2)
- Peyer's Patch - Mesenteric LN
66
Name tolerogenic signals in the intestine that activated lymphocytes undergo (4)
- Inactivation - Deletion - Anergy - Treg
67
Loss of tolerance is associated with...
Reduced numbers of FoxP3+ T cells
68
What can be said about the induction of tolerance when comparing oral feed of OVA with injection in thigh muscle?
Oral feed of a harmless antigen (OVA) induces tolerance while injection of this same antigen does not induce tolerance.
69
Which process mediates oral tolerance to harmless antigens?
Induction of a suppressive T cell response in mucosa draining lymphoid sites (PP and MLN)
70
How fast can you generate a suppressive T cell response?
Within 72h of OVA feed
71
How would you be able to demonstrate the time in which a mouse can generate a suppressive T cell response?
- Isolation - Adoptive transfer to new mouse - Suppression of "vaccination" DTH response in acceptor mice
72
How can you overcome the preferential regulatory response? How does this work?
Mucosal adjuvant. Inhibits the differentiation of mucosally induced Treg cells in the MLN
73
How are Treg preferentially induced by CD103+ DC in the mucosa/small intestine?
You need a combination of: - CD103+ DCs produce vitamine A derived retinoic acid via ALDH1A2 - Local TGF-B production in MLN
74
What happens to Treg induction if you don't have TGF-B in the environment?
No differentiation of Treg
75
How do DCs acquire tolerogenic function?
Epithelial cells are constantly sensing and tell the DCs how to differentiate
76
Where does the conditioning of phagocytes occur?
Lamina propria
77

I&I WC1 (25 decks)

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