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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
Q

Explain the ‘macrophage uptake’ way of antigen-uptake

A

Macrophages very close to the epithelium can transiently break tight junctions and put their cytoplasm into the lumen.

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26
Q

What are the differences in epithelial barrier and antigen sampling in the small intestine vs. the colon? (4)

A
  • Presence vs. absence of M cells
  • Thin vs. thick mucus layer
  • Presence vs. absence of paneth cells
  • Peyer’s Patches vs. isolated lymphoid follicles
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27
Q

Why is sensing by PRRs in the gut required?

A

To discern harmless from harmful

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28
Q

What determines the cocktail of inflammatory mediators in the gut?

A

The combination of receptor activation

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29
Q

What is the function of NFkB in the regulation of intestinal homeostasis? (2)

A
  • Maintains mucosal barrier integrity
  • Activates innate immune cells
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30
Q

What is needed for NFkB to become activated and move into the nucleus?

A

Phosphorylation, ubiquitylation and proteasomal degradation of IkB

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31
Q

What is meant with the ‘dual function’ of NFkB?

A

It causes transcription and translation of pro-inflammatory AND anti-apoptotic proteins

32
Q

What does a loss of NFkB function result in?

A

Apoptosis of epithelial cells leading to intestinal inflammation

33
Q

What kind of response occurs on the apical surface?

A

Homeostatic, anti-inflammatory response

34
Q

What kind of response occurs on the basolateral surface?

A

Invasive bacteria elicit a pro-inflammatory response

35
Q

Where do you see TLRs on the apical side?

A

Near the Peyer’s Patch

36
Q

What facilitates the difference in anti-microbial response between the small intestine and colon?

A

Small intestine and colon do not have the same base-line expression of the same type of PRRs

37
Q

Why do the small intestine and colon not have the same base-line expression of the same type of PRRs?

A

Different microbial composition

38
Q

How is balanced epithelial responsiveness ensured?

A

Repetitive microbial interaction elicits desensitization of the epithelium leading to hyporesponsiveness

39
Q

What is an example of an inhibitor expressed by epithelial cells?

A

A20 or SLPI

40
Q

Name the three main messages that are important when considering microbial sensing in the gut

A
  • NFkB functions differ depending on cell type
  • TLR have patterned expression
  • TLR signaling can induce regulatory (inhibitory) responses
41
Q

What molecules are most effective for losing innate tolerance?

A

Cytokines

42
Q

What are the homeostatic functions of macrophages in the intestine? (4)

A
  • Eliminating invading commensal bacteria
  • Phagocytosis of senescent/apoptotic epithelial cells
  • Maintenance of regulatory T cells
  • Transfer of antigens to migratory DCs
43
Q

What are the functions of macrophages during intestinal inflammation? (3)

A
  • Increased phagocytosis
  • Production of pro-inflammatory cyto- and chemokines
  • Maintenance of pro-inflammatory effector T cells
44
Q

What is the default response to harmless antigens?

A

Tolerance

45
Q

What kind of defense would you ideally want if you have a mucosal infection?

A

Mucosal defense at the mucosa sight

46
Q

Why is it extremely hard to vaccinate via a mucosal route/induce mucosal defense at the mucosa sight?

A

Predominance of tolerance in these areas normally

47
Q

Which antigen-presenting cells are the most important in the intestine?

A

DCs and macrophages

48
Q

Describe the difference in drainage between intestinal DCs and macrophages

A

DCs generally drain more. Macrophages drain less, because they mostly stay locally

49
Q

What are CD103+ lamina propria DCs?

A

Truely DCs, because they stem from a DC precursor

50
Q

What are CX3CR1+CD103- cells?

A

Macrophages, because they stem from a monocyte precursor

51
Q

What is meant with division of labour between DCs and macrophages in the intestine?

A
  • 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
Q

Why do CD103+ lamina propria DCs and CX3CR1+CD103- cells reside in different locations?

A

They have a different function

53
Q

What is the difference in location between CD103+ lamina propria DCs and CX3CR1+CD103- cells?

A

CX3CR1+CD103- cells extend their dendrites and sit much closer to the epithelium

54
Q

What happens with naive T cells after antigen-presentation in a lymphocytic site in the intestine?

A

Differentiation

55
Q

What are the inflammatory Th subsets and their cytokines?

A

Th1: IFN-y
Th2: IL-4, IL-5 IL-13
Th17: IL-17, IL-21, IL-22

56
Q

What are the regulatory Th subsets and their cytokines?

A

Tr1: IL-10
FoxP3 Treg (iTreg and nTreg_)

57
Q

What is the lamina propria/outside of the mucosa associated lymphoid tissue populated by?

A

Effector memory cells

58
Q

Which two DCs present antigen in the mucosa-draining lymph node and what kind of antigens do they present?

A
  • Migrated DCs: bacterial-derived antigens
  • Resident DCs: antigens of diffused proteins/leak with lymphatics
59
Q

How is the T cell response mounted in the case of migrated DCs?

A
  • 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
Q

How is the T cell response mounted in the case of resident DCs?

A
  • 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
Q

How is the T cell response imprinted to go back to the intestine after differentiation?

A

Migration dependent imprinting is dependent on:
- Chemokine receptors + chemokines (CCR9/CCL25)
- Adhesion molecules (alpha4beta7)

62
Q

What is alpha4beta7?

A

Adhesion molecule that allows cells that express the molecule to enter the intestinal tissue

63
Q

Describe the principle of oral tolerance in the intestine (first encounter with antigen after mucosal injection)

A

Intestinal immune system not only makes tolerance at the intestinal site, but also suppresses any systemic encounter with that antigen

64
Q

What happens when we eat a soluble protein?

A

We see it with our immune system and within that timeframe we make tolerogenic cells

65
Q

Where do functionally suppressive mucosal Treg differentiate? (2)

A
  • Peyer’s Patch
  • Mesenteric LN
66
Q

Name tolerogenic signals in the intestine that activated lymphocytes undergo (4)

A
  • Inactivation
  • Deletion
  • Anergy
  • Treg
67
Q

Loss of tolerance is associated with…

A

Reduced numbers of FoxP3+ T cells

68
Q

What can be said about the induction of tolerance when comparing oral feed of OVA with injection in thigh muscle?

A

Oral feed of a harmless antigen (OVA) induces tolerance while injection of this same antigen does not induce tolerance.

69
Q

Which process mediates oral tolerance to harmless antigens?

A

Induction of a suppressive T cell response in mucosa draining lymphoid sites (PP and MLN)

70
Q

How fast can you generate a suppressive T cell response?

A

Within 72h of OVA feed

71
Q

How would you be able to demonstrate the time in which a mouse can generate a suppressive T cell response?

A
  • Isolation
  • Adoptive transfer to new mouse
  • Suppression of “vaccination” DTH response in acceptor mice
72
Q

How can you overcome the preferential regulatory response? How does this work?

A

Mucosal adjuvant. Inhibits the differentiation of mucosally induced Treg cells in the MLN

73
Q

How are Treg preferentially induced by CD103+ DC in the mucosa/small intestine?

A

You need a combination of:
- CD103+ DCs produce vitamine A derived retinoic acid via ALDH1A2
- Local TGF-B production in MLN

74
Q

What happens to Treg induction if you don’t have TGF-B in the environment?

A

No differentiation of Treg

75
Q

How do DCs acquire tolerogenic function?

A

Epithelial cells are constantly sensing and tell the DCs how to differentiate

76
Q

Where does the conditioning of phagocytes occur?

A

Lamina propria

77
Q
A

I&I WC1 (25 decks)

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