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MIMM 314 > Lecture 6 > Flashcards

Lecture 6 Flashcards

1
Q

what are the 2 aspects of host defense?

A
  1. host resistance
  2. disease tolerance
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2
Q

how was tolerance discovered?

A

in plant kingdom

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3
Q

6 ways that disease tolerance can be acquired

A
  1. genetic
  2. receptor downregulation
  3. tissue repair
  4. circadian rhythm
  5. gut microbiota
  6. immune silencing
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4
Q

what is vigor?

A

healthy host –> no pathogen

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5
Q

what is tolerance?

A

host is protected despite the pathogen load –> increased host health for a given pathogen load

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6
Q

NORMALLY, does type 1 response drive host resistance or tolerance?

A

host resistance

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7
Q

NORMALLY, does type 2 response drive host resistance or tolerance?

A

tolerance

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8
Q

describe the relationship btwn type 1 and type 2 immunity

A

MUTUALLY ANTAGONISTIC –> both play a role in infection but oppose each other

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9
Q

what is the general role of type 1 immunity?

A

cytotoxic responses and host resistance

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10
Q

what is the general role of type 2 immuntiy?

A
  1. barrier defense
  2. tissue repair
  3. epithelial remodeling
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11
Q

describe the effect of the Hpb worm on mice

A

persistent and chronic but not replicating –> mice won’t get sick bc they tolerate it very well

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12
Q

location of Hpb in mouse infection

A

buries below crypts and villi and forms large granulomas

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13
Q

describe the lifecycle of Hpb (7 stages)

A
  1. swallow larvae
  2. break thru intestinal epithelium
  3. bury into mucosal layer and form granulomas
  4. matures in granulomas
  5. worm breaks out and creates another level of damage
  6. worm wraps around villi
  7. worms mate and release eggs
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14
Q

what type of immunity is typically involved in worm expulsion?

A

type 2

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15
Q

during what stage of the worm life cycle is TYPE 2 immunity involved?

A

during adult phase, at the end of infection

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16
Q

describe the role of type 2 immunity on worm expulsion

A
  1. damaged epithelial cells release alarmins which activate DCs and ILCs to make IL4/5/13 and activate macrophages and eosinophils which feed back on the epithelium
  2. IL4/5/13 reprogram the intestinal stem cell niche and change the differentiation pattern to create more goblet cells for weep and sweep response
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17
Q

how does type 2 involvement in worm expulsion differ from what we know about type 2 immunity?

A

normally, type 2 is involved in tolerance

but since it is triggering the weep and sweep response to reduce the pathogen load, it is responsible for HOST RESISTANCE here

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18
Q

are all mice equally susceptible to helminth infection? why?

A

no –> diff genetic backgrounds can make them more or less susceptible based on whether they are type 2 or type 1 biased

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19
Q

mice that are biased for type 2 are more susceptible or resistant to helminth infection?

A

RESISTANT

20
Q

mice that are biased for type 1 are more susceptible or resistant to helminth infection?

A

SUSCEPTIBLE

21
Q

what cytokine is produced by mice that are susceptible to helminth infection?

A

IFNy –> biased for type 1 response

22
Q

what cytokine is produced by mice that are resistant to helminth infection?

A

IL13 –> biased for type 2 response

23
Q

what is STAT6?

A

TF common in type 2 response for pro-inflammatory cytokines

24
Q

do we expect a higher or lower worm burden in STAT6 KO mice?

A

STAT6 is involved in type 2 response which we know to be important in helminth infection

therefore STAT6 KO will have higher worm burden

25
Q

what cytokines do we see in early Hpb response? what does this signify?

A

IFNy is upregulated early on in infection

indicates that type 1 and type 2 are both involved in helminth infection and are opposing each other

26
Q

do we expect a higher or lower worm burden in IFNyr KO mice? why?

what does this indicate?

A

IFNyr KO mice have a lower worm burden because type 2 response can occur earlier and stronger to remove worms

indicates that IFNy compromises host resistance

27
Q

why is the role of IFNy in helminth infection different from the normal role of IFNy?

A

IFNy normally is responsible for host resistance (type 1) but here it is COMPROMISING host resistance

28
Q

how do we expect the levels of goblet cells to change in IFNyr KO mice? why?

A

MORE goblet cells making more mucous –> bc type 2 response is occurring earlier and stronger

29
Q

looking at type 2-driven epithelial cells and goblet cells, how do their levels change in IFNyr KO?

A

more type 2-driven epithelial cells and goblet cells

30
Q

what happened when WT and IFNyr KO mice are given very high dose of worms? what does signify?

A

WT mice were fine

IFNyr KO mice were dying midway in infection

indicates that IFNy plays a role in protecting the host

31
Q

how did pathogen load change in IFNyr KO mice given a high dose of worms that survived? what does this signify?

A

IFNyr KO have no change in pathogen load

indicates that IFNy promotes disease tolerance

32
Q

describe the granuloma in IFNyr KO mice

A

IFNyr KO mice had:
- bloody granulomas
- more granulomas
- bigger granulomas

(compared with WT)

33
Q

describe the healing of granulomas in IFNyr KO mice

A

IFNyr KO mice had large scars in intestine

34
Q

what is the role of IFNy in relation to tissue damage?

A

IFNy limits the tissue damage, therefore promoting tolerance

35
Q

what does IFNy recruit at the granulomas? how do they know (2)?

A

IFNy recruits neutrophils to the granulomas

  1. saw increase in chemokines that recruit neutrophils
  2. in IFNyr KO mice, no neutrophils could be detected at granuloma
36
Q

what happens to tissue damage if neutrophil activity is removed? how does this relate to IFNy?

A

lose neutrophil activity = more tissue damage

same results as IFNyr KO –> so IFNy must be recruiting the neutrophils

37
Q

what happens to granulomas if neutrophil activity is removed?

A

lose neutrophil activity = large granulomas

38
Q

is the epithelium responsible for the IFNy signaling?

A

no –> cre mouse for IFNy KO in IEC has no diff in signaling

39
Q

what is the stroma?

A

cells underneath the epithelial lining which form the ECM

40
Q

how do stromal cells interact with the immune system?

A

when there is physical damage in intestine, stromal cells migrate and help repair and recruit immune cells

41
Q

based on the interaction of stroma with the immune cells, what is the hypothesis regarding IFNy and neutrophils activity?

A

is IFNy licensing stromal cells to induce neutrophil recruitment and allow tissue repair?

42
Q

how does IFNy signaling affect the stromal architecture?

A

in IFNyr KO –> large disruption of actin filaments

therefore, IFNy is important for proper structure of stroma

43
Q

what happens as a result of STROMAL IFNy signaling?

A

worm infection drives IFNy signaling to recruit neutrophils and licenses the stroma to change its structure and help reduce tissue damage

44
Q

what happens to neutrophil-recruiting chemokines in IFNyr KO mice? what does this mean?

A

in IFNyr KO mice –> lose chemokine signaling that recruits neutrophils

therefore, IFNy is responsible for recruiting neutrophils

45
Q

how can we confirm that IFNy signaling from STROMAL cells specifically is what recruits neutrophils?

A

use cre to make IFNy KO in stromal cells –> lose recruitment of neutrophils

46
Q

if you gave IL4 to type 1 biased mice, what would happen to host resistance after HELMINTH infection?

A

IL4 is type 2 –> will drive the mouse towards type 2 response and promote host resistance

MIMM 314 (23 decks)

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