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Health 31 > Autoinflammation > Flashcards

Autoinflammation Flashcards

1
Q

The boundaries of X are set by mutations associated with cells + molecules involved in Adaptive Immune Responses?

A

autoimmunity

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2
Q

The boundaries of X are defined by mutations in cells/ molecules involved in Innate Immunity at disease prone sites?

A

autoinflammation

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3
Q

3 examples of rare monogenic autoinflammatory diseases

A

FMF
TRAPS
HIDS

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4
Q

rare monogenic autoimmune disease examples (not covered)….

A

when single gene affected- can tell us part of immune response
ALPS
IPEX

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5
Q

difference between studying monogenic disease and polygenic disease?

A

Monogenic: caused by variation in a single gene ->tells us more about function of body better than polygenic diseases: too many contributing gene factors to come to conclusive explanation

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6
Q

name for a group of disorders that are characterized by seemingly unprovoked attacks of inflammation?

A

myogenic autoinflammatory diseases

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7
Q

what 2 things are there an absence of in autoinflammatory diseases?

A

high titer autoantibodies or antigen specific t cells

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8
Q

MAD: absence of high titer autoantibodies/ antigen specifc T cells… ->

A

abnormally increased inflammation, mediated predominantly by cells and moleculesof innate immune system

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9
Q

MAD: inborn errors of innate immune system give…

A

significant host predisposition

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10
Q

what does CAPS stand for?

A

cryopyrin associated periodic syndrome (spectrum of disease)

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11
Q

example of a mild CAPS disease (autosomal dominant) + 3 symptoms?

A

FCAS - cold induced.
rash, arthralgia and conjuctivitis

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12
Q

example of a moderate CAPS disease (autosomal dominant) + symptoms?

A

MWS

urticarial rash
sensorineural deafness
AA amyloidosis in 25% ox -> renal failure

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13
Q

example of a severe CAPS disease (sporadic) + symptoms?

A

NOMID/CINCA

  • Progressive chronic meningitis
  • Deafness
  • Visual + intellectual damage
  • Destructive arthritis

The most severe out of the 3 CAPS

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14
Q

classical autoinflammatory diseases have flares that vary in frequency and length which has prompted them to be termed as?

A

periodic fever syndromes

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15
Q

What are NLRs?

A

Inflammasomes
intracellular receptors composed of an N-terminal effector domain

comprising of caspase recruitment domains (CARD) +pyrin domains

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16
Q

What happens when NLRs are activated by PAMPS?

A

->Multimerisation of adaptor molecule apoptosis speck-like protein (ASC)

Procaspase 1 recruited to the complex +cleaved to form caspase-1 (active form of enzyme)

Caspase 1 cleaves IL-1b +IL-18 -> active forms

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17
Q

what effect does caspase 1 have on IL 1b and IL 18?

A

cleaves them into active form

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18
Q

NLRP3 is a common inflammasome. What do they all signal to give the activated form of ?

A

caspase 1 (active form of enzyme)

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19
Q

gene mutations affect inflammasomes and can make them consecutively active. Along with what do they mediate autoinflammatory diseases?

A

IL 1 b production

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20
Q

check p133 for explanation of image

A
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21
Q

What are microbial attacks caused by?

A

PAMPs

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22
Q

What are sterile attacks caused by?

A

DAMPs

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23
Q

whats at central part of microbial and sterile attack pathways -> chronic/ acute inflammation?

A

inflammasomes

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24
Q

what is IL-1b (production and) secretion like in ox with CAPS? periodic fevers

A

same stimulus as same cells but increased.
also inc of IL8
= inflamm response, very quick

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25
Q

IL-1b secretion in whole blood preps elevated in CAPS px in response to what?

A

lipopolysaccharide (LPS)

… cytokines IL6,18 also elevated

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26
Q

what effect does IL 1b have on the brain particularly the hypothalamus? 2

*image on p137

A

induces fever and pain sensitization

27
Q

what effect does IL 1b have on the bone? induces…

A

induces bone resorption + cartilage breakdown
induces production + enhanced activation of immune cells

28
Q

IL1b induces production + enhanced activation of immune cells effect…

A

-> release of inflammatory molecules

29
Q

what effect does IL 1b have on endothelial cells?

A

induces release of IL 6 -> production + release of acute phase proteins from liver

30
Q

name 2 acute phase markers that are elevated
in CAPS?

A

c reactive protein
serum amyloid a

31
Q

how do the 2 acute phase markers associated with CAPS change…
how long does response last?

A

become 10x higher than upper limit of normal

rapid. inc then dec 24-48 hours as stimulus not there anymore.
not like having pathogen in blood

32
Q

name 3 anti IL-1b therapies

A

anakinra
rilonacept
canakinumab

33
Q

anakinra is a recombinant human IL 1 receptor antagonist that stops IL 1 binding to its receptor.
what cytokine(s) does it target?

A

IL-1a,
IL-1b

34
Q

name a drug that is regarded as an IL b trap?

A

rilonacept

35
Q

name of a humanized monoclonal anti IL B antibody?

A

canakinumab

36
Q

which si oddone out in anakinra
rilonacept
canakinumab
+ why?

A

anakinra rilonacept both act on IL-1a and IL-1b

canakinumab only acts on IL-1b

37
Q

NOD sensors are internal sensors and have similar processes to activate?

A

caspase domain (CARD)

38
Q

What do NOD sensors detect?

A

peptidoglycans internally in the cell

39
Q

What do NOD sensors stimulate? 2

A

antimicrobial peptide (AMP)
type 1 interferon production (IFNb)

(drive same process of IL1b reduction

40
Q

name one condition that mutations in NOD sensors is linked to?

A

crohns

41
Q

A20 and otulin normally blocks/controls NFKB pathway (that targets pro inflammatory genes), when there is a mutation in A20 what effect does this have on inflammation?

A

increases

42
Q

A20 and OTULIN negativelt regulates NF-kB pathway by….

A

cleaving K63 and linear Ub chains

43
Q

Decrease expression of A20 or OTULIN will lead to…

A

activation of NF-kB pathway, increased proinflammatory cytokines +systemic inflammation

44
Q

what causes inhibition of NF-kB pathway in fibroblasts and B cells -> causing immunodeficiency. in A20 and OTULIN pathway?

A

Patients who carry mutations in HOIP or HOIL-1

45
Q

why do we want molcules like A20?

A

as backup plan and control repsonse.
ELSE
get cytokines shock (because want proinflammatory cytokines but not too many)

46
Q

autoinflammatory sydromes - image p145…
normally misfolded proteins are eliminated by degredation in the?

A

endoplasmic reticulum

47
Q

UPR (unfolded protein response) works as a homeostatic response to keep cells folding capacity in balance with its needs. What are the consequences of an imbalance?

A

leads to ER stress and increase in unfolded proteins

48
Q

goal of UPR?

A

keep cells folding capacity in balance with needs and want to keep making proteins but get rid of non funcitonal and effective stuff

49
Q

many autoinflammatory diseases are autosomal dominant suggesting what?

A

gain of function

50
Q

many autoinflammatory diseases are autosomal dominant, effect on cells like islet cells, neurons that turn over slowly/ not at all?
wb in other cases?

A

can inhibit translation and lead to cell death
..
in other cases -> loss of protein and effect

51
Q

TRUE OR FALSE: misfolded proteins that accmulate extracellularly can drive IL b production?

A

true

52
Q

the 4 types of human diseases associated with ER stress/protein folding defects and UPR (p149)

A

metabolic disease
neurodegenerative disease
neoplastic disease
immune disorder

53
Q

What immune response does autoinflammation show?

A

Innate immune response

54
Q

What immune response does autoimmunity show?

A

Adaptive immune response

55
Q

what type of cells involved in
1) autoinflammn
2) autoimmunity?

A

a)macrophages
b)T and B lymphocytes

56
Q

What does autoinflammation show signalling through?

A

NOD-like receptors NLR
(and inflamamsome)

57
Q

What does autoimmunity show signalling through?

A

Toll-like receptors TLR

58
Q

what MHC class does autoinflammation associate with?

A

MHC class I associations

59
Q

what MHC class does autoimmunity associate with?

A

MHC class II associations

60
Q

time/stage of onset for
1) autoinflammn
2) autoimmunity?

A

a) early - childhood
b) late (except monogenic disease) multiple sclerosis etc later in life

61
Q

there are few autoantibodies in autoinflammation. What is the major cytokine?

A

IL-1b

62
Q

AA myloidosis high/low in
1) autoinflammn
2) autoimmunity?

A

1) high
2) low

63
Q

autoinflamm causes??

A

physical agents (cold, mechanical trauma, UV light)

64
Q

what may be considered a cause of several neurological disease?

A

the unfolded protein response

Health 31 (16 decks)

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