Autoinflammation Flashcards
The boundaries of X are set by mutations associated with cells + molecules involved in Adaptive Immune Responses?
autoimmunity
The boundaries of X are defined by mutations in cells/ molecules involved in Innate Immunity at disease prone sites?
autoinflammation
3 examples of rare monogenic autoinflammatory diseases
FMF
TRAPS
HIDS
rare monogenic autoimmune disease examples (not covered)….
when single gene affected- can tell us part of immune response
ALPS
IPEX
difference between studying monogenic disease and polygenic disease?
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
name for a group of disorders that are characterized by seemingly unprovoked attacks of inflammation?
myogenic autoinflammatory diseases
what 2 things are there an absence of in autoinflammatory diseases?
high titer autoantibodies or antigen specific t cells
MAD: absence of high titer autoantibodies/ antigen specifc T cells… ->
abnormally increased inflammation, mediated predominantly by cells and moleculesof innate immune system
MAD: inborn errors of innate immune system give…
significant host predisposition
what does CAPS stand for?
cryopyrin associated periodic syndrome (spectrum of disease)
example of a mild CAPS disease (autosomal dominant) + 3 symptoms?
FCAS - cold induced.
rash, arthralgia and conjuctivitis
example of a moderate CAPS disease (autosomal dominant) + symptoms?
MWS
urticarial rash
sensorineural deafness
AA amyloidosis in 25% ox -> renal failure
example of a severe CAPS disease (sporadic) + symptoms?
NOMID/CINCA
- Progressive chronic meningitis
- Deafness
- Visual + intellectual damage
- Destructive arthritis
The most severe out of the 3 CAPS
classical autoinflammatory diseases have flares that vary in frequency and length which has prompted them to be termed as?
periodic fever syndromes
What are NLRs?
Inflammasomes
intracellular receptors composed of an N-terminal effector domain
comprising of caspase recruitment domains (CARD) +pyrin domains
What happens when NLRs are activated by PAMPS?
->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
what effect does caspase 1 have on IL 1b and IL 18?
cleaves them into active form
NLRP3 is a common inflammasome. What do they all signal to give the activated form of ?
caspase 1 (active form of enzyme)
gene mutations affect inflammasomes and can make them consecutively active. Along with what do they mediate autoinflammatory diseases?
IL 1 b production
check p133 for explanation of image
What are microbial attacks caused by?
PAMPs
What are sterile attacks caused by?
DAMPs
whats at central part of microbial and sterile attack pathways -> chronic/ acute inflammation?
inflammasomes
what is IL-1b (production and) secretion like in ox with CAPS? periodic fevers
same stimulus as same cells but increased.
also inc of IL8
= inflamm response, very quick
IL-1b secretion in whole blood preps elevated in CAPS px in response to what?
lipopolysaccharide (LPS)
… cytokines IL6,18 also elevated
what effect does IL 1b have on the brain particularly the hypothalamus? 2
*image on p137
induces fever and pain sensitization
what effect does IL 1b have on the bone? induces…
induces bone resorption + cartilage breakdown
induces production + enhanced activation of immune cells
IL1b induces production + enhanced activation of immune cells effect…
-> release of inflammatory molecules
what effect does IL 1b have on endothelial cells?
induces release of IL 6 -> production + release of acute phase proteins from liver
name 2 acute phase markers that are elevated
in CAPS?
c reactive protein
serum amyloid a
how do the 2 acute phase markers associated with CAPS change…
how long does response last?
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
name 3 anti IL-1b therapies
anakinra
rilonacept
canakinumab
anakinra is a recombinant human IL 1 receptor antagonist that stops IL 1 binding to its receptor.
what cytokine(s) does it target?
IL-1a,
IL-1b
name a drug that is regarded as an IL b trap?
rilonacept
name of a humanized monoclonal anti IL B antibody?
canakinumab
which si oddone out in anakinra
rilonacept
canakinumab
+ why?
anakinra rilonacept both act on IL-1a and IL-1b
canakinumab only acts on IL-1b
NOD sensors are internal sensors and have similar processes to activate?
caspase domain (CARD)
What do NOD sensors detect?
peptidoglycans internally in the cell
What do NOD sensors stimulate? 2
antimicrobial peptide (AMP)
type 1 interferon production (IFNb)
(drive same process of IL1b reduction
name one condition that mutations in NOD sensors is linked to?
crohns
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?
increases
A20 and OTULIN negativelt regulates NF-kB pathway by….
cleaving K63 and linear Ub chains
Decrease expression of A20 or OTULIN will lead to…
activation of NF-kB pathway, increased proinflammatory cytokines +systemic inflammation
what causes inhibition of NF-kB pathway in fibroblasts and B cells -> causing immunodeficiency. in A20 and OTULIN pathway?
Patients who carry mutations in HOIP or HOIL-1
why do we want molcules like A20?
as backup plan and control repsonse.
ELSE
get cytokines shock (because want proinflammatory cytokines but not too many)
autoinflammatory sydromes - image p145…
normally misfolded proteins are eliminated by degredation in the?
endoplasmic reticulum
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?
leads to ER stress and increase in unfolded proteins
goal of UPR?
keep cells folding capacity in balance with needs and want to keep making proteins but get rid of non funcitonal and effective stuff
many autoinflammatory diseases are autosomal dominant suggesting what?
gain of function
many autoinflammatory diseases are autosomal dominant, effect on cells like islet cells, neurons that turn over slowly/ not at all?
wb in other cases?
can inhibit translation and lead to cell death
..
in other cases -> loss of protein and effect
TRUE OR FALSE: misfolded proteins that accmulate extracellularly can drive IL b production?
true
the 4 types of human diseases associated with ER stress/protein folding defects and UPR (p149)
metabolic disease
neurodegenerative disease
neoplastic disease
immune disorder
What immune response does autoinflammation show?
Innate immune response
What immune response does autoimmunity show?
Adaptive immune response
what type of cells involved in
1) autoinflammn
2) autoimmunity?
a)macrophages
b)T and B lymphocytes
What does autoinflammation show signalling through?
NOD-like receptors NLR
(and inflamamsome)
What does autoimmunity show signalling through?
Toll-like receptors TLR
what MHC class does autoinflammation associate with?
MHC class I associations
what MHC class does autoimmunity associate with?
MHC class II associations
time/stage of onset for
1) autoinflammn
2) autoimmunity?
a) early - childhood
b) late (except monogenic disease) multiple sclerosis etc later in life
there are few autoantibodies in autoinflammation. What is the major cytokine?
IL-1b
AA myloidosis high/low in
1) autoinflammn
2) autoimmunity?
1) high
2) low
autoinflamm causes??
physical agents (cold, mechanical trauma, UV light)
what may be considered a cause of several neurological disease?
the unfolded protein response
