IID Flashcards
(33 cards)
What is an inflammasome
An intracellular multiprotein complex that detects pathogenic microorganisms and sterile stressors resulting in the release of proinflammatory cytokines (IL1b/IL-18)
Apart from inducing cytokines release, what is the other function of the inflammasome?
Mediate pyroptosis, a form of cell death that has the same upstream pathway as that of apoptosis
Pyroptosis is mediated by? (Pathway)
Mediated by inflammasome through caspase 1. Caspase 1 deficient mice does not experience defect in apoptosis and caspase 3/6/8 were shown to be not uninvolved with pyroptosis.
This process results in the release of intracellular contents
Process of inflammasome priming and activation
Priming: stressors such as DAMPs/PAMPs/LPS act on PRR which activates NFkB pathway, resulting in the transcription of pro-IL1b and inflammasome NLRP3. This also results in the deubiquitylation of The LRR domain of NLRP3, which aids the assembly of the complex.
Activation: subsequent stimulus of endogenous danger signal such as ATP, cholesterol crystals and imbalance of K+ can activate the inflammasome which attracts and cleaves pro-caspase1 into its active form. The activated caspase 1 can then cleave the pro-cytokines and release them into the extra cellular space through MV shedding, exocytosis and through caspase1-induced pores
Citation for inflammasome
Bergsbaken et al, 2009
Mutation in the inflammasome (NLRP3) results in (gain of function)
Cryopyrin associated fever syndrome characterised by periodic fever and rash
What’s the unfolded protein response (Walter and Ron,2011)
A response in the ER that regulates protein folding.
ER stress activates UPR response which induce ERAD (ER-associated protein degradation) if a misfolded protein is present
Describe the UPR response pathway
There are 3 branches in UPR.
ER stress can activate ALF6, IRE1 and PERK. Particularly IRE1 results in the transcription of XBP1 which initiates ERAD. This process involves the retrotranslocation of the misfolded protein into the ER for proteasome degradation.
Pathology associates with defected ERAD/UPR
Alzheimer’s
Beta amyloid
What happens if misfolded proteins can’t be eliminated
Accumulation of intracellular or extracellular protein aggregates
Cell death
Immune mediated damage examples
Hypersensitivity
Complement factor binding
Autoimmunity
Sepsis (SIRs)- systemic inflammatory response
5 classical signs of inflammation
Redness Heat Swelling Pain \+loss of function
Genetic risk factor forRA
PTPN22 (0.5-1%)
Increase stickiness of immune cells
Define platelets
Small biconvex, anucleated cell (1-3um) that is the second most abundant cell in the circulation
What regulates platelets
TPO secreted by liver and cMPL receptor on platelets and megakaryocyte.
CD39/73 function and action
Function to keep EC quiescence to maintain a non-adhesive surface, preventing unnecessary binding of platelets or immune cells.
both are convertases.
CD39 converts ATP (danger signal) to AMP
CD73 converts AMP to adenosine which has anti inflammatory effect on immune cell.
They are constitutively expressed on EC but can Upregulatw depending on the environment
Immune function of platelets
Platelets can take up 5-HT and mediate vasotone (5-HT is pro-constriction)
Activate NP following LPS activation (through TLR4) and induce vital Netosis
Direct killing of RBC in malaria through platelet factor 4 by binding directly onto RBC cell surface
Produce lots of IL-1b
Normal lactate concentration and in chronic inflammatory diseases
And how are they transported into cells normally? Which is the lactate receptor for T cell
1.5mM but can be up to 30 mM in chronic inflammatory diseases such as RA
Lactate transported have 2 families (MCT and SMCT) and lactate influx is dependent on the concentration gradient
On T cells, there is a SLC5A12 receptor that is a low affinity Na-lactate co transportor
Haas Et al 2015 showed that lactate can promote recruitment of leukocytes, how does this work?
For T cells, lactate can be taken up by SLC5A12 receptor which promotes entrapment of leukocytes in the tissue as inflamed tissues are hypoxic and has a lot of lactate due to T cell and other secretion (glycolysi).
The lactate taken up by T cells is converted back into acetyl coA which is then fed into the TCA cycle for energy production. The citrate produced can be used for fatty acid synthesis which can be used for IL-17 production by maintaining Pi of STAT3.
ROS generated during TCA cycle can also maintain STAT3 phosphorylation thereby contributing to the synthesis of IL17
Immunomodulatory mechanising /Moonlighting mechanism of glycolysis (more specifically GADPH)
The acetyl-coA produced from glycolysis can acetylate histones and promote gene transcription.
GADPH is an enzyme of the glycolysispathway that converts gltceraldehyde-3-phosphate to 1,3 bisphosphoaldehyde. When glycolysis is not engaged, GADPH is bound to mRNA (e.g. IFNg) which prevents ribosome from transcribing IFNg. However, when glycolysis is switched on, the affinity is higher for the substrate which releases the mRNA, allowing IFNg to be produced. This is specifically why naive T cells don’t produce IFNg unless they are activated.
Role of OPN in MS
An inflammatory mediator (not cytokine) that stimulate expression of proinflammatory mediator secretion (Th1/17) in myelin-specific T cells following binding to VLA4.
Can also induce FOXO-3a dependent apoptosis if autoreactive cells.
Yet knock et al 1992 study in MS
Showed that blockade of a4 and B1 integrin prevented leukocyte migration into the inflamed brain in an EAE model (but not other intergrin). Suggesting that leukocyte infiltration is primarily mediated by VCAM-1 and these integrins. Led to the development of Natalizab (VLA4 blockade mAb)
Natalizumab efficacy and S/E
DecreaSe RRMS by 68%
Reduced MRI lesions by 92%
Rare S/E of leukoenchalopathy initiated by John Cunningham virus. Fatal and shows the importance of normal surveillance of WBC in brain to prevent opportunistic infections
Does the Brain have adaptive immune system?
No
