Atherosclerosis as an autoinflammatory condition Flashcards
What suggests that atherosclerosis is not a new condition?
CTs of ancient egyptian mummies have shown atherosclerosis
What is the literal translation of atherosclerosis?
hardening of the arteries
What sort of debris result in reversbile fatty lesions?
modified lipoproteins; apoptotic cells
What are the inflammatory drivers in atherosclerosis?
lipoprotein deposition and oxidation; mechanical stress; angiogenesis with micro-haemorrhage; thrombosis
What carries cholesterol in the blood?
LDL particles- cholesterol surrounded by apoprotein B
Where do LDLs deposit?
under the endothelial lining of arteries and bind to matrix proteoglycans
What happens to trapped LDL partlces?
oxidized by ROS then phagocytosed by macrophages
What increases the ROS in the blood and therefore oxidised LDL?
smoking; HT
What receptor do macrophages use to take up ox-LDL?
scavenger receptors
What happens to macropahges that take up ox-LDL?
develop cholesterol ester cytoplasmic droplets and become foam cells
How is LDL physiologically removed?
via LDL receptor
What is the difference between LDL and scavenger uptake of LDL?
uptake via LDLR is controlled via receptor downregulation, whilst scavenger recetpors take up ox-LDL and is not regulated- foamy cells
What happens to cholesterol-laden macrophges?
die by apoptosis or necrosis and release proinflammatory cytokines
What factors do foam cells release?
free radicals; proteases; VSMC growth factors; angiogenic factors; apoptosis
What is the effect of arterial blood flow on endothelial cells?
via biochemical signalling has a dramatic effect on gene expression- laminar shear stress turns OFF genes that promote inflam and atherosclerosis (adhesion moecules); turns ON anti-oxidant and anti-cell death genes
What pro-inflammatory pathways does ox-LDL stimulate?
AP-1 and NFkB
Give an example of how the proinflammatory pathways be modulated in atherosclerosis?
activation of Nrf2 which inhibits the AP-1 pathway by sulforaphane suppresses the pro-inflammatory activation in the aorta
Why is ox-LDL antigenic?
when modified reveals neoepitopes e.g phosphorylcholine that then bind to macropahges
Why does interrupted blood have such an effect on endothelial cells?
protection from injury- if injured, risk of infection, need proinflammatory environment to protect
What indicates that natural antibodies are important in clearing debris?
IgM deficiecy accelerates atherosclerosis
What cells secrete natural antibodies?
B1 cells- germline encoded
How does IgM activate macrophages?
via scavenger receptor A pathway
How does IgG activate macropahges?
FcyR ligation
How can IgG binding be used clinically?
use IgG tagged with near infra red immunofluorensce- LO1 to stain for atherosclerotic plaques, as it binds to heavily oxidised LDL- being developed for in vivo use
What is LO1?
an IgG anti-oxidised LDL autoantibody
What is the effect of IgM and IgG against LDL in CVS risk?
negatively associated with CV events
What is the role of C1q in athoersclerosis?
deficiency accelerates atherosclerosis- impaired apoptotic cell clearance
What is the role of MBL in atherosclerosis?
deficiency accelerates
What is the role of DAF and CD59 in atherosclerosis?
inhibits atherosclerosis
What is the function of C5 and C6 in atherosclerosis?
makes worse- reduced lesions with anti-C5a and in c6 deficient rabbits
How does endotoxin accelerate atherosclerosis?
activating the alternative complement pathway
What is the effect of transferring T cells from mice given LDL?
induces increased plaques
What is the effect of amygdala (stress) on atheroslcerosis?
results in increased proinflammatory monocyte release frmo the bone marrow and activation of sympathetics- increased inflam and HT–CVS events
Why is the burden of CVS disease likely to rise despite widespread use of statins to reduce cholesterol?
persistence of RFs e.g smoking and sedentary lifestyle; increasing obesity, metabolic syndrome and diabetes
What are DAMPs?
molecules normally sequesterd in cells and released in injury e.g heat shock prteins of high-mobility group protein 1 or newly generated altered molcuels e.g formation of AGEs
What is most of the research in atherosclerosis based upon?
LDLr deficient or apoE deficient mice in which atherosclerotic lesions develop as high plasma cholesterol levels can be sustained
Why has the innate immune system evolved mechanisms to mediate removle of oxidatively modifed molecules; cells and debris?
proinflammatory and immunogenic
What is the mechanism by which recognition of oxidation damaged molecules occurs?
detection of oxidation-specific epitopes which constitute common motifs of oxidative damage
When are oxidative-specific epitopes formed?
when LDL is oxidised or when cells undergo apoptosis or death
What OSEs do scavenger receptors recognise?
oxidised phospholipids (CD36) and malondialdehyde (MDA)-modifed structures SR-A
What OSEs do IgM natural antibody and CRP recognise?
oxidised phospholipids
What initially suggested that immune mechanisms were invovled in atherosclerosis?
activated T cells and HLA-II expression was detected in atherosclerotic plaques; vascular cells can produce and respond to cytokines
What are atherosclerotic lesions?
asymmetric focal thickenings of htei nnermost layer of the artery, the intima
What are fatty streaks?
sites of accumulation of lipid droplets and immune cells - foam cells especially
What is found in the atheroma?
centre is foam cells, dead cells and extracellular lipid droplets surroudned by a capt of SM cells and colalgen-rich matrix
What is the difference between the ApoE KO and LDL KO models of atherosclerosis?
ApoE KO develops sontaneous atherosclerosis whilst LDLR KO reponds to fat feeding by hypercholesterolaemia and lesion devleopment
What is the initiating step in atherosclerosis?
when plasma levels of VLDL and LDL rise, the lipoproteins infilitrate the artery wall that once exceeds capacity for elimiation become retained in the ECM
What happens when the lipids are trapped in the ECM?
LDLs are modified which releases bioactive phospholipids that activate endothelial cells
What is the result of endothelial activation in the inital stage of atherosclerosis?
express leukocyte adhesion molecules which monocytes, platelts and lymphocytes adhere to
What ahppens when platelet adhesion in inhibited in hypercholesterolaemic mice?
reduces leukocyte infiltration and atherosclerosis
Where does endotehlial activation occur preferentially?
sites of haemodynamic strain- increases adhesion mocluesl and inflammatory genes
Give an examples of a chemokine involved in atherosclerosis that causes leukocytes to migrate into the underlying intima?
MCP-1 atttracts leukocytes bearing CCR2 (monocytes, T and B cells )
What happens when MCP-1 or CCR2 are gene targeted?
disease development is ingivited
What cytokine/growth factor is produced in inflamed intima?
M-CSF
What is the result of M-CSF production in the intima?
induces entering monocytes to differentiate into macrophages and upregulation of PRRs
What happens when cholesterol derived from uptake of oxLDL cannot be mobilised from the cell?
it accumulates as cytosolic droplets
What is the role of inflammation in foam cell production?
pro-inflam cytokines and endotoxins inhibit expression of transporters which export cholesterol from the cell
What suggests that atherosclerosis depends on TLR activation?
many cells in human atherosclerotic lesions have activated NFkB; deletion of TLR4 or MyD88 inhibits atherosclerosis in apoE deficient mice
What is the function of AGEs, which are increased in diabetics in atherosclerosis?
trigger NFkB actiation, vascular inflammation and increases atherosclerosis in hypercholeserolamic mice
What is the result of macrophage activation in atherosclerosis?
release of vasoactive molecules and ROS; proteolytic enzymes which can destabilise plaques
What type of T cells dominate in atherosclerosis?
CD4
What indicates that T and B cells play a signifcant role in atherosclerosis?
immunodeficient (SCID) apoE mice devleop much smaller lesions, with transfer of T cells from immunocompetent apoE deficient mice to immunodeficient mice restoring lesion development
What is the result of anti-CD40L antibodies?
reduction and stabilisation of lesions- however there are thrombotic complications because platelts depend on CD40L expression
What suggests that phospholipid e.g phosphocholine antibodes are atheroprotective?
vaccination with S.pneucmonia which express phospholipids similar to human, reduces athersoclerosis in apoE mice
What type of Th cells predominate in atherosclerosis?
Th1- increased IFNy and Th stimulating cytokines IL-12 and IL-18
What happens to mice deficient in Tbet?
significant reduction in atherosclerosis in hypercholesterolaemic mice
Why is IFNy pro-atherogenic?
promotes macrophage and endothelial acivation with production of adhesion molecules; cytokines; chemokines; radical; proteases
What are hte most important SRs for ox-LDL and acetylated LDL?
CD36 and SR-A
What indicates that IgM NAbs are atherprotective?
deficient mice develop significantly greater atherosclerosis than controls; splenectomy enhances atheroscleorisis is atheroprotective; titres of ox-LDL-specific IgM titers are inversely assocaited with CVD
What confirms that OSEs are a major target of innate immunity?
20-30% of all IgM in plasma of mice and in newborn human cord blood bind to OSEs
Why do DCs act as efficient sentiensl of PAMPs and DAMPs?
rich repertoire of PRRs; long dendrite-like cytoplasmic processes and robust phagocytic and endocytic activity
What specific serum biomarkers of adaptive humoral immune reponses correlate with atherosclerotic disease?
levels of antibodies specific for certain heat-shock proteins and oxLDL
How has immune tolerance induction been trialled in atherosclerosis?
subcut and oral/nasal immunisations reductin atherosclerosis include HSP65 and apoB 100–increased Tregs
How has adoptive cell transfer been used in atherosclerosis?
trasfer of IL-10 treated Apo-B-100 loaded DCs into ApoE deficient mice reduced atherosclerosis
How could the tolerance induction protocols in atherosclerosis be improved?
more data about the actual antigen specificity of proatherogenic effector T cells nad antibodies to refine and optimise the tolernace induction
what current trials are being done into the use of anti-inflammatory drugs to reduce CVS events?
anti-IL-1b antibody therapy and methotrexate- treatment in RA reduces CVD risk
Why would anti-IL-1b be useful?
made in atherosclerotic lesions; cholesterol crystals activate the inflammasome which leads to IL-1b secretion
