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Module 3 > Atherosclerosis as an autoinflammatory condition > Flashcards

Atherosclerosis as an autoinflammatory condition Flashcards

1
Q

What suggests that atherosclerosis is not a new condition?

A

CTs of ancient egyptian mummies have shown atherosclerosis

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2
Q

What is the literal translation of atherosclerosis?

A

hardening of the arteries

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3
Q

What sort of debris result in reversbile fatty lesions?

A

modified lipoproteins; apoptotic cells

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4
Q

What are the inflammatory drivers in atherosclerosis?

A

lipoprotein deposition and oxidation; mechanical stress; angiogenesis with micro-haemorrhage; thrombosis

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5
Q

What carries cholesterol in the blood?

A

LDL particles- cholesterol surrounded by apoprotein B

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6
Q

Where do LDLs deposit?

A

under the endothelial lining of arteries and bind to matrix proteoglycans

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7
Q

What happens to trapped LDL partlces?

A

oxidized by ROS then phagocytosed by macrophages

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8
Q

What increases the ROS in the blood and therefore oxidised LDL?

A

smoking; HT

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9
Q

What receptor do macrophages use to take up ox-LDL?

A

scavenger receptors

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10
Q

What happens to macropahges that take up ox-LDL?

A

develop cholesterol ester cytoplasmic droplets and become foam cells

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11
Q

How is LDL physiologically removed?

A

via LDL receptor

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12
Q

What is the difference between LDL and scavenger uptake of LDL?

A

uptake via LDLR is controlled via receptor downregulation, whilst scavenger recetpors take up ox-LDL and is not regulated- foamy cells

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13
Q

What happens to cholesterol-laden macrophges?

A

die by apoptosis or necrosis and release proinflammatory cytokines

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14
Q

What factors do foam cells release?

A

free radicals; proteases; VSMC growth factors; angiogenic factors; apoptosis

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15
Q

What is the effect of arterial blood flow on endothelial cells?

A

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

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16
Q

What pro-inflammatory pathways does ox-LDL stimulate?

A

AP-1 and NFkB

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17
Q

Give an example of how the proinflammatory pathways be modulated in atherosclerosis?

A

activation of Nrf2 which inhibits the AP-1 pathway by sulforaphane suppresses the pro-inflammatory activation in the aorta

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18
Q

Why is ox-LDL antigenic?

A

when modified reveals neoepitopes e.g phosphorylcholine that then bind to macropahges

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19
Q

Why does interrupted blood have such an effect on endothelial cells?

A

protection from injury- if injured, risk of infection, need proinflammatory environment to protect

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20
Q

What indicates that natural antibodies are important in clearing debris?

A

IgM deficiecy accelerates atherosclerosis

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21
Q

What cells secrete natural antibodies?

A

B1 cells- germline encoded

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22
Q

How does IgM activate macrophages?

A

via scavenger receptor A pathway

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23
Q

How does IgG activate macropahges?

A

FcyR ligation

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24
Q

How can IgG binding be used clinically?

A

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

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25
Q

What is LO1?

A

an IgG anti-oxidised LDL autoantibody

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26
Q

What is the effect of IgM and IgG against LDL in CVS risk?

A

negatively associated with CV events

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27
Q

What is the role of C1q in athoersclerosis?

A

deficiency accelerates atherosclerosis- impaired apoptotic cell clearance

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28
Q

What is the role of MBL in atherosclerosis?

A

deficiency accelerates

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29
Q

What is the role of DAF and CD59 in atherosclerosis?

A

inhibits atherosclerosis

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30
Q

What is the function of C5 and C6 in atherosclerosis?

A

makes worse- reduced lesions with anti-C5a and in c6 deficient rabbits

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31
Q

How does endotoxin accelerate atherosclerosis?

A

activating the alternative complement pathway

32
Q

What is the effect of transferring T cells from mice given LDL?

A

induces increased plaques

33
Q

What is the effect of amygdala (stress) on atheroslcerosis?

A

results in increased proinflammatory monocyte release frmo the bone marrow and activation of sympathetics- increased inflam and HT–CVS events

34
Q

Why is the burden of CVS disease likely to rise despite widespread use of statins to reduce cholesterol?

A

persistence of RFs e.g smoking and sedentary lifestyle; increasing obesity, metabolic syndrome and diabetes

35
Q

What are DAMPs?

A

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

36
Q

What is most of the research in atherosclerosis based upon?

A

LDLr deficient or apoE deficient mice in which atherosclerotic lesions develop as high plasma cholesterol levels can be sustained

37
Q

Why has the innate immune system evolved mechanisms to mediate removle of oxidatively modifed molecules; cells and debris?

A

proinflammatory and immunogenic

38
Q

What is the mechanism by which recognition of oxidation damaged molecules occurs?

A

detection of oxidation-specific epitopes which constitute common motifs of oxidative damage

39
Q

When are oxidative-specific epitopes formed?

A

when LDL is oxidised or when cells undergo apoptosis or death

40
Q

What OSEs do scavenger receptors recognise?

A

oxidised phospholipids (CD36) and malondialdehyde (MDA)-modifed structures SR-A

41
Q

What OSEs do IgM natural antibody and CRP recognise?

A

oxidised phospholipids

42
Q

What initially suggested that immune mechanisms were invovled in atherosclerosis?

A

activated T cells and HLA-II expression was detected in atherosclerotic plaques; vascular cells can produce and respond to cytokines

43
Q

What are atherosclerotic lesions?

A

asymmetric focal thickenings of htei nnermost layer of the artery, the intima

44
Q

What are fatty streaks?

A

sites of accumulation of lipid droplets and immune cells - foam cells especially

45
Q

What is found in the atheroma?

A

centre is foam cells, dead cells and extracellular lipid droplets surroudned by a capt of SM cells and colalgen-rich matrix

46
Q

What is the difference between the ApoE KO and LDL KO models of atherosclerosis?

A

ApoE KO develops sontaneous atherosclerosis whilst LDLR KO reponds to fat feeding by hypercholesterolaemia and lesion devleopment

47
Q

What is the initiating step in atherosclerosis?

A

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

48
Q

What happens when the lipids are trapped in the ECM?

A

LDLs are modified which releases bioactive phospholipids that activate endothelial cells

49
Q

What is the result of endothelial activation in the inital stage of atherosclerosis?

A

express leukocyte adhesion molecules which monocytes, platelts and lymphocytes adhere to

50
Q

What ahppens when platelet adhesion in inhibited in hypercholesterolaemic mice?

A

reduces leukocyte infiltration and atherosclerosis

51
Q

Where does endotehlial activation occur preferentially?

A

sites of haemodynamic strain- increases adhesion mocluesl and inflammatory genes

52
Q

Give an examples of a chemokine involved in atherosclerosis that causes leukocytes to migrate into the underlying intima?

A

MCP-1 atttracts leukocytes bearing CCR2 (monocytes, T and B cells )

53
Q

What happens when MCP-1 or CCR2 are gene targeted?

A

disease development is ingivited

54
Q

What cytokine/growth factor is produced in inflamed intima?

A

M-CSF

55
Q

What is the result of M-CSF production in the intima?

A

induces entering monocytes to differentiate into macrophages and upregulation of PRRs

56
Q

What happens when cholesterol derived from uptake of oxLDL cannot be mobilised from the cell?

A

it accumulates as cytosolic droplets

57
Q

What is the role of inflammation in foam cell production?

A

pro-inflam cytokines and endotoxins inhibit expression of transporters which export cholesterol from the cell

58
Q

What suggests that atherosclerosis depends on TLR activation?

A

many cells in human atherosclerotic lesions have activated NFkB; deletion of TLR4 or MyD88 inhibits atherosclerosis in apoE deficient mice

59
Q

What is the function of AGEs, which are increased in diabetics in atherosclerosis?

A

trigger NFkB actiation, vascular inflammation and increases atherosclerosis in hypercholeserolamic mice

60
Q

What is the result of macrophage activation in atherosclerosis?

A

release of vasoactive molecules and ROS; proteolytic enzymes which can destabilise plaques

61
Q

What type of T cells dominate in atherosclerosis?

A

CD4

62
Q

What indicates that T and B cells play a signifcant role in atherosclerosis?

A

immunodeficient (SCID) apoE mice devleop much smaller lesions, with transfer of T cells from immunocompetent apoE deficient mice to immunodeficient mice restoring lesion development

63
Q

What is the result of anti-CD40L antibodies?

A

reduction and stabilisation of lesions- however there are thrombotic complications because platelts depend on CD40L expression

64
Q

What suggests that phospholipid e.g phosphocholine antibodes are atheroprotective?

A

vaccination with S.pneucmonia which express phospholipids similar to human, reduces athersoclerosis in apoE mice

65
Q

What type of Th cells predominate in atherosclerosis?

A

Th1- increased IFNy and Th stimulating cytokines IL-12 and IL-18

66
Q

What happens to mice deficient in Tbet?

A

significant reduction in atherosclerosis in hypercholesterolaemic mice

67
Q

Why is IFNy pro-atherogenic?

A

promotes macrophage and endothelial acivation with production of adhesion molecules; cytokines; chemokines; radical; proteases

68
Q

What are hte most important SRs for ox-LDL and acetylated LDL?

A

CD36 and SR-A

69
Q

What indicates that IgM NAbs are atherprotective?

A

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

70
Q

What confirms that OSEs are a major target of innate immunity?

A

20-30% of all IgM in plasma of mice and in newborn human cord blood bind to OSEs

71
Q

Why do DCs act as efficient sentiensl of PAMPs and DAMPs?

A

rich repertoire of PRRs; long dendrite-like cytoplasmic processes and robust phagocytic and endocytic activity

72
Q

What specific serum biomarkers of adaptive humoral immune reponses correlate with atherosclerotic disease?

A

levels of antibodies specific for certain heat-shock proteins and oxLDL

73
Q

How has immune tolerance induction been trialled in atherosclerosis?

A

subcut and oral/nasal immunisations reductin atherosclerosis include HSP65 and apoB 100–increased Tregs

74
Q

How has adoptive cell transfer been used in atherosclerosis?

A

trasfer of IL-10 treated Apo-B-100 loaded DCs into ApoE deficient mice reduced atherosclerosis

75
Q

How could the tolerance induction protocols in atherosclerosis be improved?

A

more data about the actual antigen specificity of proatherogenic effector T cells nad antibodies to refine and optimise the tolernace induction

76
Q

what current trials are being done into the use of anti-inflammatory drugs to reduce CVS events?

A

anti-IL-1b antibody therapy and methotrexate- treatment in RA reduces CVD risk

77
Q

Why would anti-IL-1b be useful?

A

made in atherosclerotic lesions; cholesterol crystals activate the inflammasome which leads to IL-1b secretion

Module 3 (33 decks)

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