Mar29 M3-Immunology Cardiovascular Flashcards
important process other than lipids that contributes to ats
chronic infection and inflammation
chronic inflammation links what 3 CV conditions
- ats
- acute coronary syndromes
- metabolic syndrome (htn, diabetes, dyslipidemia, obesity)
different types of inflammation
- acute (injury)
- chronic (systemic disease)
- auto-inflammation (diff from auto-immunity) = periodic fever syndromes
autoinflammmation def
- defects and-or abnormal activation of the INNATE immunity
- (auto-immunity involves T, B cells, Abs and loss of tolerance, NOT AUTO-INFLAMMATORY conditions)
important molecules in innate immunity also found on all kinds of cells
TLRs (a type of PRR), type 1 integral membrane glycoprotein with leucine rich EC domains (LRRs) motifs and a cytoplasmic domain homologous to IL-1R called toll or IL-1R or TIR domain
TLRs found on what cells
APCs, granulocytes, B, T, NK cells, platelets, epith cells, adipocytes, fibroblasts so role in immunity as well as NON immune role (metabolism)
key PRR families
TLR 1,2,6 = recognize lipoproteins TLR 4 = recognize LPS TLR 5 = flagellin *these are on cell surface** (some are inside the cell and recognize nucleic acids)
TLR found in ats plaques
TLR-4 = the one that recognizes LPS
important IC protein downstream of TLRs when they’re activated
NF kappa B, essential in infection and ats
what NF kappa B does in cells with TLRs
cleaves pro-IL1b and pro-IL18 to IL-1b and IL-18, very potent inflammatory cytokines
other way to cleave pro-IL1b and pro-IL18 to IL-1b and IL-18 in cells with TLRs
- NOD-like receptors called the inflammasome **most important one is called NALP3 (or NLPR3) **
- macromolecular enzyme complex that cleaves pro-IL1b and pro-IL18 to IL-1b and IL-18
effect of IL1b in the body
- induces fever
- makes endothelial cells make IL-6. IL-6 leads to release of acute phase proteins by the liver
- CRP release by liver (through IL-6 from endoth effect)
CRP is marker for what other than infection and inflammation
-ATS and CVD
exogenous PAMPs associated with ats
CMV, H pylori and HSP60 in chlamydia pneumonia
endogenous PAMPs associated with ats
- glucose
- cholesterol
- uric acid
(important) PRRs involvement in ats
- in ats, monocytes get in intimal layer of coronary arteries
- become lipid laden (loaded) macrophages called FOAM cells
- cholesterol cristals get in them via scavenger Rs called CD36
- oxidized LDL also gets in
- NF kappa beta and inflammasome triggered (by the cristals) and prod of IL-1b and IL-18
- these cytokines involved in plaque destabilization
IL-1b role in the pancreas (how does it cause diabetic pts to get worse due to chronic low grade inflammation)
- beta cell receptors for FFA, LPS, LPS and glucose lead to IL-1b prod when activated
- IL 1b producing beta cells die
- IL 1b increases sugar as a consequence of that (bc you now have less insulin producing cells)
structure of the NLPR3 protein (part of the inflammasome) + other prot that’s part of the inflammasome
- NLPR3 = NBD (central), leucine rich repeat (LRR) (C-term), pyrin domain (N terminus)
- when activated = conformational change releasing it from auto-inhibited state
- (ASC prot also in inflammasome)
substance that activates the inflammasome (to prod IL-1b) in ats
cholesterol crystals
consequence of inflammasome knockout in mice (NLRP3 or ASC)
no production of IL-1b
when cholesterol crystals appear in ats lesions
in early ats lesions
cause of ats mediated thrombosis
- growth of SM cells in intima + infiltration by macrophages and foam cells
- MI and angina = plaque ruptures
- no blood = infarction
- key to prevent plaques and stabilize them*
(EXAM) plaque activation and rupture is linked to what immune system component
TH1 (T helper cells 1) and their cytokines, especially IFN gamma
(EXAM) important substance contributing to plaque stability
collagen (in fibrous cap of the plaque).
produced by SM cells
(EXAM) what IFN-g from th1 does
- induces CD40L, boosting the prod of proteases that degrade collagen and weaken the fibrous cap
- inhibits prolif of SM, affecting collagen synthesis
- CD40L and CD40 interaction: tissue factor triggering the coagulation cascade and thrombus formation
(EXAM) important cells in the ats plaque
- T cell
- foamy macrophages
- SM migrating to upper layer. will produce collagen that stabilizes the plaque for a long time
(EXAM) consequence of CD40-CD40L T cell-macrophage interaction
- release of IFN gamma
- release of procoagulants, metalloproteinases, collagenases that destabilize the plaque
2 antigens that are the reason why T cells migrate in the ats plaque
- oxidized LDL
- B2 glycoprotein 1
why macrophages and foam cells stay in the intima in ats
netrin 1, a neuronal cue molecule in the brain, also in ats plaque and keeps them there
(important) why statins prevent CV death mainly
- induce Foxp3 expression on naive CD4+ T cells to make functional FoxP3+ CD4+ T reg cells
- T reg cells have an important role in stabilizing the ats plaque
- (+ role in getting macrophages out of ats plaque via CCR7-dependent macrophage emigration pathway)
other roles of statins on immune system + important one in CVS
- role in getting macrophages out of plaque via CCR7-dependent macrophage emigration pathway
- reduces LDL, higher HDL
- interfere with MHC 2 Ag presentation
- inhibit T cell prolif
- impair Th1 diff
- affect leukocyte motility
- etc
how statins affect plaque size
- DOESN’T change
- LDL out but replaced with collagen = good because stabilizes the plaque
T reg cells 2 sides to what they can do in ats
- can help by suppressing T cells
- can lose foxp3 and transform into T follicular helper cells that promote ats
important co-stimulatory molecules in the immune system
CD28 on T cell and B7 on APCs (B cells, macrophages) interaction
immune senescence def
- with age and with recurrent inflammation like with viruses, the expression of CD28 on T cells is downregulated
- proportion of lymphocytes expressing CD28 goes down
in what patients do you find CD4+CD28null cells
- chronic inflammation pts
- *accelerated ats is noted in pts with autoimmune diseases, post-transplant, metabolic syndrome, chronic and latent infections
one cytokine for CD4 and CD8 cells that is important for plaque stability and that makes the difference between stable angina and unstable angina
- IFN gamma**
- more IFN gamma in unstable angina
why having more CD28- T cells contributes to ats and plaque rupture
- release IFN gamma
- macrophages receive it
- release MMPs that destabilize the plaque
2 diseases where CV event chances are higher
- diabetes
- rheumatoid arthritis
- almost equal chances of CV event*
immune related therapeutic opportunities to treat ats in the future
- vaccinate for oxidized LDL
- vaccinate for chronic latent viruses like CMV
- block lymphocyte-macrophages interaction with novel Abs
protein found to help measure CV risk
CRP (better than lipids)
effect of canakinumab (IL-1b Ab) on CV risk and lipids
- CV risk reduced by 50%
- CRP reduced
- LDL, HDL, TG unchanged
- but fatal complications because much more infectious diseases*
