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
