 | | Immune competent cells and atherosclerotic lesion development |
|  | | Talk goals Refresh memory, provide immunology tools Immune cell types in the plaque Immune-activating compounds Monocyte functional commitment in blood Macrophage subsets Novel innate antigen receptors |
|
 | | Cholesterol X Inflammation = CVD |
|  | | Slide 4 |
|
 | | Inducers Sensors Mediators Effectors Sepsis LPS TLR4 TNF-a, IL-6, PGE2 endoth hepato hypoth leukoc |
|  | | Slide 6 |
|
 | | Chlamydia pneumoniae? Peptidoglycan debris? Pathogen burden? |
|  | | Self-lipids drive foam cell formation |
|
 | | Y |
|  | | B-lymphocyte |
|
 | | Figure 2-10 |
|  | | Figure 2-10 |
|
 | | Slide 13 |
|  | | Immune balance – revised view |
|
 | | IL-17 |
|  | | Criss-cross activation in antigen presentation |
|
 | | Criss-cross activation in antigen presentation |
|  | | Innate vs. adaptive immunity - 1 |
|
 | | Innate vs. adaptive immunity - 2 |
|  | | Know your compartment … |
|
 | | Spleen and lymph nodes critical compartments for immunity singles bar match T-cell with MHC-peptide speed dating T-cells sniffing APC for match |
|  | | Slide 22 |
|
 | | Atherosclerosis - steps |
|  | | Sanz Science 451:953 (2008) |
|
 | | Slide 25 |
|  | | Heterogeneity of mouse peripheral blood monocytes |
|
 | | Heterogeneity of mouse peripheral blood monocytes |
|  | | Slide 28 |
|
 | | All leukocyte subsets get in numbers – function |
|  | | Slide 30 |
|
 | | Weber C et al., 8:802 (2008) |
|  | | Slide 32 |
|
 | | Slide 33 |
|  | | Slide 34 |
|
 | | M and DC in advanced plaque |
|  | | Slide 36 |
|
 | | Macrophages – foam cells critical in three domains of atherosclerosis |
|  | | Slide 38 |
|
 | | J Immunol 175:342 (2005) |
|  | | Slide 40 |
|
 | | Pro- versus Anti-inflammatory Acute versus chronic inflammation ‘Deactivation’ |
|  | | Zelcer et al, JCI 2006 |
|
 | | Slide 43 |
|  | | Slide 44 |
|
 | | Slide 45 |
|  | | Slide 46 |
|
 | | Issues discussed Maturation of monocytes in blood Tissue compartments Plaque composition Functional macrophage subsets in situ: inflammation vs beneficial New receptors for self and for pathogen explain mechanisms |
|  | | Scavenger receptor family |
|
 | | Slide 49 |
|  | | SELF |
|
 | | Science 320:674, 2008 |
|  | | Nature, May 21st 2008 |
|
 | | Processing of IL-1beta through the NALP3 inflammasome |
|  | | Benko et al., 2008 |
|
 | | Toll-like receptor (TLR) family |
|  | | Slide 56 |
|
 | | Monitor outside world Monitor intracellularly: infection, phagocytosis, budding |
|  | | Peptidoglycan provides rigor to all bacteria |
|
 | | Slide 59 |
|  | | Slide 60 |
|
 | | peptidoglycan or other persisting compound |
|  | | peptidoglycan |
|
 | | RLR (RIG-I like) receptor family RNA helicases |
|  | | Slide 64 |
|
 | | Slide 65 |
|  | | Slide 66 |
|
 | | TLR MHC-II |
|  | | Hepatitis C virus NS3-4A cleaves in both pathways |
|
 | | Issues discussed Maturation of monocytes in blood Tissue compartments Plaque composition Functional macrophage subsets in situ: inflammation vs beneficial New receptors for self and for pathogen explain mechanisms |
|  | | Promises ahead Imaging of macrophage subsets blood-plaque-adipose tissue Selective CCR-targeting, CX3CR1 over CCR2 Targeted modulation of functional subsets Plaque and adipose tissue therapy preferred over systemic |
|
 | | Monocyte-M heterogeneity and tissue lipids |
|  | | Ly6C-high monocytes dominate Hypercholesterolemia-Associated Monocytosis (HAM) and give rise to macrophages in atheromata |
|
 | | Monocyte subsets differentially employ CCR2,CCR5, and CX3CR1 to accumulate within atherosclerotic plaques |
|  | | Obesity induces a phenotypic switch in adipose tissue macrophage polarization |
|
 | | Slide 75 |
|  | | TLR |
|
 | | APC equipped to deal with self components |
|  | | Intracellular sensors for innate immunity |
|
 | | Human myelin foamy macrophages are unresponsive to LPS Boven et al., Brain 2006 |
|  | | Slide 80 |
|
 | | Slide 81 |
|  | | Vol. 134:97-111 (2008) |
|
 | | Slide 83 |
|  | | Biological therapies |
|
 | | Nomenclature biological therapies |
|  | | Gut flora determines local CD4+IL17+ |
|
 | | 12:1365 (2006) |
|  | | Circulating LPS in healthy primates Role in setting “immunostat”, physiological inflammation Virus affecting mucosal barrier function provokes microbial translocation: fertile ground |
|
 | | Slide 89 |
|  | | In vitro model human myelin foamy macrophages: unresponsive to LPS |
|
 | | Slide 91 |
|  | | Innate immunity by all cell types Barrier function Uptake and degradation of compounds Expression of innate antigen receptors Production of cytokines, notably IFNs type I HLA-I cytotoxic CD8 T-cells inside HLA-II helper CD4 T-cells outside |
|
 | | Slide 93 |
|  | | Slide 94 |
|
 | | Heterogeneity of mouse peripheral blood monocytes |
|  | | Foam cells multiple sclerosis atherosclerosis |
|
 | | Macrophage specialization in anatomical sites |
|  | | Toll-like receptors |
|
 | | In and out of macrophages and DC: control by lipid mediators |
|
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