Cardiovasculaire Geneeskunde.nl

Immune competent cells and atherosclerotic lesion development

Slides (presentatie) - Mar. 12, 2009

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

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Inducers Sensors Mediators Effectors Sepsis LPS TLR4 TNF-a, IL-6, PGE2 endoth hepato hypoth leukoc

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Chlamydia pneumoniae? Peptidoglycan debris? Pathogen burden?

Self-lipids drive foam cell formation

Y

B-lymphocyte

Figure 2-10

Figure 2-10

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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

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Atherosclerosis - steps

Sanz Science 451:953 (2008)

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Heterogeneity of mouse peripheral blood monocytes

Heterogeneity of mouse peripheral blood monocytes

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All leukocyte subsets get in numbers – function

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Weber C et al., 8:802 (2008)

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M and DC in advanced plaque

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Macrophages – foam cells critical in three domains of atherosclerosis

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J Immunol 175:342 (2005)

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Pro- versus Anti-inflammatory Acute versus chronic inflammation ‘Deactivation’

Zelcer et al, JCI 2006

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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

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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

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Monitor outside world Monitor intracellularly: infection, phagocytosis, budding

Peptidoglycan provides rigor to all bacteria

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peptidoglycan or other persisting compound

peptidoglycan

RLR (RIG-I like) receptor family RNA helicases

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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

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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

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Vol. 134:97-111 (2008)

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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

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In vitro model human myelin foamy macrophages: unresponsive to LPS

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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

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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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