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Technische Universität München
Das angeborene Immunsystem:Das angeborene Immunsystem:
Nutzen oder Schaden?Nutzen oder Schaden?
Hermann Wagnerg
Technische Universität München
I t d d ti i it i i dInnate and adaptive immunity is required
Janeway, Immunobiology
Technische Universität München
Immunity
Innate(angeboren)
Adaptive(erworben)( )
Non-specific(phagocytosis)
Specific(antibodies)(phagocytosis) (antibodies)
Ilja Metschnikow Nobelprice 1908 Paul Ehrlich
Technische Universität München
Innate Immunity
Julius Hoffmann Bruce Beutler Ralph Steinman
Nobelprice 2011
Technische Universität München
LPS (Bacteria)S
Flagellin (Bacteria)
RNA DNA (bacterial or viral)
Lipoproteins (Bacteria)Haemaglutinin
RSV-F Protein Profilin (T. gondii)
MD2 ssds
g(Measles)
TLR4
TLR5
CD14
C p G -m o t i fsTLR11
T R IF
T R A MMyD88MyD88 TLR3
TLR7/8
TLR2 (1, 6)TLR4
MyD88
T IR A P
T R A MMyD88
T R IF
MyD88
TLR7/8
TLR9MyD88
TIR A P
MyD88
Technische Universität München
LPS (Bacteria)RSV F Protein
Flagellin (Bacteria)
TLR signalling pathways
RNA DNA (bacterial or viral)
ssds
Lipoproteins (Bacteria)Haemoglutinin(Measles) CD14
RSV-F Protein
MD2
T R IFM D88 TLR3
TLR2
TLR4 TLR5C p G -m o t if s
T IR A PT R A MMyD88 MyD88
T R IFMyD88
TLR3TLR7/8
TLR9MyD88
TIR A P
MyD88
MyD88IRAKTRAF-6
IRF3/IRF-7
IFN-
Typ 1 IFNR STAT-1NFB ERK1,2 p38
TNF-, IL-12, etc. IFN- (many genes)
Technische Universität München
Cytoplasmic Receptors:NLR‘s: Nucleotide-binding oligomerisation domain-
like receptors
NOD1NOD2
N-terminusCARDCARDNOD2
(n=5)CARD
NLR P3NLR P6
N-terminusPYDNLR P6
(n=13)PYDPYD
Macrophage activation via endogenous ligands p g g glike …
Uric acid crystals(Gout)
Cholesterol crystals(Arteriosclerosis)
drive inflammasomeaggregation
or
Technische Universität München
PAMPS versus DAMPS(pathogen‐derived) (modified self)(p g ) ( )
Lipopeptide Heat schock proteins LPS HMGB’s Flagellin MRP‐8/14 ss RNA
DNA Hyluronan DNA Hyluronan
Heparin sulfateMatrix components
Haemozoin modified Lipids (OxLDL)
etc. β‐amyloid
Surfactant Protein A Surfactant Protein A
concern: contamination (LPS etc.)
Technische Universität München
TLR2 E d d t f Li id O d tiTLR2 senses Endproducts of Lipid Oxydation(Carboxyethyl pyrrole (CEPs))
(4-hydroxy-7-oxohept-5-enoic acid) (2-(-carboxyethyl pyrrole))
• CEPs are generated during inflammation/wound healing• accumulate in ageing tissues and highly vascularised melanomas• CEPs are recognized by TLR2 leading to angiogenesis that is independent of vascular
endothelial growth factor (VEGF)• both TRL2 and MyD88 are required• CEPs – present in low-density lipoprotein – accumulate in artheriosclerotic plaques and are
found in the retina (choroidal neovascularization and age-related macular degeneration)
West et al., Nature 2010
Adipositas / Inflammation / Metabolic diseasesAdipositas / Inflammation / Metabolic diseases
Nature Reviews Immunology 2011, 11:85
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