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

Technische Universität München

1998

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

Jin and Lee, ImmunityJin and Lee, Immunity(2008) 29:182

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

Technische Universität München

NACHT

Technische Universität München

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

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

G t t & f tiGut anatomy & function

Modified from Abreu, Nat. Rev. Immunol. (2010)

Technische Universität München