Transcript 1. dia - Department of Immunology

CELLS & MECHANISMS OF INNATE IMMUNITY
EPITHELIAL CELLS
•Pattern recognition receptors (PRR)
•Cytokine, chemokine secretion
NEUTROPHIL GRANULOCYTES
•Phagocytósis
•Intracellular cytotoxicity
MONOCITE – MACROPHAGE – DENDRITIC CELL NETWORK
•Pattern recognition receptors (PRR)
•Internalizing receptors
•Phagocytosis
NATURAL KILLER CELLS
•Cytotoxicity
•Cytokine production
FIRST LINE OF DEFENSE BY INNATE IMMUNITY
Soluble proteins – Defensins
Enzymes - Complement system - Chemotaxis
Recognition by Pattern Recognition Receptors
Macrophage & dendritic cell subsets
Neutrophils
Pro-inflammatory cytokine secretion
Local effects
Systemic effects
Chemokine receptors & ligands – cell recruitment, other functions
Cytotoxicity – NK cells
CONTACT SURFACES
GASTROINTESTINAL
SYSTEM
Physical, chemical, biological borders
EYE
AIRWAY SYSTEM
Sinuses
Trachea
Lungs
Oral cavity
Esophagus
Stomach
Alimentary
tract
UROGENITAL SYSTEM
SKIN
Kidney
Bladder
Vagina
WALDEYER RING
Tonsils, adenoids
Palatinal, pharyngeal
lingual and tubar tonsils
Demage
Mucus
Infection
glycoproteins, proteoglycanes,
enzymes
THE EPITHELIUM
AS AN IMPORTANT FIRST LINE OF DEFENSE
EPITHELIAL MONOLAYER
DEFENSE LINES OF NATURAL IMMUNITY
ANATOMICAL BORDERS
Skin
Inhibits entry of pathogens, pH3 – 5 inhibits growth
Mucosa
Normal bacterial flora competes for binding sites and nutrients
Mucus keeps away pathogens from the surface
Cilia remove pathogens
PHYSIOLOGICAL BORDERS
Temperature
Physiological body temperature and fever inhibits growth of
certain pathogens
Low pH
Most pathogens are destroyed in the stomach
Chemical
Lysosyme degrades bacterial cell wall
Type I interferons induce anti-viral resistance
The complement system is able to lyse bacteria and promotes
phagocytosis
PHAGOCYTOSIS/ENDOCYTOSIS
Many cells can take up microorganisms by receptor-mediated internalization
Special professional phagocytes (monocyte, neutrophil, macrophage) are able to
internalize, kill and degrade microorganisms
INFLAMMATION
Tissue demage and infection results in the leakage of anti-bacterial proteins and
peptides to the affected tissue
Phagocytic cells leave the blood stream and enter inflammed tissues
ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES
Dendritic cell
Epithelial
cells
Stroma cells
NK cell
NKT cell
DC
Granulocyte
Macrophage
PERIFÉRIÁS
PERIFÉRIÁS
TISSUE – SPECIFIC CELLULAR COMMUNICATION NETWORKS
SZÖVETEK
LIMFOID SZERVEK
PHAGOCYTOSIS, RECOGNITION RECEPTROS, SIGNAL
TRANSDUCTION, EFFECTOR MECHANISM
Pattern recognition
Receptors (PRR)
Engagement of PRR
triggers phagocytosis
and cytokine
production
Chemoattractant cytokines called chemokines direct migration of
leukocytes to the appropriate anatomical sites
FAGOCYTE SYSTEM
GRANULOCYTES
MONOCYTE – MACROPHAGE – DENDRITIC CELL
Gatekeeper function
Sensing commensals and pathogens
Rapid activation of innate immunity
Priming adaptive immune responses
Maintenance of self tolerance
Defence against infectious
diseases
Elimination of tumor cells
Transplantation
RECOGNITION
BY THE INNATE IMMUNE SYSTEM
PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS
Toll receptormediated signaling
Toll receptor
PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes)
RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS
RECOGNITION IS ESSENTIAL
Macrophage, dendritic cell – ACT AS TISSUE SENSORS (GATE KEEPERS)
Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF
INFLAMMATION
INNATE/NATURAL IMMUNITY
RECOGNITION
Richard Pfeiffer, a student of Robert Koch – ENDOTOXIN
There must be a receptor that recognizes endotoxin
Lipopolysaccharide (LPS) receptor remained elusive
The Dorsoventral Regulatory Gene Cassette Spätzle/Toll/Cactus controls
the potent antifungal response in Drosophila adults
Bruno Lemaitre, A Hoffmann et al, Cell, 1996
Spätzle:
Toll ligand
Toll:
Receptor
Cactus:
I-kB
Dorsal:
NF-kB
Drosomycin is not synthesized
INNATE (NATURAL) IMMUNITY
RECOGNIZING RECEPTORS
PROTECTIVE MECHANISMS
Enzyme systems
Multicellular (Metazoa)
Sea urchin 600 million years
Toll-receptors
C. elegans
Drosophila
700 million years
IN PLANTS
complement
TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL
STRUCTURES
Bacteria
Virus
CpG DNA
ssRNS
dsRNA
Peptidoglycane
Gram+
TLR3
IFN
TLR7
TLR8
TLR2
Interferon
producing cell
PC/DC
Flagellin
LPS
Gram-
TLR4
TLR6
TLR9
TLR5
Macrophage/Dendritic cell
ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE
PATHOGEN
DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION
THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES
4
2
1
5
6
6
3
1
7
NLR
7 9 10
8
RLH
RLH
NLR=NOD/NALP (IL-1β)
RLH=RIG-1/MDA5 (IFN)
Conventional DC
TLR1 –
TLR2 –
Plasmacytoid DC
bacterial lipoprotein (together with TLR2)
bacterial lipoprotein, peptidoglycane, lipoteicholic acid
IL-1β
(heteromer with TLR1 and TLR6)
IL-12/23
TLR3 – viral dsRNS, polyI:C
IL-10
TLR4 – bacterial LPS
TLR5 – bacterial flagellin
TLR6 –
bacterial lipoprotein (with TLR2)
TLR7 – viral ssRNA
TLR8 – GU rich viral ssRNS, imidazoquinolin (antiviral drug)
TLR9 – unmethylated CpG DNA
Th1/Th17/Th2 TLR10 – mdified viral nucleotides
IFNαβ
NK/DC
CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALS
TLR3
Fibroblast
Epithelial cell
DC
TLR
LRR
MEMBRANE
TIR
domain
CELL MEMBRANE
Bacteria
MEMBRANES OF
INTRACELLULAR VESICLES
vírus
TIR: Toll-Interleukin Receptor
signaling domain
SIGNALING
IN INNATE IMMUNITY
TOLL RECEPTORS ACTIVATE PHYLOGENETICALLY
CONSERVED SIGNAL TRANSDUCTION PATHWAYS
Fungus
Bacterium
Protease
LPB
LPS
Toll
Tube
Spätzel
CD14
Cactus
Relish
Pelle
TLR4
MyD88
CD14
NFkB
Drosophila
TRIF
IRAK
IL-1R associated
Kinase
Peptid
TLR3
TLR4
Inflammation
Acute phase response
Danger signal
IL-6
IRF3
STAT1
IFN
Macrophage
Sensing of LPS by TLR4 leads to activation of the
Transcription factor NFkB and the synthesis of
inflammatory cytokines.
TLR4 activation can lead to the
production of either inflammatory
cytokines or antiviral type I interferons.
TOLL RECEPTOR MEDIATED SIGNALLING
NEW THERAPEUTIC TARGET
Figure 3 The 'hourglass' shape of the innate immune response. Although microbial stimuli are chemically complex
and although the innate immune response ultimately involves the activation of thousands of host genes, innate
immune signals traverse a channel of low complexity. Ten Toll-like receptors (TLRs), four TIR (Toll/interleukin-1
receptor homologous region) adaptors and two protein kinases are required for most microbial perception. This
circumstance lends itself to effective pharmacotherapeutic intervention. NF-B, nuclear factor-B; STAT1, signal
transducer and activator of transcription 1.
THE ACUTE PHASE RESPONSE
IL- 6
Mannose binding
lectin/protein
C-reactive protein
COMPLEMENT
MBL/MBP
COMPLEMENT
Liver
Serum Amyloid Protein (SAP)
Mannose/galactose binding
Fibrinogen
Chromatin, DNA, Influenza
IL-6 induces the production of acute phase protiens
RECOGNITION BY SOLUBLE
MOLECULES
MANNOSE BINDING LECTIN
PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS
MANNOSE
RECEPTOR
Toll receptor
MANNOSE
BINDING
LECTIN
CR3
Toll receptor
OTHER PATTERN RECOGNITION MOLECULES
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN
VARIOUS SPECIES
Prokariotic cells
Eukariotic cells
Mannose
Glucoseamin
Mannose
Galactose
Sialic acid
MANNOSE RECEPTORS ON PHAGOCYTES
Mannose
Bacterium
Mannose Receptor
Macrophage/dendritic cells
PATTERN RECOGNITION BY MANNAN BINDING LECTIN
Bacterium
lysis
Complement
activation
LECTIN PATHWAY
CR3
Macrophage
Phagocytosis
Strong binding
No binding