SinusesTracheaLungs

AIRWAY SYSTEM EYEOral cavityEsophagus

StomachAlimentary

tract

GASTROINTESTINAL SYSTEM

Demage

Infection

Mucus

glycoproteins, proteoglycanes, enzymes

KidneyBladderVagina

UROGENITAL SYSTEM

WALDEYER RINGTonsils, adenoidsPalatinal, pharyngeal lingual and tubar tonsils

SKINSKIN

CONTACT SURFACESCONTACT SURFACESPhysical, chemical, biological bordersPhysical, chemical, biological borders

PHYSIOLOGICAL BORDERSTemperature Physiological body temperature and fever inhibits growth of

certain pathogens

Low pH Most pathogens are destroyed in the stomach

Chemical Lysosyme degrades bacterial cell wallType I interferons induce anti-viral resistance The complement system is able to lyse bacteria and promotes phagocytosis

PHAGOCYTOSIS/ENDOCYTOSISMany cells can take up microorganisms by receptor-mediated internalization

Special professional phagocytes (monocyte, neutrophil, macrophage) are able to internalize, kill and degrade microorganisms

INFLAMMATIONTissue 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

ANATOMICAL BORDERSSkin Inhibits entry of pathogens, pH3 – 5 inhibits growth

Mucosa Normal bacterial flora competes for binding sites and nutrients Mucus keeps away pathogens from the surfaceCilia remove pathogens

DEFENSE LINES OF NATURAL IMMUNITY

THE EPITHELIUM AS AN IMPORTANT FIRST LINE OF DEFENSE

EPITHELIAL MONOLAYEREPITHELIAL MONOLAYER

DC

Epithelial cells

PERIFÉRIÁS LIMFOID SZERVEK

PERIFÉRIÁS SZÖVETEK

Stroma cells

TISSUE – SPECIFIC CELLULAR COMMUNICATION NETWORKS

Granulocyte

Macrophage

NK cell

NKT cell

Dendritic cell

ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES

FAGOCYTE SYSTEMFAGOCYTE SYSTEMGRANULOCYTESGRANULOCYTES

MONOCYTE – MACROPHAGE – DENDRITIC CELLMONOCYTE – MACROPHAGE – DENDRITIC CELL

Defence against infectiousdiseasesElimination of tumor cellsTransplantation

Gatekeeper functionSensing commensals and pathogensRapid activation of innate immunityPriming adaptive immune responsesMaintenance of self tolerance

TISSUE MACROPHAGES AND DENDRITIc CELLS TISSUE MACROPHAGES AND DENDRITIc CELLS INTERNALIZE SOLUBLE MATERIAL AND PARTICLESINTERNALIZE SOLUBLE MATERIAL AND PARTICLES

C-TYPE LECTINSMMR/CD206DC-SIGN/209

Langerin/CD207

CARBOHYDRATESCARBOHYDRATES

SCAVENGER RECEPTORSSCAVENGER RECEPTORSCD36, SR-A

LIPID RECEPTORSLIPID RECEPTORSLDL-R, CD91

LIPIDSLIPIDS

OPSONIZING RECEPTORS

FcR, CR

PROTEINSPROTEINS

INFECTEDINFECTEDDEAD CELLSDEAD CELLS

UPTAKEUPTAKEMacropinocytosisMacropinocytosis

Receptor-mediated endocytosisReceptor-mediated endocytosisFagocytosisFagocytosis

COLLECTION OF ENVIRONMENTAL INFORMATON, CONCENTRATIONCOLLECTION OF ENVIRONMENTAL INFORMATON, CONCENTRATION

ION CHANNELSION CHANNELS ABC TRANSPORTERSABC TRANSPORTERS

Chemoattractant cytokines called chemokines direct migration of leukocytes to the appropriate anatomical sites

EXPRESSION OF THE RECEPTOR DETERMINES INTERACTION WITH LIGANDS

PHAGOCYTOSIS, RECOGNITION RECEPTORS, SIGNAL PHAGOCYTOSIS, RECOGNITION RECEPTORS, SIGNAL TRANSDUCTION, EFFECTOR MECHANISMTRANSDUCTION, EFFECTOR MECHANISM

Pattern recognitionReceptors (PRR)

Engagement of PRR triggers phagocytosis

and cytokine production

RECOGNITION

BY THE INNATE IMMUNE SYSTEM

PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENSPHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS

Toll receptor-mediated signaling

Toll receptor

PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS

RECOGNITION IS ESSENTIALRECOGNITION IS ESSENTIALMacrophage, dendritic cell – ACT AS Macrophage, dendritic cell – ACT AS TISSUE SENSORS (GATE KEEPERS) TISSUE SENSORS (GATE KEEPERS) Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF

INFLAMMATIONINFLAMMATION

INNATE/NATURAL IMMUNITY

RECOGNITION

Richard Pfeiffer, a student of Robert Koch – ENDOTOXIN ENDOTOXIN There must be a receptor that recognizes endotoxinLipopolysaccharide (LPS) receptor remained elusive

The Dorsoventral Regulatory Gene Cassette Spätzle/Toll/Cactus controls the potent antifungal response in Drosophila adultsBruno Lemaitre, A Hoffmann et al, Cell, 1996

Spätzle: Toll ligand

Toll: Receptor

Cactus: I-kB

Dorsal: NF-kB

Drosomycin is not synthesized

Multicellular Multicellular (Metazoa) (Metazoa)

Sea urchinSea urchin 600 600 million yearsmillion years

ccomplementomplement

C. elegansC. elegans

Toll-Toll-rreeceptorsceptors

DrosophilaDrosophila700 million years700 million years

INNATE (NATURAL) IMMUNITY

RECOGNIZING RECEPTORS PROTECTIVE MECHANISMS Enzyme systems

IN PLANTS

MaMaccrorophage/Dendritic cellphage/Dendritic cell

TLR5TLR5

FlageFlagelllinlin

VViirusrus

TLR3TLR3

ddssRNARNA

TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL STRUCTURES

TLR2TLR2

PeptidoglycanePeptidoglycane

Gram+

TLR4TLR4

LPSLPS

TLR6TLR6

Gram-

InterferonInterferonproducing cellproducing cellPC/DCPC/DC

IFN

BaBacctteeririaa

CpG DNACpG DNA

TLR9TLR9TLR7TLR7TLR8TLR8

ssRNSssRNS

ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN

Conventional DC Plasmacytoid DC

5

887733 7 10

99

NLR=NOD/NALP (IL-1NLR=NOD/NALP (IL-1ββ))RLH=RIG-1/MDA5 (IFN)RLH=RIG-1/MDA5 (IFN)

NLRNLR

IL-1βIL-12/23

IL-10

Th1/Th17/Th2

IFNαβ

NK/DC

1

24 6

16

RLHRLHRLHRLH

DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPESTHROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES

TLR1 – bacterial lipoprotein (together with TLR2)TLR2 – bacterial lipoprotein, peptidoglycane, lipoteicholic acid

(heteromer with TLR1 and TLR6)TLR3 – viral dsRNS, polyI:CTLR4 – bacterial LPSTLR5 – bacterial flagellinTLR6 – bacterial lipoprotein (with TLR2)TLR7 – viral ssRNATLR8 – GU rich viral ssRNS, imidazoquinolin (antiviral drug)TLR9 – unmethylated CpG DNATLR10 – mdified viral nucleotides

TTLRLR

CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALSCONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALS

MEMBRANEMEMBRANE

TLR3TLR3 FibroblastFibroblastEpithelial cellEpithelial cellDCDC

CELL MEMBRANEBacteriaBacteria

MEMBRANES OF

INTRACELLULAR VESICLESvírus

LRR

TIRdomain

TIR: Toll-Interleukin Receptor signaling domain

SIGNALING

IN INNATE IMMUNITY

BaBacctteeriumrium

CD14CD14TLR4TLR4

LPSLPS

NFkBNFkBMyD88MyD88

IRAKIRAK

LPBLPB

IL-6IL-6

FungusFungus

TollToll

CCaacctustusTubeTube

SpätzelSpätzel

PeptidPeptid

ProteasProteasee

PellePelleRelRelishish

TOLL RECEPTORS ACTIVATE PHYLOGENETICALLY CONSERVED SIGNAL TRANSDUCTION PATHWAYS

InflammationAcute phase responseDanger signal

MacrophageDrosophila

CD14CD14TLR4TLR4

TRIFTRIF

IRF3STAT1

IFN

TLRTLR33

IL-1R associated Kinase

Liver

C-reactive proteinCOMPLEMENT

Serum Amyloid Protein (SAP)

Mannose/galactose binding

Chromatin, DNA, Influenza

Fibrinogen

Mannose binding lectin/protein

MBL/MBPCOMPLEMENT

IL- 6

THE ACUTE PHASE RESPONSE

IL-6 induces the production of acute phase protiens

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.

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.

TOLL RECEPTOR MEDIATED SIGNALLING

NEW THERAPEUTIC TARGET