TWO ARMS OF THE IMMUNE SYSTEM

• INNATE IMMUNITY

• ACQUIRED IMMUNITY

MIKROBES90%

PATHOGENIC

COMMENSAAL

PEOPLE

7 BILLIONINDIVIDUALS

GENETIC POLIMORPHISMMHC GENES

Recognition of common & variable structures

VARIABILITYRAPID MULTIPLICATION

CHANGES

Földrajzi határokPopuláció sűrűség

BiodiverzitásÉletforma

BIOMASSBIOMASS ENVIRONMENTENVIRONMENT MANKINDMANKIND

v

vv

vv

v

vv

v

v

v

v

v v v

v

vv

v

vv

v

vv

EPIDEMY

LIFE AMONG MICROBESLIFE AMONG MICROBES

BaktBakteriaeria

VVírusesíruses

Multicellular parazites (worms)Multicellular parazites (worms)

Unicellular pUnicellular paarazitesrazites

VARIABILITYVARIABILITYRapid evolutionRapid evolution

AdaptationAdaptationSelectionSelection

ENVIRONMENTENVIRONMENTMicrobial and other effectsMicrobial and other effects

Animals total mass < 5x – 25x Microbes

VVíírusrus

3 3 óraóra

3 3 óraóra18 - 30 év

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

MICROBES WITHIN OUR BODYMICROBES WITHIN OUR BODY

90% of the cells is microbe10% human cell

1012 (1.5kg) bacteria in the gutSpecial microbial environment at the mucosal epithelial surface

Integrated phylogeny of metabolism and immunityIntegrated phylogeny of metabolism and immunity

Required for survivalRequired for survivalParalel development or organ systems and signaling pathwaysParalel development or organ systems and signaling pathways

Drosophila fat body – liver, fat tissue, lymph nodesDrosophila fat body – liver, fat tissue, lymph nodes

• Nutrient sensingNutrient sensing• Energy efficiency• Energy storage• Energy surplus• Metabolic syndrome

• Pathogen sensingPathogen sensing• Food deprivation• Defense against pathogens• High energy expenditure• Impaired immune responses• Chronic inflammation

METABOLIC HOMEOSTASIS – PROPER IMMUNE SYSTEMMETABOLIC HOMEOSTASIS – PROPER IMMUNE SYSTEM

Hotamisligil & Erbay NRI 2008

IMMUNE RESPONSEIMMUNE RESPONSE

ReproductionReproduction ThermoregulationThermoregulation LactationLactation

HIGHEST ENERGY CONSUMING SYSTEMSHIGHEST ENERGY CONSUMING SYSTEMS

Loss of apetite – induction of leptin synthesis

Usage of local energy and nutrient stores

Chronic nutrient deficiency or overnutrition lead to pathological conditionsChronic nutrient deficiency or overnutrition lead to pathological conditions

Pre-adipocytes – Macrophages – Adipocytes – Dendritic cellsPre-adipocytes – Macrophages – Adipocytes – Dendritic cells

SHARED GENES IN PHYSIOLOGICAL CONDITIONS & METABOLIC SHARED GENES IN PHYSIOLOGICAL CONDITIONS & METABOLIC DISEASE STATES DISEASE STATES

SENSINGSENSING

RECOGNITIONRECOGNITION

SIGNAL SIGNAL TRANSDUCTIONTRANSDUCTION

RESPONSERESPONSE

INNATE IMMUNITYINNATE IMMUNITY

CellsCells

ReceptorsReceptors

Signaling Signaling pathwayspathways

Cell-to-cell Cell-to-cell collaborationcollaboration

Effector Effector mechanismsmechanisms

DEFENCE SYSTEMSDEFENCE SYSTEMS

ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES

DC

Epithelial cells

Stroma cells

TISSUE SPECIFIC CELL – TO – CELL COMMUNICATION NETWORKS

Granulocyte

Macrophage

NK cell

NKT cell

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

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

RECOGNITION

BY THE INNATE IMMUNE SYSTEM

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

RECOGNITION RECOGNITION

BY THE INNATE IMMUNE SYSTEMBY THE INNATE IMMUNE SYSTEM

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

588

7733 7 1099

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 CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALSDANGER SIGNALS

MEMBRANEMEMBRANE

TLR3TLR3 FibroblastFibroblastEpithelial cellEpithelial cellDCDC

CELL MEMBRANEBacteriaBacteria

MEMBRANES OF

INTRACELLULAR VESICLESvírus

SIGNALING

IN INNATE IMMUNITY

BaBacctteeriumrium

CD14CD14TLR4TLR4

LPSLPS

NFkBNFkBMyD88MyD88

IRAKIRAK

LPBLPB

IL-6IL-6

FungusFungus

TollToll

CCaacctustusTubeTube

SpätzelSpätzel

PeptidPeptid

ProteaseProtease

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

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