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