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THE TWO „ARMS” OF THE IMMUNE SYSTEM. INNATE/NATURAL IMMUNITY ACQUIRED IMMUNITY. WHY IS THE IMMUNE SYSTEM S O IMPORTANT?. Virus. V iruses. 18 - 30 years. 3 hours. 3 hours. VARIABILITY Rapid evolution Adaptation Selection. Biomass: 90% microbes Animal mass< 5 – 25x microbes. - PowerPoint PPT Presentation
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THE TWO „ARMS” OF THE IMMUNE SYSTEM
• INNATE/NATURAL IMMUNITY
• ACQUIRED IMMUNITY
WHY IS THE IMMUNE SYSTEM SWHY IS THE IMMUNE SYSTEM SOO IMPORTANT? IMPORTANT?
VVirusesiruses
MMulticellular parazites ulticellular parazites (helminths)(helminths)
MMonocellular paonocellular parrazitesazites
VirusVirus
3 3 hourshours
3 3 hourshours
BacBacteriateria
PATHOGENS
Biomass: 90% microbes
Animal mass < 5 – 25x microbes
18 - 30 years
VARIABILITYVARIABILITYRapid evolutionRapid evolution
AdaptationAdaptationSelectionSelection
NATURAL/INNATE• Rapid, prompt
response (hours)• No variable receptors• No improvement
during the response• No memory• Not transferable• Can be exhausted,
saturated
CHARACTERISTICS OF INNATE IMMUNITY
ADAPTIVE/ACQUIRED• Time consuming (several
days)• Variable antigen receptors • Efficacy is improving
during the response• Memory• Can be transferred• Regulated, limited
COMMON EFFECTOR MECHANISMS FOR THE ELIMINATION OF PATHOGENS
CELLS
HUMORAL
FACTORS
Phagocytes (monocyte/macrophage, neutrophil, dendritic cell)
Killer cells (NK cell, δ T cell)
B1 lymphocytes (CD5+)
B lymphocytes (B2)
T lymphocytes
helper T cell
cytotoxic T cell
Enzymes (lysozyme, pepsin, trypsin)
Antibacterial peptides
Complement system
Cytokines, chemokines
Antibodies
TWO LINES OF IMMUNE DEFENSE
INNATE/NATURAL IMMUNITY
ACQUIRED/ADAPTIVE IMMUNITY
SENSINGSENSING
RECOGNITIONRECOGNITION
SIGNALINGSIGNALING
RESPONSERESPONSE
INNATE IMMUNITYINNATE IMMUNITY
CellsCells
ReceptorsReceptors
Signaling Signaling pathwayspathways
Cell-Cell Cell-Cell collaborationcollaboration
Effector Effector functionsfunctions
DEFENSE SYSTEMSDEFENSE SYSTEMS
ADAPTIVE IMMUNITYADAPTIVE IMMUNITY
SENSINGSENSING
RECOGNITIONRECOGNITION
SIGNALINGSIGNALING
RESPONSERESPONSE
SinusesTracheaLungs
BRONCHIAL TRACT EYES
Oral cavityesophagus
StomachIntestines
GASTROINTESTINAL SYSTEM
SKIN
PHYSICAL BARRIERS PROTECTING OUR BODY FROM
THE ENVIRONMENT
Damage
Infection
KidneyBladderVagina
UROGENITAL SYSTEMWALDEYER RINGTonsils, adenoids
Palatinal, pharyngeal lingual and tubar tonsils
EPITELIAL SURFACES ARE IMPORTANT IN THE FIRST LINE OF DEFENSE
α2-macroglobulin inhibits potentially damaging proteases
About 10% of serum proteins are protease inhibitors.
Human defensins are variable antimicrobial peptides
Peptides of 30-40 amino acids, amphipathic character They penetrate microbial membranesOngoing race between pathogens and the immune system of the host
Normal flora
Cells of human body: 90% microbes, 10% human
Symbiotic, non-pathogenic microbes– mucosal membrane, skinBacteria, Fungi, Protozoa Gut – colonalization after birth1012 bakteria/g (1.5 kg) intestinal content1000 species100-times more bacterial genes then eukaryotic
„peaceful” commensalismsvitamins (i.e. K1 vitamin)real ecosystem, survival of the fittest,
competition with pathogenic organismthe few who brake in through the gut
epithelium induce local immune responseImportant role in:
- development of mucosal and systemic immunity- normal development of peripheral lymphoid organs- maintenance of basic level of immunity
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
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
IL-1R associated Kinase
WHAT IS RECOGNIZED BY INNWHAT IS RECOGNIZED BY INNAATE AND ACQUIRED TE AND ACQUIRED IMMUNITY?IMMUNITY?
Common pattern of groups of pathogensCommon pattern of groups of pathogensPathogen Associated Molecular PatternPathogen Associated Molecular Pattern
PAMPPAMPRecognition by receptorsRecognition by receptors
Pattern Recognition ReceptorPattern Recognition ReceptorPRRPRR
9-19-133 various various Toll-Toll-rreecceptoreptorssTLR familyTLR family
SSeveral millions antigen receptorseveral millions antigen receptors
UUnique structural elenique structural elemmentsentsAntigenic determinantAntigenic determinant
Recognition by highly speciRecognition by highly speciffic ic aantigen receptorsntigen receptors
B cell receptorB cell receptor BCR (sIg) BCR (sIg)T cell receptorT cell receptor TCR TCR
RECEPTORS
InInnate immunitynate immunity
AncientAncient 450 450 million yearsmillion years
AAcquired immunitycquired immunity
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 cellpDpDCC
IFN
BaBacctteeririaa
CpG DNACpG DNA
TLR9TLR9TLR7TLR7TLR8TLR8
ssRNSssRNS
ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN
TTLRLR
CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALSCONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALS
MEMBRANEMEMBRANE
TLR3TLR3 FibroblastFibroblastEpithelial cellEpithelial cellDCDC
CELL MEMBRANEBacteriaBacteria
MEMBRANES OF
INTRACELLULAR VESICLESvirus
LRR
TIRdomain
TIR: Toll-Interleukin Receptor signaling domain
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 ESSENTIAL
FcR, CR
RECOGNITION
CYTOPLASMIC SENSORSCYTOPLASMIC SENSORS
VESZÉLYT ÉRZÉKELŐ KONZERVÁLT RECEPTOROKVESZÉLYT ÉRZÉKELŐ KONZERVÁLT RECEPTOROK
NLR: NOD-like receptorRLR: RIG-like receptor
TLR
CYTOPLASMCYTOPLASM
CARD-CARD-helicase
RLH
CONSERVED RECEPTORS SENSING DANGER SIGNALSCONSERVED RECEPTORS SENSING DANGER SIGNALSNLR nod-like receptors
Leucin rich repeatsLeucin rich repeatsNucleotide binding domain
NLRP1 – ASCNLRP1 – ASCNLRP3 – ASC – CARDINALNLRP3 – ASC – CARDINAL
NBDNBDNN CC
PYRPYR
CARDCARD
NOD1/2, IPAF/NLRC4NOD1/2, IPAF/NLRC4
MEMBRANMEMBRAN
TLR3TLR3
BIRBIRIPAFIPAF
FibroblastFibroblastEpithelial cellEpithelial cellDCDC
NBDNBD
NBDNBD
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 – modified viral nucleotides
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
IL-1R associated Kinase
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
EFFECTOR MECHANISMS OF INNATE IMMUNITY
Bacterium
Complement proteins Lysis of bacteria
Inflammation
Complement-dependent phagocytosis
COMPLEMENT
PhagocytosisIntracellular killing
PHAGOCYTOSIS Phagocyte
Bacterium
CELLULAR AND HUMORAL MECHANISMS OF INNATE IMMUNITY
INFLAMMATION
BacteriumLPS
Cytokines Neutrophil
NK-cell
Macrophage
TNF
IL-12
IFN
NK-CELLSVirus-infected
cell
NK-cell Lysis of infected cell
DegradationACTIVATION
Uptake
PHAGOCYTOSIS
MECHANISMS OF INNATE IMMUNITY
Phagocyte
PRR
0.5 - 1 hours
The amount of internalized particles is limited Antigen + Antibody
ACQUIRED IMMUNITY
Bacterium
Intracellular killing
Antigen presentationT cell
ACQUIRED IMMUNITY
PHAGOCYTE SYSTEMPHAGOCYTE SYSTEM
NEUTROPHIL GRANULOCYTENEUTROPHIL GRANULOCYTEMONOCYTE – MACROPHAGE – DENDRITIC CELLMONOCYTE – MACROPHAGE – DENDRITIC CELL
Defence against infectiousdiseasesElimination of tumor cells
Gatekeeper functionSensing commensals and pathogensRapid activation of innate immunityPriming adaptive immune responsesMaintenance of self tolerance
Macrophages ingest and degrade particulate antigens through the use of long Macrophages ingest and degrade particulate antigens through the use of long pseudopodia that bind and engulf bacteria. The engulfed bacteria are degraded pseudopodia that bind and engulf bacteria. The engulfed bacteria are degraded when the phagosome fuses with a vesicle containing proteolytic enzymes when the phagosome fuses with a vesicle containing proteolytic enzymes (lysosome), forming the phagolysosome. Specialized compartments also exist in (lysosome), forming the phagolysosome. Specialized compartments also exist in the macrophage to promote antigen processing for presentation to antigen-the macrophage to promote antigen processing for presentation to antigen-specific T cells.specific T cells.
PHAGOCYTOSIS
Opsonization enhances the efficiency of phagocytosis of pathogens by phagocytes
Killing of bacteria by neutrophils: azurophilic and specific granules
azurofil ic specific granulsLyzozyme NADPH oxidaseDefensins LyzozymeMieloperoxidaseCathepsin Gelastase
Phagocyte oxidase (Phox) produces reactive oxidative species (ROS) that help destroy pathogens
Failure of phagocytes to produce reactive oxigen speciesin chronic granulomatous didease
PROTECTIONPROTECTION
against against bacteriabacteria and and fungifungi is down is down
regulatedregulated
NK-cellIL-12
macrophageIFNcytokines
neutrophilTNF-
INFLAMMATION – ACUTE PHASE RESPONSE
hrs
Pla
sma
leve
l
1 2 3 4 5
LPS (endotoxin) (Gram(-) bacteria)
TNF-
IL-1IL-6
Kinetics of the release of pro-inflammatory citokines in bacterial
infection
TNF-IL-1IL-6
Few hours
ACUTE PHASE RESPONSE
Bacterium
LPS
DANGER SIGNAL
ACTIVATION
PRR
MECHANISMS OF INNATE IMMUNITY
INFLAMMATORY RESPONSE INFLAMMATORY RESPONSE
The classic symptoms of inflammation:
redness (rubor) - vasodilation, swelling (tumor) - edema, heat (calor) – increased perfusion, pain (dolor) – factors stimulating nociceptors,
loss of function (functio laesa)
CONSEQUENCECONSEQUENCESS OF OF MACROPHAGE AMACROPHAGE ACTIVATIONCTIVATIONSYNTHESIS OF SYNTHESIS OF CCYTOKINESYTOKINES
Systemic effects of pro-inflammatory cytokines
Systemic release of TNFa initiates septic shock
Septic shockLocal production of TNFα (and IL1) is beneficial, and protective, BUT systemic releasemay cause deathDrop in blood volume and hence blood pressure Disseminated intrvascular coagulation
Pro-inflammatory cytokines activate endothel which recruits immunocytes from blood to infected tissues (extravasatio)
Liver
C-reactive proteinPhosphocolin
binding (e.g.fungi)COMPLEMENT
Serum Amyloid Protein (SAP)
Mannose/galactose binding
Fibrinogen
Mannose binding lectin/protein
MBL/MBPCOMPLEMENT
IL- 6
THE ACUTE PHASE RESPONSE
IL-6 induces the production of acute phase protiens
Phosphocoline bindingFungi, bacterialCell wall.
Lysis of bacteria
COMPLEMENT ACTIVATION
InflammationChemotaxis
Complement-dependent phagocytosis
Bacterium
COMPLEMENT
Lectin pathwayAlternative
pathway
Antigen + Antibody
ACQUIRED IMMUNITY
Complement-proteins
Few minutes – 1 hour
Enzymes get fragmented, complement activity can be exhausted
MECHANISMS OF INNATE IMMUNITY
RECOGNITION BY SOLUBLE RECOGNITION BY SOLUBLE MOLECULESMOLECULES
MANNOSE BINDING LECTINMANNOSE BINDING LECTIN
EEukariotic cellsukariotic cells
GluGluccooseseaminamin
MannMannoseose
GalaGalactosectose
NeuraminNeuraminic acidic acid
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
MannoseMannose
ProkarProkariotic cellsiotic cells
PATTERN RECOGNITION BY MANNAN BINDING LECTINPATTERN RECOGNITION BY MANNAN BINDING LECTIN
Strong binding No binding
BaBacteriumcterium
lysis
Complementactivation
MacrophagePhagocytosis
CR3
LECTIN PATHWAY
NK cells
Type I IFNs increase their cytotoxicity (100x)
IL12, and TNFα are also able to activate them
IFNγ production --- MF, DC activation
- 5-10% of lymphocytes in circulation- bigger than T or B lymphocytes - several granules in their cytoplasm- have no antigen binding receptors („null cells”)- participants of native immunity