RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN.
-
Upload
allan-ramsey -
Category
Documents
-
view
245 -
download
0
Transcript of RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN.
RECOGNITION BY SOLUBLE RECOGNITION BY SOLUBLE MOLECULESMOLECULES
MANNOSE BINDING LECTINMANNOSE BINDING LECTIN
PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENSPHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS
CR3
Toll receptor
Toll receptor
OTHER PATTERN RECOGNITION MOLECULES
MANNOSE RECEPTOR
MANNOSE BINDING LECTIN
EEukariotic cellsukariotic cells
GluGluccooseseaminamin
MannMannoseose
GalaGalactosectose
NeuraminNeuraminidaseidase
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES
MannoseMannose
ProkarProkariotic cellsiotic cells
MaMaccrorophage/dendritic cellsphage/dendritic cells
MannMannose ose ReRecceptoreptor
BaBaccttereriumiumMannMannoseose
MANNOSE RECEPTORS ON PHAGOCYTES
PATTERN RECOGNITION BY MANNAN BINDING LECTINPATTERN RECOGNITION BY MANNAN BINDING LECTIN
Strong binding No binding
BaBacteriumcterium
lysis
Complementactivation
MacrophagePhagocytosis
CR3
LECTIN PATHWAY
WHAT IS RECOGNIZED BY INNWHAT IS RECOGNIZED BY INNAATE AND ACQUIRED TE AND ACQUIRED IMMUNITY?IMMUNITY?
HOHOW DO THEY RECOGNIZE PATHOGENS?W DO THEY RECOGNIZE PATHOGENS?
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
RECEPTORS
InInnate immunitynate immunity
AncientAncient
TLR
CYTOPLASMCYTOPLASM
CARD-CARD-helicase
RLH
CONSERVED RECEPTORS SENSING DANGER SIGNALSCONSERVED RECEPTORS SENSING DANGER SIGNALSNLR
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
paracrine
autocrine
Infected cell
subtypes
IFN-
IFN-
IFN response
IRF-3
IRF-7
Virus
IFN-
IFN-
NFBAP-1
Type I IFN receptor
IFN response
VÍRUS INDUCED TYPE I INTERFERON PRODUCTION
Plasma membrane
Cytoplasm
Type I. IFN receptor Type II. IFN receptorType III. IFN receptor (IFNλ)
TYK2 JAK1TYK2 JAK1
JAK2
JAK1JAK1
JAK2
STAT1STAT1
STAT2
Nucleus
STAT1 STAT2P
P
STAT1 STAT2P
P
STAT1STAT1 PP
STAT1STAT1 PP
IRF9
ISREISRE GAS – promoter elementsGAS – promoter elements
Antiviral immunity Antimycobacterial immunity
ISG15, Mx,OAS and
PKR
IL-10R2IFNLR1IFNAR1/2 IFNAG1/2
Interferon-stimulated genes
INTERFERON EFFECTOR PATHWAYS
• 1. Mx GTPase pathway– block viral transcription
• 2. 2',5'-oligoadenylate-synthetase (OAS)-directed ribonuclease L pathway– degrade viral RNA
• 3. Protein kinase R (PKR) pathway– inhibit translation
• 4. ISG15 ubiquitin-like pathway– modify protein function
CONTROL ALL STEPS OF VIRAL REPLICATION
Oligomer accumulationin cytoplasmic
membranes(e.g. ER)
(Nucleus)
(Cytoplasm)
ISRE MxA
MxA monomer
MxA oligomer
Trapped viralcomponents
(Nucleus)
(Cytoplasm)
ISRE OAS1
Inactive OAS1 monomer
Induction byviral dsRNA
Active OAS1 tetramer
synthetized pppA(2’p5’A)ninactive
RNaseLmonomer
active RNaseLdimer
cleaved RNA
(Nucleus)
(Cytoplasm)
ISRE PKR
Inactive PKR monomer
Active PKR dimer
Induction byviral RNAs
EIF2 EIF2P Inhibition of
translation
Mechanism of action of Mechanism of action of MxA, OAS1 and PKRMxA, OAS1 and PKR
EFFECTS OF TYPE I INTERFERONS
Plasmacytoid dendritic cells produce 1000x more type I interferon than other cells
NATURAL INTERFERON PRODUCING CELLS – IPC
After viral infection they are accumulated at the T cell zone of the lymph nodes
vírus
NF-κB IRF3
ACTIVATION OF TRANSCRIPTION FACTORS UPON INNATE ACTIVATION OF TRANSCRIPTION FACTORS UPON INNATE IMMUNE RESPONSEIMMUNE RESPONSE
Primary responsePrimary response
TRIF
TANK
IKKε TBK1
IRF-3
TRIF
TRAM
TLR3
TLR4
MyD88
IRF-5
TLR7TLR8TLR9
IFN-β, IFN-α1
RIG-1
Stimulation of Ig-productionin B-cells
Type I interferon receptor
IRF-7
Increased citotoxicity of NK-cells
Activation of - and γδ T-cells
Increased cross-presentationin myeloid dendritic cells
IRAK-1
TRAF-6
IRF-7
MULTIPLE EFFECTS OF TYPE I INTERFERONS
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
Cytokines/chemokines produced by activated Cytokines/chemokines produced by activated macrophages - macrophages -
local and systemic effects local and systemic effects
Szisztémás hatás
Failure of phagocytes to produce reactive oxigen speciesin chronic granulomatous didease
PROTECTIONPROTECTION
against against bacteriabacteria and and fungifungi is down is down
regulatedregulated
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
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
Lysis of infected cell
ACTIVATION OF NATURAL KILLER CELLS
Kinetics of the activity of the complement system and NK
cells in virus infection
IFNIL-12
2 4 6 8 101 3 5 7 9 1211 13
Complement system
NK-cells
days
Rel
atív
szi
nt/a
ktiv
itás
NK-CELLS
Virus-infectedcell
PRR
RECOGNITIONACTIVATION
RECOGNITION OF ALTERED HOST CELLS
MECHANISMS OF INNATE IMMUNITY
CELLS
HUMORAL
FACTORS
Phagocytes (monocyte/macrophage, neutrophil, dendritic cell)
Killer cells (NK cell, δ T cell)
B1 lymphocytes (CD5+)
Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin)
Antibacterial peptides
Complement system
Cytokines, chemokines
TWO LINES OF IMMUNE DEFENSE
TWO TYPES OF IMMUNE RESPONSES
INNATE/NATURAL IMMUNITY
B1 cells:Fast response within 48 hrsT cell independentSurface IgMLong life spanPeritoneal cavity
γδ T-cells:skin, gutslimited diversityBinds pathogen derived organic phosphatesexpress NKG2DNKT-cells:fast responselipid antigensswift cytokine release
NATURAL/INNATE• Rapid, prompt response
(hours)• No variable receptors• Limited number of
specificities• No improvement during
the response• No memory• Not transferable• Can be exhausted,
saturated
CHARACTERISTICS OF INNATE IMMUNITY
COMMON EFFECTOR MECHANISMS FOR THE ELIMINATION OF PATHOGENS
TOW LEVELS OF DEFENSE
TWO TYPES OF THE IMMUNE RESPONSE
INNTE/NATURAL IMMUNITY
Protects without prior activation or multiplication against pathogens
AQUIRED/ADAPTIVE IMMUNITY
Protects after activation and clonal expansion against pathogens
First line of defense
Inrerited
Persistant presence
Rapid response
Short term protection