Fcε receptor signaling
description
Transcript of Fcε receptor signaling
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
FCΕ RECEPTOR SIGNALING
Tímea Berki and Ferenc BoldizsárSignal transduction
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
TÁMOP-4.1.2-08/1/A-2009-0011
Mast cell activation mechanisms
• They express several hundred thousand high affinity receptors for IgE (FceR1) and thus respond to IgE-directed antigens
• Express the pathogen-recognizing Toll-like receptors (TLRs) which probably account for the ability of mast cells to mount an effective innate immune response
Stem cell factor cKit Production of cytokines
Pathogens TLRsGranule constituents: histamine, proteases, proteoglycans
Allergens FceRI Synthesis of eicosanoids from arachidonic acid
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Selected mediators produced by mast cells
Mediators Potential role in atherosclerosis
Pro-inflammatory cytokines:IL-4, IL-5, IL-6, IL-13, IL-18, IFN- , γTNF-α
•chemotaxis •endothelial cell activation •monocyte recruitement •induction of protease expression
Chemokines:MCP-1, IL-8, RANTES, eotaxin, leukotriene
•monocyte recuitement •foam cell formation
Proteases:Tryptase, chymase, angiotensin converting enzyme (ACE), carboxypeptidase, cathepsin G, cysteinyl cathepsins
•endothelial cell activation •fibrinogen cleavage •angiotensis II generation •lipoprotein degradation •tissue/vascular remodelling •protease activation
Hematopoeitic factors:IL-3, GM-CSF
•hematopoiesis •foam cell formation
Growth factors:bFGF, VEGF, TGF-b, PDGF
•angiogensis •cellular proliferation
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Other mast cell activators• MIP-1a: macrophage inflammatory chemokine• C3a, C5a anaphylatoxins: complement• Neuropeptides : P-substance, somatostatin, VIP• FcgR - IgG
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IgE bound FceR I
a1a2
Ce2
C e4
C H3Ce2
C e3
C e4
V L
C L
VH VH
Cε1
Ce1
VL
CL
b
N
C
P
g
N N
C C
ITAMsPP
P P
a
IgE
FceR I
Bound IgE
a
N
C
b
N
C
P
g
N N
C C
ITAMs
PP
P P
FceR I
LYN SYK
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FceR II
N N N
C-terminal tail
Head domain
Coiled-coil stalk
N-linked glycolisation
Ce2
C e4
C H3Ce2
C e3
C e4
V L
C L
VHV
H
C1ε
Ce1
VL
CL
IgE
FceR II
IgE bound FceR II
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IL-4 and IL-13 signal induceIgE switch
P
P
JAK3JAK1P
P
P
STAT6
Tyk1
IL-4
IL-4Ra gC
Tyk2
JAK1P
P
P
STAT6
IL-13
IL-4Ra IL-13Ra1/2
STAT6 dimertranslocates to nucleus
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The IgE promoter region
BSAP – B cell specific activator proteinC/EBP CCAAT/enhancer binding proteinPU.1 – Spi1 equivalent in humans
Ie
Ce1 Ce2 Ce3 Ce4SeIe
NFBStat6C/EBP PU.1 BSAPAP-1
Activation/cytokineresponsive promoter
IL-4,13 CD40L
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Signal transduction pathways
IP3
Plasma membrane
GRB2
SOS
SYK
PLCg
Ca2+
LATGADs
DAG
PKC
SPL-76
LYNP
P
a
bg
FceR I a
bg
FceR I
BTK
VAV
Nck
Antigen
IgE
Cytoplasm
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FceRI mediated signaling
PIP3
BTK Sphingosine
SK
PLD
IP3
PIP2
RAS
RAS
MAPKKKor RAF MAPKK MAPKs
Cytokines Degranulation
Transcription factors
Plasma membraneLipid raft
GRB2
SOS
NTAL
?
P PY
P Y
PY
GAB2
GRB2
a
bg
FceR I
LYNSYK SYK PI3K
PLCg
VAV
Ca2+
GTP
GDP
S1P
FYN
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Similarities in TcR and FceR signaling
LynLck
gg b
a
IgE
ITAM
FceRI
Antigen-specific receptor
Src-family kinase
Syk-family kinase
ZAP-70 expression is restricted to T cells, NK cells and a subpopulation of CLL
Syk is present in most hematopoetic cell types
TCR
CD3a b
zzgd e e
CD3
ITAM
SykZAP-70 ZAP-70
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Biological effects of FcεR signaling
PP P
PPP
PP
P PSignaling pathways
Enzymatic modificationof arachidonic acid
Transcriptional activationof cytokine genes
Granule withpreformed mediators
Granule exocytosis
Lipid mediators
Secretion Secretion
Cytokines
Leukotrienes ProstaglandinsVasoactive amines Cytokines, e. g., TNF
Vascular dilatation,smooth muscle contraction
Tissue damage Vascular dilatationSmooth musclecontraction
Inflammation(leukocyte recruitment)
Allergen
Proteases
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Mast cell mediators• Biogen amines: histamin, serotonin (H1,2,3,4R) →
vasodilatation, plasma leak, smooth muscle consriction
• Serin proteases: tryptase, chymase, carboxypeptodase A, cathepsin G
• Proteoglycans: heparin, chondroitin sulphate• Lipid mediators: rapid de novo synthesis
ProstaglandineD2, Leukotrien C4, D4, E4, PAF → vasodilatation, bronchus constriction
• Cytokines: TNF, IL-1, IL-4, IL-5, IL-6, IL-13, MIP-1a, IL-3, GM-CSF