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Fcε receptor signaling

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Fcε receptor signaling

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Fcε receptor signaling

  3. Mast cell activation mechanisms Granule constituents: histamine, proteases, proteoglycans • TheyexpressseveralhundredthousandhighaffinityreceptorsforIgE (FceR1) and thusrespondtoIgE-directedantigens • Express thepathogen-recognizingToll-likereceptors (TLRs) whichprobably account fortheability of mastcellstomount an effectiveinnateimmuneresponse Pathogens TLRs Synthesis of eicosanoids from arachidonic acid Allergens FcRI Production of cytokines Stem cell factor cKit

  4. Selectedmediatorsproducedbymastcells

  5. Othermastcellactivators • MIP-1a: macrophageinflammatorychemokine • C3a, C5a anaphylatoxins: complement • Neuropeptides : P-substance, somatostatin, VIP • FcgR - IgG

  6. IgEboundFceR I VH VL VL VH IgE C1 CL CL Cε1 BoundIgE N C4 C4 CH3 C2 C2 a C3 FcRI FcR I g a g 1 N N N N 2 b b P P P P N C N LYN SYK ITAMs P P P P P P C C C C C C ITAMs

  7. IgEboundFcR II FcRII Head domain VH VL VL VH C-terminal tail IgE Ce1 CL CL Cε1 Ce4 Ce4 CH3 Ce2 Ce2 Coiled-coil stalk Ce3 N-linked glycolisation FcR II N N N

  8. IL-4 and IL-13 signalinduceIgEswitch IL-4 IL-13 IL-4R C IL-4R IL-13R1/2 P P JAK1 JAK3 JAK1 Tyk1 P P Tyk2 P P P P STAT6 dimer translocatestonucleus STAT6 STAT6

  9. The IgEpromoterregion Activation/cytokine responsive promoter I S C1 C2 C3 C4 C/EBP PU.1 NFB BSAP Stat6 AP-1 I • CD40L IL-4,13 BSAP – B cell specific activator protein C/EBP CCAAT/enhancer binding protein PU.1 – Spi1 equivalent in humans

  10. Signaltransductionpathways IgE a a FcRI FcRI g g Antigen b b Plasmamembrane Cytoplasm LYN SYK BTK GRB2 SOS Nck SPL-76 GADs LAT PLC P IP3 DAG VAV P PKC Ca2+

  11. FcRI mediatedsignaling a FcRI ? NTAL g b Lipidraft Plasma membrane PIP2 PIP3 Sphingosine S1P PLC BTK FYN SK SYK SYK PI3K LYN Y P P GAB2 PLD Y P GRB2 GRB2 Y P SOS VAV RAS IP3 GDP RAS GTP MAPKKK or RAF MAPKK MAPKs Transcriptionfactors Ca2+ Cytokines Degranulation

  12. Similarities in TcR and FceR signaling a b TCR IgE d e e g z g z g Antigen-specific receptor a CD3 CD3 FcRI b Lck Lyn ZAP-70 ZAP-70 ITAM ITAM Syk Src-family kinase Syk-family kinase ZAP-70 expression is restrictedto T cells, NK cells and a subpopulation of CLL Syk is presentin most hematopoeticcelltypes

  13. Biologicaleffects of FcεRsignaling Allergen P P P P Signalingpathways P P P P P P Transcriptional activation of cytokine genes Enzymatic modification of arachidonic acid Granulewith preformedmediators Cytokines Lipid mediators Granuleexocytosis Secretion Secretion Proteases Vasoactiveamines Cytokines, e. g., TNF Leukotrienes Prostaglandins Tissuedamage Vasculardilatation, smoothmusclecontraction Inflammation (leukocyterecruitment) Smoothmuscle contraction Vasculardilatation

  14. Mastcellmediators • Biogenamines: histamin, serotonin (H1,2,3,4R) →vasodilatation, plasmaleak, smoothmuscleconsriction • Serin proteases:tryptase, chymase, carboxypeptodase A, cathepsin G • Proteoglycans:heparin, chondroitinsulphate • Lipidmediators: rapid de novosynthesis ProstaglandineD2, Leukotrien C4, D4, E4, PAF → vasodilatation, bronchusconstriction • Cytokines: TNF, IL-1, IL-4, IL-5, IL-6, IL-13, MIP-1a, IL-3, GM-CSF

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