Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP /1/A

FCΕ RECEPTOR SIGNALING Tímea Berki and Ferenc Boldizsár Signal transduction Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP /1/A

TÁMOP /1/A Mast cell activation mechanisms They express several hundred thousand high affinity receptors for IgE (Fc  R1) 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 TLRs Granule constituents: histamine, proteases, proteoglycans Allergens Fc  RI Synthesis of eicosanoids from arachidonic acid

TÁMOP /1/A Selected mediators produced by mast cells MediatorsPotential role in atherosclerosis Pro-inflammatory cytokines: IL-4, IL-5, IL-6, IL-13, IL-18, IFN-γ, TNF-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- , PDGF angiogensis cellular proliferation

TÁMOP /1/A Other mast cell activators MIP-1  : macrophage inflammatory chemokine C3a, C5a anaphylatoxins: complement Neuropeptides : P-substance, somatostatin, VIP Fc  R - IgG

TÁMOP /1/A IgE bound Fc  R I 11 22 C2C2 C4C4 C H3 C2C2 C3C3 C4C4 VLVL CLCL VHVH VHVH C ε1 C1C1 VLVL CLCL  N C P  N N CC ITAMs PP PP  IgE Fc  R I IgE Bound IgE  N C  N C P  N N CC ITAMs PP PP Fc  R I LYN SYK

TÁMOP /1/A Fc  R II N N N C-terminal tail Head domain Coiled-coil stalk N-linked glycolisation C2C2 C4C4 C H3 C2C2 C3C3 C4C4 VLVL CLCL VHVH VHVH C ε1 C1C1 VLVL CLCL IgE Fc  R II IgE bound Fc  R II

TÁMOP /1/A IL-4 and IL-13 signal induce IgE switch P P JAK3 JAK1 P P P STAT6 Tyk1 IL-4 IL-4R CC Tyk2 JAK1 P P P STAT6 IL-13 IL-4R  IL-13R  1/2 STAT6 dimer translocates to nucleus

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

TÁMOP /1/A Signal transduction pathways IP3 Plasma membrane SYK PLC  Ca 2+ LAT GADs DAG PKC SPL-76 LYN P P    Fc  R I    BTK VAV Nck Antigen IgE Cytoplasm

TÁMOP /1/A Fc  RI mediated signaling PIP 3 BTK Sphingosine SK PLD IP 3 PIP 2 RAS MAPKKK or RAF MAPKKK or RAF MAPKK MAPKs CytokinesCytokinesDegranulationDegranulation Transcription factors Plasma membraneLipid raft GRB2 SOS NTAL ? P P Y P Y P Y GAB2 GRB2    Fc  R I LYN SYK PI3K PLC  VAV Ca 2+ GTPGTP GDPGDP S1P FYN

TÁMOP /1/A Similarities in TcR and Fc  R signaling Lyn Lck   IgEITAM Fc  RI 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 CD3   ITAM Syk

TÁMOP /1/A Biological effects of FcεR signaling P PP PP P PP PP Signaling pathways Enzymatic modification of arachidonic acid Enzymatic modification of arachidonic acid Transcriptional activation of cytokine genes Transcriptional activation of cytokine genes Granule with preformed mediators Granule exocytosis Lipid mediators Secretion Cytokines LeukotrienesProstaglandins Vasoactive amines Cytokines, e. g., TNF Vascular dilatation, smooth muscle contraction Tissue damage Vascular dilatation Smooth muscle contractionInflammation (leukocyte recruitment) Allergen Proteases

TÁMOP /1/A 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-1 , IL-3, GM-CSF