Signaling compartments and proteolysis in regulation of immune responses and the communikation between the immune- and nervous systems  Page description

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Details of project

  
Identifier
44711
Type NI
Principal investigator Gergely, János
Title in Hungarian Jelátviteli kompartmentek és proteolózis az immunválasz, valamint az immun- és idegrendszer közötti kommunikáció szabályozásában
Title in English Signaling compartments and proteolysis in regulation of immune responses and the communikation between the immune- and nervous systems
Panel Immunity, Cancer and Microbiology
Department or equivalent Department of Immunology (Eötvös Loránd University)
Participants Ábrahám, István
Erdei, Anna
Gráf, László
Hegyi, György
Juhász, Gábor
László, Glória
Matkó, János
Nyitray, László
Prechl, József
Sármay, Gabriella
Sass, Miklós
Szilágyi, László
Starting date 2003-01-01
Closing date 2005-12-31
Funding (in million HUF) 82.800
FTE (full time equivalent) 0.00
state closed project





 

Final report

  
Results in Hungarian
Több új immunreceptor-kölcsönhatást (FcR/CR/BCR; sejthalál-R/TCR), és több szabályozó mechanizmust azonosítottunk a lipid raftok és más membrán mikro-kompartmentek, valamint limfocita adaptor fehérjék részéről, melyek fontosak a limfociták effektor funkcióiban ill. a sejthalál folyamatában. Leírtuk az utóbbi folyamatokban kritikus miozin motorfehérje izotípusok néhány molekuláris kapcsolatának szerkezeti hátterét és szabályozási lehetőségét. Kimutattuk egyes komplement (C) faktorok és receptorok sokrétű szerepét az immunválasz szabályozásában és, hogy a belőlük származtatott peptidekkel az allergiás hízósejtválasz gátolható. Leírtuk a C-rendszer szabályozó szerepét a Sclerosis Multiplex (SM) állatmodelljében is. Kimutattuk a tripszin-szerű proteáz aktivitás szabályozó szerepét a B-sejt válaszban, és valószínűsítettük szerepüket a mielin bázikus fehérje specifikus hasításában, mely fontos eleme lehet az SM kialakulásának. Eredményeink alapját képezik szelektív immunmodulánsok kifejlesztésének autoimmun ill. allergiás kórképekben. Kimutattunk egyes immunrendszeri effektor- és idegrendszeri funkciók között fellépő, a citokin hálózat ill. steroid hormonok (ösztrogének, glukortikoidok) útján megvalósuló kommunikációs útvonalakat. Új módszereket is kifejlesztettünk (pl. antigén-targetingre alkalmas egyláncú ellenanyag konstrukciók) és a projekt támogatásával beszereztünk egy konfokális mikroszkópot, melyen több új metodikát optimalizáltunk a celluláris kommunikáció vizsgálatára.
Results in English
We identified several novel immunoreceptor cross-talk elements (FcR/CR/BCR; cell death-R/TCR) and regulatory mechanisms by lipid rafts, other membrane-compartments, as well as adaptor proteins, which are essential in the lymphocytes’ effector functions and cell death. Structural and regulatory aspects of some important molecular interactions of myosin motor protein isotypes, essential players in the above processes, were also described. Multiple regulatory functions of the complement system in the immune response and the inhibitory potential of C3a-derived peptides in the allergic mast cell response were identified. The regulatory potential of the complement system was also shown in an animal model of Sclerosis Multiplex (SM). We have shown that trypsin-like protease activities are involved the B cell response through formation of soluble receptors and that trypsin-4, specifically cleaving MBP, may be a critical element in development of SM. Our results form a basis for development of selective immunomodulators for autoimmune- and allergic diseases. We explored several novel communication pathways between effector mechanisms of the immune system and certain nervous system functions, through the inflammatory cytokine network and steroid hormones. New methods and molecular constructs (e.g. antigen-targeting by engineered single-chain antibodies) and several modern confocal imaging techniques for studying cellular communication were also developed with the support of the grant.
Full text http://real.mtak.hu/1232/
Decision
Yes





 

List of publications

  
Fodor K, Harmat V, Neutze R, Gráf L, Katona G: Atomic Resolution structure of a Trypsin:polypeptide inhibitor complex as a model of the catalytic Michaelis complex, Biochemistry (accepted, in press), 2006
Bíró A, Hérincs Z, Fellinger E, Szilágyi L, Barad Zs, Gergely J, Gráf L, Sármay G: Characterization of a trypsin-like serine protease of activated B cells mediating the cleavage of surface proteins., Biochim Biophys Acta 1624: 60-69, 2003
Molnár E, Prechl J, Isaák A, Erdei A: Targeting with scFv: immune modulation by complement receptor specific constructs., J Mol Recognition 16: 318-323, 2003
Erdei A, Andrásfalvy M, Péterfy H, Tóth G, Pecht I: Regulation of mast cell activation by complement derived peptides, Immunology Letters (review) 92: 39-42, 2004
Mastellos D, Prechl J, László G, Papp K, Oláh E, Argyropoulos E, Franchini S, Tudoran R, Markiewski M, Lambris JD, Erdei A: Novel monoclonal antibodies against mouse C3 interfering with complement activation: description of fine specificity and applications to various immunoassays., Molecular Immunology 40: 1213-1221, 2004
Gombos I, Detre C, Vámosi G, Matkó J: Rafting MHC-II domains in the APC (presynaptic) plasma membrane and the thresholds of T cell activation and immunological synapse formation, Immunology Letters 92: 117-124, 2004
Vereb G, Matkó J, Szöllősi J: Cytometry of Fluorescence Resonance Energy Transfer, Methods in Cell Biology 75: 105-152, 2004
Gombos I, Bacsó Z, Detre C, Nagy H, Goda K, Andrásfalvy M, Szabó G, Matkó J: Cholesterol-sensitivity of detergent resistance: A rapid flow cytometric test for detecting constitutive or induced raft association of membrane proteins, Cytometry 61A: 117-126, 2004
Medgyesi D, Sárközi R, Koncz G, Arató K, Váradi Gy, Tóth GK, Sármay G: Functional consequences of a MAPK docking site on human FcgRIIb, Immunology Letters 92: 83-90, 2004
Zoualy M, Sármay G: B lymphocyte signaling pathways in systemic autoimmunity, Arthritis & Rheumatism 50: 2730-2741, 2004
Medgyesi D, Uray K, Sallai K, Hudecz F, Koncz G, Abramson J, Pecht I, Sármay G, Gergely J: Functional mapping of the Fc gamma RII binding site on human IgG1 by synthetic peptides, European Journal of Immunology 34: 1127-1135, 2004
Kövesdi D, Pászty K, Enyedi Á, Kiss E, Matkó J, Ludányi K, Rajnavölgyi É, Sármay G: Antigen receptor-mediated signalling pathways in transitional immature B cells, Cellular Signalling 16: 881-889, 2004
Kiss E, Sármay G, Matkó J: Ceramide-modulation of antigen-triggered Ca2+-signals and cell fate: diversity in the responses of various immunocytes, Annals of New York Academy of Sciences (accepted, in press), 2006
Gombos I, Lőrincz A, Pomozi I, Steinbach G, Garab Gy, László G, Matkó J: How much do the different lipid raft markers overlap? A fluorescence imaging study, FEBS Journal, Vol. 272 Suppl. 1: 220, 2005
Detre C, Kiss E, Varga Z, Ludányi K, Pászty K, Enyedi Á, Panyi G, Rajnavölgyi É, Matkó J: Dual face of ceramide: non-apoptotic ceramide stimuli modulate antigen-specific T cell activation through blocking plasma membrane ion channels, FEBS Journal, Vol. 272 Suppl. 1: 193, 2005
Látos H, Uzonyi B, Prechl J, Matkó J, László G: Correlation between the origin and functional properties of monocyte/macrophage cells and their CD19 and CD21 expression., Magyar Immunológia 2004/3: 51-52, 2004
Matkó J, Szöllősi J: Regulatory Apects of Membrane Microdomain (Raft) Dynamics in Live Cells: A Biophysical Approach., In: “Membrane Microdomain Signaling: Lipid Rafts in Biology and Medicine” (Ed. M. Mattson), Humana Press, Totowa, NJ, 2005
Virág V, Prechl J, Erdei A: Production of tetrameric single-chain antibodies using enzymatic biotinylation, FEBS Journal Vol. 272, Suppl.1: 519, 2005
Sármay G, Kertész A, Takács B, Angyal A, Medgyesi D, Váradi G, Tóth G: The role of Grb2 associated binder 1 (Gab1) scaffolding adaptor protein on signal transduction in human B cells, FEBS Journal, Vol. 272 Suppl. 1: 323, 2005
Maus M , Kövesdi D, Medgyesi D, Sarmay G: The role of Grb2 associated binder 2 (Gab2) scaffolding adaptor protein in B cell receptor signaling, FEBS Journal, Vol. 272 Suppl. 1: 322, 2005
Detre C, Kiss E, Varga Z, Ludányi K, Pászty K, Enyedi Á, Kövesdi D, Panyi G, Rajnavölgyi É, Matkó J: Death or survival: Membrane ceramide controls the fate and activation of antigen-specific T cells depending on signal strength and duration, Cellular Signalling 18:294-306, 2006
Molnár E, Prechl J, Balogh P, Balla B, Erdei A: A subpopulation of mouse T-cells expresses type 2 complement receptor (CR2/CD21), Magyar Immunológia 2004/3: 54-55., 2004
Sármay G, Angyal A, Kertész Á, Maus M, Medgyesi D: The multiple function of Grb2 associated binder (Gab) adaptor/scaffolding protein in immune cell signalling, Immunology Letters 104: 76-82, 2006
E. Csomor, Zs. Bajtay, N. Sándor, S. Thiel, G. J. Arlaud, A. Erdei: Immobilized C1q induces maturation of human monocyte-derived dendritic cells, FEBS Journal, Vol. 272 Suppl. 1: 288, 2005
Ludanyi K, Gogolak P, Rethi B, Detre C, Matko J, Rajnavolgyi, E: Fine tuning of helper T cell activation and cell death by antigen presenting cells, Cellular Signaling 16:939-950, 2004
Terényi N, Prechl J, Erdei A: MOG peptide specific antibody response in the mouse model of multiple sclerosis shows no correlation with the severity of disease, FEBS Journal, Vol. 272 Suppl. 1: 293, 2005
Szekeres Zs , Isaák A, Prechl J, Erdei A: Generation of a fusion protein containing DNA-like peptide and a single chain antibody, FEBS Journal, Vol. 272 Suppl. 1: 529, 2005
Hódi Zs, Németh A, Kovács E, Hetényi Cs, Bodor A, Perczel A, Nyitray L: The dynein light chain binds to a non-coiled-coil tail domain of myosin-Va that includes an alternatively spliced exon coding for three amino acid residues, FEBS Journal, Vol 272,Suppl. 1: 335, 2005
Nyilas R, Szepesi Zs, Papp AM, Lőrincz LM, Veisenberger E, Tóth J, Medveczky P, Szilágyi L, Juhász G: Light-induced upregulation of Matrix Metalloproteinase-9 and -2 at transcriptional and protein level in rat eye, FENS, Lisszabon, 2004
Barabás K, Szegő É, Kövesdi D, Barad Zs, Kaszás A, Sármay G, Juhász G, Ábrahám I: Is the B-cell activation and immune response-induced MAPK phosphorylation in GnRH neuron estrogen-dependent?, Steroids and Nervous System, Torino,Italy, 2005
Gombos I, Kiss E, Detre C, László G, Matkó J: Cholesterol and sphingolipids as lipid organizers of the immune cells’ plasma membrane: Impact on the functions of MHC molecules, effector T-lymphocytes and T-cell death, Immunology Letters 104: 59-69, 2006
Kertész Á, Takács B, Váradi Gy, Tóth GK, Sármay G: Design and functional activity of phosphopeptides with potential immunomodulating capacity, based on the sequence of Grb2 associated binder 1 (Gab1), Annals of New York Academy of Sciences (accepted, in press), 2006
Angyal A, Medgyesi D, Sármay G: Grb2 associated binder 1 (Gab1) adaptor/scaffolding protein regulates Erk signal in human B cells, Annals of New York Academy of Sciences (accepted, in press), 2006
Debreczeni J, Farkas L, Harmat V, Hetényi Cs, Hajdú I, Závodszky P, Kohama K, Nyitray L: Structural evidence for non-canonical binding of Ca2+ to a canonical EF- hand of a conventional myosin, Journal of Biological Chemistry 280: 41458-41464, 2005
Hegyi G, Belagyi J: Intermonomer cross-linking of F-actin alters the dynamics of its interaction with H-meromyosin in the weak-binding state, FEBS Journal 273(9):1896-905, 2006
Toth J, Kovacs M, Wang F, Nyitray L, Sellers JR: Myosin V from Drosophila reveals diversity of motor mechanisms within the myosin V family, Journal of Biological Chemistry 280:30594-603, 2005
Markiewski MM, Mastellos D, Tudoran R, DeAngelis RA, Strey CW, Franchini S, Wetsel RA, Erdei A, Lambris JD: C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury, Journal of Immunology 173:(2): 747-754, 2004
Andrasfalvy M, Péterfy H, Tóth G, Matkó J, Abramson J, Kerekes K, Vámosi G, Pecht I, Erdei A: The β subunit of the type I Fcε receptor is a target for peptides inhibiting IgE-mediated secretory response of mast cells, Journal of Immunology 175: 2801-2806, 2005
Isaák A, Prechl J, Gergely J, Erdei A: The role of CR2 in autoimmunity, Autoimmunity (accepted, in press), 2006
Terényi N, Prechl J, Erdei A: The role of complement system in the patogenesis of Experimental Allergic Encephalomyelitis and Multiple Sclerosis, in: Current Topics in Complement (Ed JD Lambris) pp. 177-188, 2006
Bajtay Zs, Csomor E, Sándor N, Erdei A: Expression and role of Fc- and complement-receptors on human dendritic cells, Immunology Letters 104: 46-52, 2006
Fodor K, Harmat V, Hetenyi C, Kardos J, Antal J, Perczel A, Patthy A, Katona G, Graf L: Extended intermolecular interactions in a serine protease-canonical inhibitor complex account for strong and highly specific inhibition, Journal of Molecular Biology 350 (1): 156-169, 2005
Medveczky P, Antal J, Patthy A, Kekesi K, Juhasz G, Szilagyi L, Graf L: Myelin basic protein, an autoantigen in multiple sclerosis, is selectively processed by human trypsin 4, FEBS Letters 580(2):545-52, 2006
Kovács Z, Kékesi KA, Szilágyi N, Ábrahám I, Székács D, Király N, Papp E, Császár I, Szegő É, Barabás K, Péterfy H, Erdei A, Bártfai T, Juhász G: Facilitation of spike-wave discharge activity by lipopolysaccharides in Wistar albino GLAXO/RIJSWIJK rats, Neuroscience 140: 731-742, 2006
Fodor K, Szenthe B, Medveczky P, Gráf L: The pacifastin inhibitor family: structure and specificity, Current Protein and Peptide Science (accepted, in press), 2006
Kovács Z, Kékesi KA, Szilágyi N, Ábrahám I, Székács D, Király N, Papp E, Császár I, Szegő É, Barabás K, Péterfy H, Erdei A, Bártfai T, Juhász G: Facilitation of spike-wave discharge activity by lipopolysaccharides in Wistar albino GLAXO/RIJSWIJK rats, Neuroscience 140: 731-742, 2006
Szegő É, Barabás K, Balog J, Szilágyi N, Korach KS, Juhász G, Ábrahám I: Estrogen induces Estrogen Receptor α-dependent cAMP Response Element-Binding protein phosphorylation via Mitogen Activated Protein Kinase pathway in basal forebrain cholinergic neurons, Journal of Neuroscience 26: 4104-4110, 2006
Kovács Zs, Kékesi KA, Bobest M, Török T, Szilágyi N, Szikra T, Szepesi Zs, Nyilas R, Dobolyi Á, Palkovits M, Juhász G: Post mortem degradation of nucleotides int he brain: Comparison of human and rat brains for estimation of in vivo concentrations of nucleosides, Journal of Neuroscience Methods 148: 88-93, 2006
Galambos R, Juhász G, Lorincz M, Szilágyi N: The human retinal functional unit, International Journal of Psychophysiology 57: 187-194, 2005
Ábrahám IM, Herbison AE: Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo, Neuroscience 131: 945-951, 2005
Akdemir F, Farkas R, Chen P, Juhász G, Medvedova L, Sass M, Wang L, Wang X, Chittarajan S, Gorski S, Rodriguez A, Abrams J: Autophagy occurs upstream or parralel to the apoptosome during cytolytic cell death, Development 133: 1457-1465, 2006
Rusten TE, Lindmo K, Juhász G, Sass M, Seglen PO, Breck A, Stenmark H: Programmed autophagy in the drosophila fat body is induced by ecdysone and effected through the PI3K pathway, Developmental Cell 7: 179-192, 2004
Ábrahám IM, Meerlo P, Luiten PGM: Concentration dependent actions of glucocorticoids on neuronal viability and survival., Dose-Response, 4: 38-54, 2006
Hódi Zs, Németh A, Hetényi Cs, Bodor A, Perczel A, Nyitray L: Alternatively spliced exon B of myosin Va is essential for binding of the tail light chain shared by dynein, J. Muscle Res. Cell Motility. 26:73, 2005
Farkas L, Debreczeni J, Harmat V, Hetényi Cs, Hajdú I, Závodszky P, Kohama K, Nyitray L: Ca2+ inhibits the activity of a myosin II by binding to an EF-hand of a calmodulin-like light chain and altering the dynamics of the neck region, J. Muscle Res. Cell Motility. 26:72, 2005
Süveges D, Németh A, Gáspári Z, Tóth G, Nyitray L: Helical tail fragments of myosin VI exist as monomeric, highly flexible structures, J. Muscle Res. Cell Motility. 26:74, 2005
Tóth J, Medveczky P, Szilágyi L, Gráf L: Central nervous system proteases in health and disease, Handbook of Neurochemistry and Molecular Neurobiology, 3rd ed. (Lajtha A ed.) Springer-Verlag (in press), 2006



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