Dorottya Kövesdi

Publications (10)27.34 Total impact

• Source

  Available from: Eszter Szarka

  Article: Exacerbation of collagen induced arthritis by Fcγ receptor targeted collagen peptide due to enhanced inflammatory chemokine and cytokine production.

  Eszter Szarka, Zsuzsa Neer, Péter Balogh, Monika Adori, Adrienn Angyal, József Prechl, Endre Kiss, Dorottya Kövesdi, Gabriella Sármay
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  ABSTRACT: Antibodies specific for bovine type II collagen (CII) and Fcγ receptors play a major role in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). Our aim was to clarify the mechanism of immune complex-mediated inflammation and modulation of the disease. CII pre-immunized DBA/1 mice were intravenously boosted with extravidin coupled biotinylated monomeric CII-peptide epitope (ARGLTGRPGDA) and its complexes with biotinylated FcγRII/III specific single chain Fv (scFv) fragment. Disease scores were monitored, antibody titers and cytokines were determined by ELISA, and binding of complexes was detected by flow cytometry and immune histochemistry. Cytokine and chemokine secretion was monitored by protein profiler microarray. When intravenously administered into collagen-primed DBA/1 mice, both CII-peptide and its complex with 2.4G2 scFv significantly accelerated CIA and increased the severity of the disease, whereas the monomeric peptide and monomeric 2.4G2 scFv had no effect. FcγRII/III targeted CII-peptide complexes bound to marginal zone macrophages and dendritic cells, and significantly elevated the synthesis of peptide-specific IgG2a. Furthermore, CII-peptide containing complexes augmented the in vivo secretion of cytokines, including IL-10, IL-12, IL-17, IL-23, and chemokines (CXCL13, MIP-1, MIP-2). These data indicate that complexes formed by the CII-peptide epitope aggravate CIA by inducing the secretion of chemokines and the IL-12/23 family of pro-inflammatory cytokines. Taken together, these results suggest that the in vivo emerging immune complexes formed with autoantigen(s) may trigger the IL-12/23 dependent pathways, escalating the inflammation in RA. Thus blockade of these cytokines may be beneficial to downregulate immune complex-induced inflammation in autoimmune arthritis.
  Biologics: Targets & Therapy 01/2012; 6:101-15.
• Article: Differential expression of FCRLA in naïve and activated mouse B cells.

  Evdokiya S Reshetnikova, Ludmila V Mechetina, Olga Y Volkova, Sergey V Guselnikov, Nikolai A Chikaev, Dorottya Kövesdi, Boris Alabyev, Gabriella Sármay, Peter D Burrows, Alexander M Najakshin, Alexander V Taranin
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  ABSTRACT: FCRLA is an intracellular B cell protein that belongs to the FcR-like family. Using newly generated FCRLA-specific antibodies, we studied the constitutive expression pattern of mouse FCRLA and monitored changes during an immune response and following in vitro B cell activation. All B cell subpopulations examined expressed FCRLA. However, the level of FCRLA expression is determined by the stage of B cell differentiation. Low expression of FCRLA is characteristic of naïve follicular and marginal zone B cells. High expression was detected in a small fraction of activated B cells scattered along migratory pathways in the lymphoid tissues. FCRLA-bright cells could be subdivided into two subpopulations, with high and low/undetectable level of intracellular immunoglobulins, which phenotypically resemble either plasma or memory B cells. High expression of FCRLA in subset(s) of terminally differentiated B-cells suggests that, being an ER protein, FCRLA may participate in the regulation of immunoglobulin assembly and secretion.
  Cellular Immunology 10/2011; 272(2):182-92. · 1.97 Impact Factor
• Source

  Available from: Gabriella Sarmay

  Article: Estrogen augments the T cell-dependent but not the T-independent immune response.

  Mónika Adori, Endre Kiss, Zsuzsanna Barad, Klaudia Barabás, Edda Kiszely, Andrea Schneider, Dorottya Kövesdi, Erna Sziksz, István M Abrahám, János Matkó, Gabriella Sármay
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  ABSTRACT: Estrogen plays a critical regulatory role in the development and maintenance of immunity. Its role in the regulation of antibody synthesis in vivo is still not completely clear. Here, we have compared the effect of estrogen on T cell-dependent (TD) and T cell-independent type 2 (TI-2) antibody responses. The results provide the first evidence that estrogen enhances the TD but not the TI-2 response. Ovariectomy significantly decreased, while estrogen re-administration increased the number of hapten-specific IgM- and IgG-producing cells in response to TD antigen. In vitro experiments also show that estrogen may have a direct impact on B and T cells by inducing rapid signaling events, such as Erk and AKT phosphorylation, cell-specific Ca(2+) signal, and NFkappaB activation. These non-transcriptional effects are mediated by classical estrogen receptors and partly by an as yet unidentified plasma membrane estrogen receptor. Such receptor- mediated rapid signals may modulate the in vivo T cell-dependent immune response.
  Cellular and Molecular Life Sciences CMLS 02/2010; 67(10):1661-74. · 6.57 Impact Factor
• Article: The development of mature B lymphocytes requires the combined function of CD19 and the p110δ subunit of PI3K.

  Dorottya Kövesdi, Sarah E Bell, Martin Turner
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  ABSTRACT: Mice lacking either CD19 or p110δ have reduced numbers of marginal zone and B1 B cells but normal numbers of naïve B2 cells which occupy the follicles of the lymphoid organs. We show here that mice lacking both CD19 and p110δ have normal B cell development in the bone marrow but have a significant reduction in the number of naïve B2 cells in the bone marrow, spleen and lymph nodes. These p110δ/CD19 double mutant B cells show a survival defect and reduced responsiveness to the pro-survival cytokine BAFF despite normal NFκB2/p100 processing and elevated expression of Bcl-2. Although the combined loss of p110δ and CD19 did not increase switching to Ig-lambda in immature B cells, mature B lymphocytes from the lymph nodes of p110δ/CD19 double mutant mice express highly elevated levels of mRNA encoding RAG-1 and RAG-2, which confirms the existing synergy between CD19 and p110δ-mediated signaling.
  Self/Nonself - Immune Recognition and Signaling 01/2010; 1(2):144-153.
• Article: Grb2 associated binder 2 couples B-cell receptor to cell survival.

  Máté Maus, Dávid Medgyesi, Dorottya Kövesdi, Dorottya Csuka, Gábor Koncz, Gabriella Sármay
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  ABSTRACT: B-cell fate during maturation and the germinal center reaction is regulated through the strength and the duration of the B-cell receptor signal. Signaling pathways discriminating between apoptosis and survival in B cells are keys in understanding adaptive immunity. Gab2 is a member of the Gab/Dos adaptor protein family. It has been shown in several model systems that Gab/Dos family members may regulate both the anti-apoptotic PI3-K/Akt and the mitogenic Ras/MAPK pathways, still their role in B-cells have not been investigated in detail. Here we studied the role of Gab2 in B-cell receptor mediated signaling. We have shown that BCR crosslinking induces the marked phosphorylation of Gab2 through both Lyn and Syk kinases. Subsequently Gab2 recruits p85 regulatory subunit of PI3-K, and SHP-2. Our results revealed that Ig-alpha/Ig-beta, signal transducing unit of the B-cell receptor, may function as scaffold recruiting Gab2 to the signalosome. Overexpression of Gab2 in A20 cells demonstrated that Gab2 is a regulator of the PI3-K/Akt but not that of the Ras/MAPK pathway in B cells. Accordingly to the elevated Akt phosphorylation, overexpression of wild-type Gab2 in A20 cells suppressed Fas-mediated apoptosis, and enhanced BCR-mediated rescue from Fas-induced cell death. Although PH-domain has only a stabilizing effect on membrane recruitment of Gab2, it is indispensable in mediating its anti-apoptotic effect.
  Cellular signalling 11/2008; 21(2):220-7. · 4.09 Impact Factor
• Article: Death or survival: membrane ceramide controls the fate and activation of antigen-specific T-cells depending on signal strength and duration.

  Cynthia Detre, Endre Kiss, Zoltán Varga, Katalin Ludányi, Katalin Pászty, Agnes Enyedi, Dorottya Kövesdi, György Panyi, Eva Rajnavölgyi, János Matkó
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  ABSTRACT: Sphingomyelinase (SMase)-mediated release of ceramide in the plasma membrane of T-lymphocytes induced by different stimuli such as ligation of Fas/CD95, irradiation, stress, inflammation or anticancer drugs primarily involves mitochondrial apoptosis signaling, but under specific conditions non-apoptotic Fas-signaling was also reported. Here we investigated, using a quantitative simulation model with exogenous C2-ceramide (and SMase), the dependence of activation and fate of T-cells on the strength and duration of ceramide accumulation. A murine, influenza virus hemagglutinin-specific T-helper cell (IP12-7) alone or together with interacting antigen presenting B-cells (APC) was used. C2-ceramide induced apoptosis of TH cells above a 'threshold' stimulus (>25 microM in 'strength' or >30 min in duration), while below the threshold C2-ceramide was non-apoptotic, as confirmed by early and late apoptotic markers (PS-translocation, mitochondrial depolarization, caspase-3 activation, DNA-fragmentation). The modest ceramide stimuli strongly suppressed the calcium response and inhibited several downstream signal events (e.g. ERK1/2-, JNK-phosphorylation, CD69 expression or IL-2 production) in TH cells during both anti-CD3 induced and APC-triggered activation. Ceramide moderately affected the Ca2+ -release from internal stores upon antigen-specific engagement of TCR in immunological synapses, while the influx phase was remarkably reduced in both amplitude and rate, suggesting that the major target(s) of ceramide-effects are membrane-proximal. Ceramide inhibited Kv1.3 potassium channels, store operated Ca2+ -entry (SOC) and depolarized the plasma membrane to which contribution of spontaneously formed ceramide channels is possible. The impaired function of these transporters may be coupled to the quantitative, membrane raft-remodeling effect of ceramide and responsible, in a concerted action, for the suppressed activation. Our results suggest that non-apoptotic Fas stimuli, received from previously activated, FasL+ interacting lymphocytes in the lymph nodes, may negatively regulate subsequent antigen-specific T-cell activation and thus modulate the antigen-specific T-cell response.
  Cellular Signalling 03/2006; 18(3):294-306. · 4.06 Impact Factor
• Article: Antigen receptor-mediated signaling pathways in transitional immature B cells.

  Dorottya Kövesdi, Katalin Pászty, Agnes Enyedi, Endre Kiss, János Matkó, Katalin Ludányi, Eva Rajnavölgyi, Gabriella Sármay
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  ABSTRACT: Engagement of antigen receptors on immature B cells induces apoptosis, while at the mature stage, it stimulates cell activation and proliferation. The difference in B cell receptor (BCR)-mediated signaling pathways regulating death or survival of B cells is not fully understood. We aimed to characterize the pathway leading to BCR-driven apoptosis. Transitional immature B cells were obtained from the spleen of sublethally irradiated and auto-reconstituted mice. We have detected a short-lived BCR-driven activation of mitogen-activated protein kinases (ERK1/2 and p38 MAPK) and Akt/PKB in transitional immature B cells that correlated with the lack of c-Fos expression, reduced phosphorylation of Akt substrates and a susceptibility for apoptosis. Simultaneous signaling through BCR and CD40 protected immature B cells from apoptosis, however, without inducing Bcl-2 expression. The BCR-induced apoptosis of immature B cells is a result of the collapse of mitochondrial membrane potential and the subsequent activation of caspase-3.
  Cellular Signalling 09/2004; 16(8):881-9. · 4.06 Impact Factor
• Article: Developmental differences in B cell receptor-induced signal transduction.

  Dorottya Kövesdi, Gábor Koncz, Roland Iványi-Nagy, Yael Caspi, Masamichi Ishiai, Tomohiro Kurosaki, János Gergely, Joseph Haimovich, Gabriella Sármay
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  ABSTRACT: We have compared early signaling events at various stages of B cell differentiation using established mouse cell lines. Clustering of pre-B cell antigen receptor (BCR) or BCR induced the tyrosine phosphorylation of various proteins in all cells, although the phosphorylation pattern differed. In spite of the pre-BCR-induced tyrosine phosphorylation, we could not detect an intracellular Ca(2+) signal in pre-B cells. However, co-clustering of the pre-BCR with CD19 did induce Ca(2+) mobilization. In contrast to the immature and mature B cells, where the B cell linker protein (BLNK) went through inducible tyrosine phosphorylation upon BCR clustering, we observed a constitutive tyrosine phosphorylation of BLNK in pre-B cell lines. Both BLNK and phospholipase C (PLC)gamma were raft associated in unstimulated pre-B cells, and this could not be enhanced by pre-BCR engagement, suggesting a ligand-independent PLC gamma-mediated signaling. Further results indicate that the cell lines representing the immature stage are more sensitive to BCR-, CD19- and type II receptors binding the Fc part of IgG (Fc gamma RIIb)-mediated signals than mature B cells.
  Cellular Signalling 07/2002; 14(6):563-72. · 4.06 Impact Factor
• Article: BCR mediated signal transduction in immature and mature B cells.

  Gábor Koncz, Csaba Bodor, Dorottya Kövesdi, Róbert Gáti, Gabriella Sármay
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  ABSTRACT: Ligation of B cell receptors (BCR) on immature B cells may induce apoptosis, while in mature B cells it stimulates cell activation and growth. The signaling pathway regulating the differential functional response, death or survival of the B cell is not fully characterized. We have tested the intracellular signaling requirement of these processes using B cells isolated from the spleen of irradiated auto-reconstituted (transitional immature B cells) and untreated mice (mature B cells), respectively. We compared the BCR induced intracellular [Ca2+] transient, protein tyrosine phosphorylation and ERK phosphorylation, furthermore, the activation of Elk-1 and CREB transcription factors. The BCR induced rise of intracellular [Ca2+] did not significantly differ in the two populations, only a slight difference in the late phase of the response was observed. Immature B cells responded with a maximum tyrosine phosphorylation to a five times lower dose of anti-IgM compared to the mature population. Most importantly, we have found a significant difference in the tyrosine phosphorylation of the Gab family adaptor proteins, Gab1/2. In contrast to mature B cells, crosslinking of BCR on immature B cells did not induce tyrosine phosphorylation of Gab2, thus the Gab2-organized signal amplification complex could not be produced. Furthermore, we detected a significant difference in the kinetics of BCR induced ERK, Elk-1 and CREB phosphorylation. In immature B cells, ERK was transiently phosphorylated, ceasing after 120 min, while in mature cells, ERK phosphorylation was sustained. Elk-1 and CREB activation was also transient in immature B cells, followed the kinetics of ERK phosphorylation. The lack of sustained Erk1/2 activation suppresses the transcription factors necessary for the proliferation signal. Since ERK is regulated by the phosphorylated Gab1/2, these data demonstrate that BCR triggered phosphorylation and signal amplification of Gab1/2 is a critical step in a life or death decision of B cells.
  Immunology Letters 07/2002; 82(1-2):41-9. · 2.53 Impact Factor
• Article: A hipothalamusz-hipofízis-gonád tengely és a humorális immunválasz kölcsönhatásának molekuláris mechanizmusa és szerepe az autoimmun betegségek kialakulásában: neuro-immuno-endokrin kölcsönhatások = Molecular mechanism of hypothalamo-pituitary-gonadal axis and humoral immune response interaction and its role in development of autoimmune disease: neuro-immuno-endocrine interactions

  István Ábrahám, Klaudia Barabás, Éva Batáryné Szegő, Dorottya Kövesdi, Dávid Medgyesi, Gabriella Sármay
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  ABSTRACT: A hypothalamus-hipofizis-gonád (HPG) tengely és az immunrendszer fontos kölcsönhatásban van egymással. Vizsgálatainkban ezen kölcsönhatásnak molekuláris mechanizmusait próbáltuk feltárni. Kísérleteinkben megmutattuk, a HPG tengely irányításában fontos szerepet betöltő GnRH neuronban lévő jelátviteli molekulák, mint az ERK fokozott aktivitást mutat T sejt dependens B sejt immunválasz kialakulásakor a 6. napon nőstény egerekben. Ebben feltehetőleg a citokinek, mint pl. az Il-10 jelentős szerepet játszhatnak. Ez a jelenség T sejt idenpendens B sejt válaszban nem mutatható ki. Megfigyeltük továbbá, hogy az ösztrogén jelentősen növeli a T sejt dependens B sejt immunitásban megfigyelhető ERK foszforilációt a GnRH neuronban. Érdekes módon ezek a változások nem alakították át az állatok ösztrusz ciklusának menetét. A HPG tengely végpontjában felszabaduló ösztrogén jelentősen növelte az antitestek és a B sejetek mennyiségét, és ez a növekedés a T sejtektől függ. A B és a T sejtekben az ösztrogén aktiválta ERK, Akt és NF?B jelátvivő molekulákat azonban csak a T sejtekben indukál növekedést az intraellularis Ca2+ koncentrációban. Az ösztrogén ezeket a nem-klasszikus hatásokat feltehetően a B és T sejtek membránjában meglévő ösztrogén receptorokon keresztül hozza létre. Kísérleti eredményeink fontos támpontot adhatnak a HPG tengely és az immunválasz interakciójának molekuláris mechanizmusaihoz, mely közelebb vihet minket a nemi dimorfizmust mutató autoimmun betegségek megértéséhez is. | Hypothalamo-pituitary-gonadal (HPG) axis has a critical interaction with the immune system. In our experiments, we investigated the molecular mechanism of this particular interaction. Our findings clearly demonstrate that T cell-dependent immune response induces signalling molecule activation, ERK, in the central processor unit of HPG axis, the gonadotropin releasing hormone (GnRH) neuron in female mice at sixth day following immunization. This phenomenon may depend on the cytokines such as Il-10 and it could not be observed in T cell independent immune response. Estrogen further enhances the immune response-induced ERK phospohrylation in GnRH neurons. Interestingly, T cell dependent immune challenge did not alter the estrus cycle. The estrogen, the ?endpoint? of the HPG axis, significantly increases the antibody concentration, the number of B cells and this enhancement highly depends on T cells. Although estrogen induces activation of several signalling molecules such as ERK, Akt and NF?B in B and T cells the estrogen-induced Ca2+ increase was only detected in T cells. It is very likely that estrogen exerts its non-classical actions via estrogen receptors in B and T cells. Taken together, these results shed a light on the molecular mechanism of interaction of HPG axis and immune response. Accordingly, our data may also help to understand the mechanism of certain gender related autoimmune diseases.