Gabriella Sármay Ph.D., D.Sc. Professor   Email: sarmayg(at)ttk.elte.hu

Short CV.:

• Graduated: as biologist, 1972, Eötvös Loránd University, Faculty of Natural Sciences
• PhD:1985, biology, Hungarian Academy of Sciences, Budapest
• D.Sc.: 1993, biology, Hungarian Academy of Sciences, Budapest
• Research training abroad: The Wellcome Research Laboratories, Beckenham, UK, (12 month,1977);
• Postdoc: Karolinska Institutet, Dept. of Tumor Biology, Stockholm, Sweden (1985,1986,1987); The Weizmann Institute of Science, Dept. of Chemical Immunology, Israel (1990, 1991), Sandoz Forschungsinstitute, Vienna International Research Cooperation Center, guest researcher (1992-1995).
• Széchenyi professorial fellowship: 1997-2000
• Present position: professor, ELTE TTK, Biological Institute, Department of Immunology, head of the Signal Transduction laboratory.

 

Research interest:

My main interest is the regulation of the humoral immune response, the “crosstalk” between receptors expressed on B lymphocytes. Binding of antigens and other ligands to the corresponding receptors on B cells stimulates intracellular signalling pathways that interact with each other and construct signalling networks determining the fate of the cell: activation, proliferation, differentiation or cell death. Simultaneously bound ligands induce signals that may collaborate and control B cells’ negative or positive selection, playing crucial role in maintenance of tolerance.

Failed positive selection may result in the development of autoimmune diseases. In our earlier works we studied the function of FcγR expressed on various cell types, identified the phosphatase responsible for FcγRIIb mediated inhibition of human B cells. We investigated differential signalling in immature and mature B cells and the function of the adaptor protein; Grb2 associated binder (Gab2) in B cell signalling. We have first described that Gab2 couples BCR mediated signals to cell survival. Disregulated signalling or failure in receptor crosstalk may lead to survival of autoreactive B cells, which escape from control and instead of remaining quiet or being deleted, produce autoantibodies against self tissue components. This might lead to the development of autoimmune diseases.

Recently we are working on Rheumatoid arthritis (RA), a systemic autoimmune disease. Approximately 70 % of RA patients produce autoantibodies specific for citrullinated self protein (anti-citrullinated protein/peptide antibodies, ACPA) (Fig. 1). First, by using a citullin/arginin containing peptide panel, we want to characterize various patients’ groups that may have different prognosis or might need different therapy. In collaboration with the MTA-ELTE Research Group of Peptide chemistry our aim is to identify new citrullinated peptide epitopes that can be used for diagostic purposes and that are suitable to develop novel diagnostic and therapeutic tools. We also study if receptor crosstalk in B cells from RA patients differs from that of healthy controls, and try to identify potential new drug targets. The present biological therapies do not cure the disease, only reduce symptoms; in our new project we will follow the recovery of various B cells subsets after biological therapy, and the role of regulatory B cells in RA. Finally, we study a mouse model of rheumatoid arthritis, collagen induced arthritis and want to clarify the role of T-bet and regulatory B cells in the disease pathomechanism.

 

Research projects

B-cell specific targeting: therapeutic possibilities for Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease, has a worldwide distribution with an estimated prevalence of about 1%, currently there is no cure for the disease. Therapies may only reduce the pain and stabilize the condition of the patients. Anti-citrullinated protein/peptide antibodies (ACPA) are present in sera samples of about 80 % of the patients. Detection of antibodies in patient's sera recognizing cyclic citrullinated peptides (CCP) has diagnostic significance. Identification of novel citrullinated peptide epitopes provides a better diagnosis of the disease, dissecting the patients into subgroups that may have different prognosis or need different therapy. The peptides are synthesized at the HAS-ELTE Research Group of Peptide Chemistry.

Fig.1. The hypothetical evolution of ACPA-positive RA from a pre-disease state into the chronic polyarthritis that fulfils criteria for RA.
(Lars Klareskog, Vivianne Malmström, Karin Lundberg, Leonid Padyukov, Lars Alfredsson; Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis; Seminars in Immunology 2011, 23: 92-98)

Our aims are:

1.) to develop new tools for the detection of ACPA, thus for the early diagnosis of RA. We develop and assess the diagnostic performances of immunoassays based on the recognition of new citrullinated fibrin/filaggrin/vimentin/collagen-derived synthetic peptides corresponding to the immunodominant epitopes recognized by ACPA. We also want to identify epitope peptides that are recognized by BCR on B cells of RA patients

2.) to design and synthesize bispecific multivalent peptide constructs that can be recognized by BCR on one hand and trigger effector mechanisms on the other. Such constructs would allow the development of potential therapies designed to eliminate B-cells responsible for ACPA production.

3.) to reveal the mechanism of B-cell regulation by FcγRIIb enhanced antibodies (FcγRIIbE), and its consequences on the life of B-cells. FcγRIIbE anti-CD19 antibody may inhibit B-cell signaling without killing the cells. We will gain new information on the interaction between CD19, Fcγ and toll-like recepetor 9 (TLR9) on B-cells, and elucidate the mechanism of B-cell inhibition by FcγRE antibodies, possibly applicable for RA therapy.

 

The multiple level of immunoregulation in Rheumatoid arthritis: the role of B-cells

Recent data strongly suggest that B cells are central players in RA. We want to investigate B-cell dependent factors in the pathogenesis of rheumatoid arthritis at the level of: autoantibodies (ACPA), B-cell subpopulations including naive, memory and regulatory B-cells, cytokine secretion, biological therapies and a mice model, collagen induced arthritis (CIA) (Fig. 2).

Fig. 2. The multiple level of immunoregulation by B cells (left)
Paws of CIA mice (right, up), bone deformities of an RA patient (right, down).

Major objectives:

1.) Our aim is to set up a HTS system based on Surface Plasmon Resonance analysis for screening the sera of RA patients and compare the affinity of antibodies specific for previously identified and new citrullinated peptide epitopes. We will also screen RA sera by an antibody-complement microarray (ABC array). Question: can we divide patients into subgroups having different severity of disease or different response to treatment based on affinity differences or complement activation properties of ACPA?

2.) Effector B cells may produce pro-inflammatory cytokines, while regulatory B cells (Breg) secrete IL-10 and contribute to the attenuation of immune response.
Questions: What kinds of stimuli induce cytokine secretion by B-cells? We want to identify signals resulting in differentiation of regulatory B cells. Are B cell subsets different in healthy donors and RA patients?

3.) Biological therapies profoundly improve the conditions of RA patients. Question: how biological therapies (rituximab, TNF blockers or IL-6 receptor antagonist) influence the recovery of B cell subsets (naïve, memory, Breg)?

4.) The transcription factor, T-bet is synergistically induced by BCR and TLR9 mediated signals in mice. Questions: how T-bet expression is regulated in different B cell subsets, how T-bet could contribute to the pathogenesis of CIA?

Significance

The combined data on specific recognition of citrullinated peptides and on the affinity of ACPA will provide better chance to dissect RA patients into subgroups, that might need different therapies and/or might have different prognosis of the disease. Exploring the signals leading to differentiation of Breg cells and resulting in cytokine secretion by various B cell subsets would support the development of new B cell targeted therapies. Monitoring the recovery of B cell functions after biological therapies will help to understand the mode of action of the biologicals as well as the pathomechanism of RA. Studying the mice model will provide new data on the role of transcription factors and regulatory B cells in the model of autoimmune arthritis.

 

Methods/Experience

• Cell culture, immuno-biochemical, protein chemical, and molecular biological techniques
• Signal transduction research: SDS PAGE electrophoresis, Western blot, ELISA, phospho-flow method
• Collagen induced arthritis mice model
• Cell analysis by multiparameter flow-cytometry and confocal microscopy, cell sorting (Becton-Dickinson FACSCalibur; BD FACS Aria III).

 

Support:

• NKTH ANR TÉT Hungarian- French bilateral consortial research grant (45 mFt, 2010-2013)
• OTKA-NFÜ CK 80689 Targeted research grant (49 mFt, 2010-2013)
• OTKA NK 104846 Consortial research grant (123 mFt, 2013-2016)

 

Selected publications:

• Bankó Z, Pozsgay J, Szili D, Tóth M, Gáti T, Nagy G, Rojkovich B, Sármay G. Induction and Differentiation of IL-10-Producing Regulatory B Cells from Healthy Blood Donors and Rheumatoid Arthritis Patients. J Immunol. 2017 Feb 15;198(4):1512-1520. doi: 10.4049/jimmunol.1600218.
• Huber K, Sármay G, Kövesdi D. MZ B cells migrate in a T-bet dependent manner and might contribute to the remission of collagen-induced arthritis by the secretion of IL-10. Eur J Immunol. 2016 Sep;46(9):2239-46. doi: 10.1002/eji.201546248.
• Pozsgay J, Babos F, Uray K, Magyar A, Gyulai G, Kiss É, Nagy G, Rojkovich B, Hudecz F, Sármay G.  In vitro eradication of citrullinated protein specific B-lymphocytes of rheumatoid arthritis patients by targeted bifunctional nanoparticles.  Arthritis Res Ther. 2016 Jan 16;18:15. doi: 10.1186/s13075-016-0918-0.
• Pozsgay J, Szarka E, Huber K, Babos F, Magyar A, Hudecz F, Sarmay G. Synthetic Peptide-Based ELISA and ELISpot Assay for Identifying Autoantibody Epitopes. Methods Mol Biol. 2016;1352:223-33. doi: 10.1007/978-1-4939-3037-1_17.  
• Szili D, Cserhalmi M, Bankó Z, Nagy G, Szymkowski DE, Sármay G. Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcγRIIb and CD19. MAbs. 2014 Jul-Aug;6(4):991-9. doi: 10.4161/mabs.28841.
• Szili D, Bankó Z, Tóth EA, Nagy G, Rojkovich B, Gáti T, Simon M, Hérincs Z, Sármay G. TGFβ activated kinase 1 (TAK1) at the crossroad of B cell receptor and Toll-like receptor 9 signaling pathways in human B cells. PLoS One. 2014 May 6;9(5):e96381. doi: 10.1371/journal.pone.0096381.
• Kövesdi D, Angyal A, Huber K, Szili D, Sármay G. T-bet is a new synergistic meeting point for the BCR and TLR9 signaling cascades. Eur J Immunol. 2013 Nov 18. doi: 10.1002/eji.201343841. [Epub ahead of print]
• Szarka E, Babos F, Magyar A, Huber K, Szittner Z, Papp K, Prechl J, Pozsgay J, Nagy G, Rojkovich B, Gáti T, Kelemen J, Baka Z, Brózik M, Pazár B, Poór G, Hudecz F, Sármay G. Recognition of new citrulline containing peptide epitopes by autoantibodies produced in vivo and in vitro by B cells of Rheumatoid arthritis patients. Immunology. 2013 Oct 1. doi: 10.1111/imm.12175. [Epub ahead of print]
• Babos F, Szarka E, Nagy G, Majer Z, Sármay G, Magyar A, Hudecz F. Role of N- or C-terminal biotinylation in autoantibody recognition of citrullin containing filaggrin epitope peptides in rheumatoid arthritis. Bioconjug Chem. 2013 May 15;24(5):817-27. doi: 10.1021/bc400073z. Epub 2013 May 6.
• Maus M, Medgyesi D, Kiss E, Schneider AE, Enyedi A, Szilágyi N, Matkó J, Sármay G. B cell receptor-induced Ca2+ mobilization mediates F-actin rearrangements and is indispensable for adhesion and spreading of B lymphocytes. J Leukoc Biol. 2013 Apr;93(4):537-47. doi: 10.1189/jlb.0312169. Epub 2013 Jan 29.
• Szarka E, Neer Z, Balogh P, Adori M, Angyal A, Prechl J, Kiss E, Kövesdi D, Sármay G.: Exacerbation of collagen induced arthritis by Fcγ receptor targeted collagen peptide due to enhanced inflammatory chemokine and cytokine production. Biologics: Targets and Therapy, 2012;6:101-15.
• Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, Jakobsson PJ, Baum W, Nimmerjahn F, Szarka E, Sarmay G, Krumbholz G, Neumann E, Toes R, Scherer HU, Catrina AI, Klareskog L, Jurdic P, Schett G.: Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012 122(5):1791-802.
• Anikó Hancz, Gábor Koncz, Dániel Szili, Gabriella Sármay: TLR9-mediated signals rescue B-cells from Fas-induced apoptosis via inactivation of caspases Immunology Letters 143 (2012) 77– 84 .
• Adori M; Kiss E; Barad Zs; Schneider A; Barabas K; Kiszel E ; Sziksz E; Matko J; Abraham I; Sarmay G: Estrogen enhances T-cell dependent but not the T-independent immune response, Cell Mol Life Sci 67 (10), pp. 1661-1674, 2010
• Maus M., Medgyesi D., Kövesdi D., Csuka D., Koncz G., Sármay G.: Grb2 associated binder 2 couples B-cell receptor to cell survival, Cellular Signaling 21, pp. 220-227, 2009
• Angyal A, J Prechl, G Sármay: Possible therapeutic applications of single-chain antibodies in systemic autoimmune diseases, Expert Opinion on Biological Therapy, 7, No. 5, pp. 691-704,2007
• Sarmay G, Angyal A, Kertesz A, Maus M, Medgyesi D.: The multiple function of Grb2 associated binder (Gab) adaptor/scaffolding protein in immune cell signaling., Immunol Lett. 104(1-2), pp. 76-82, 2006
• Zouali M, Sarmay G.: B lymphocyte signaling pathways in systemic autoimmunity: implications for pathogenesis and treatment. Arthritis Rheum. 50(9), pp. 2730-2741, 2004
• Kövesdi, D., Koncz, G., Iványi-Nagy, R., Ishiai, M ., Kurosaki, T., Gergely, J., Haimovich, J., and Sármay, G. Developmental differences in B cell receptor induced signal transduction Cell Signaling 2002, 14: 563-572
• Sarmay G, Koncz G, Gergely J.: Human type II Fcgamma receptors inhibit B cell activation by interacting with the p21(ras)-dependent pathway., J Biol Chem. 271(48), pp. 30499-30504, 1996
• Sarmay G, Pecht I, Gergely J.: Protein-tyrosine kinase activity tightly associated with human type II Fc gamma receptors., Proc Natl Acad Sci U S A. 91(10), pp. 4140-4144, 1994

 

List of all publications