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AG Thomas Winkler

Focus of research: AG Thomas Winkler

The group of Professor Thomas Winkler is interested in the regulation of processes generating immune receptor diversity and autoimmunity.

 

Prof. Dr. Thomas Winkler

Professur für Genetik (Prof. Dr. Winkler)

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During the development of B lymphocytes, the genes encoding immunoglobulins are compiled in a process of genetic recombination, that is responsible for the enormous variability of the antibody repertoire. We are interested in the regulation of this process, which is called VDJ-recombination. Although its mechanism is well understood, its regulation is still unclear. For example,  recombination of V-, D- and J-segments of all seven antigen-receptor gene clusters (3 immunoglobulin-gene cluster & 4 T-cell receptor gene cluster) occurs through the same enzyme machinery, but its expression is tightly regulated. Antibody genes are exclusively expressed in B cells, while T cell receptor genes are only recombined in T lymphocytes. In addition, recombination of gene segments for the light and heavy receptor chains is coordinated in a timely manner (Fig. 1), leading to each B lymphocyte only expressing one combination of heavy and light chain (a process termed allelic exclusion).

Fig. 1: Regulation of VDJ-recombination during the development of B lymphocytes (G. Galler).

The focus of our research work lies in the approachability of the Ig heavy chain gene cluster for the VDJ recombinase. We investigate epigenetic mechanisms of gene regulation through methods of chromatin analysis (ChIP-Seq, ChIP-on-Chip) and try to identify regulatory sequences within the IgH-gene locus.

Autoantibodies against DNA (ANAs) are characteristic for the autoimmune disease systemic lupus erythematodes (SLE). In our group, we investigate both the mechanisms of immunologic dysregulation that are causal for the emergence of ANAs, as well as their role in SLE pathology, especially for glomerulonephritis. In our projects, we work on murine models of SLE. Herein, we utilize spontaneous and genetically modified disease models, that we established through gene targeting.

Currently, we follow the hypothesis that such autoantibodies arise due to dysregulations during a process called germinal centre reaction. To adress this hypothesis, we use a mouse model overexpressing a patient-derived autoantibody.

Fig. 2: Indirect immunofluorescence of a monoclonal antibody on the nucleus of Hep2 cells (left) and direct immunofluorescence of IgG autoantibody depositions in the kidney (right).

Infection with the human cytomegaly virus (HCMV, HHV5) usually occur without onset of symptoms, with the virus being prevalent in 50-90% of the adult human population. Severe disease occurs in patients with a compromised immune system, as for example after an organ graft. Additionally, HCMV is an important congenically transferred pathogen, that can lead to severe prenatal manifestations.

In order to better understand the humoral immune response against this virus, our group cooperates with the group of Prof. Michael Mach from the Institute of Clinical Virology (University Hospital Erlangen). We hope to develop novel therapeutic concepts on the foundation of our findings.

We investigate both the human cytomegaly virus (HCMV) as well as its murine relative (murine cytomegaly virus, MCMV). Utilizing mice, we model MCMV infection in the context of clinically relevant immunosupression after bone-marrow transplantation. Novel therapeutic concepts utilizing memory B cells or monoclonal antibodies are tested in these mouse models. In a cooperation with the University Hospital Erlangen Clinic V, we want to translate these concepts into a clinical setting.

Fig. 3: In vivo bioluminescence imaging of a MCMV infection.

 

Thomas Winkler on Google Scholar

5 Key Publications

  1. Schmitt, H., S. Sell, J. Koch, M. Seefried, S. Sonnewald, C. Daniel, T.H. Winkler, and L. Nitschke. 2016. Siglec-H protects from virus-triggered severe systemic autoimmunity. J Exp Med213:1627-1644.
  2. Sell, S., M. Dietz, A. Schneider, R. Holtappels, M. Mach, and T.H. Winkler. 2015. Control of murine cytomegalovirus infection by gammadelta T cells. PLoS path11:e1004481.
  3. Pötzsch, S., N. Spindler, A.K. Wiegers, T. Fisch, P. Rucker, H. Sticht, N. Grieb, T. Baroti, F. Weisel, T. Stamminger, L. Martin-Parras, M. Mach, and T.H. Winkler. 2011. B cell repertoire analysis identifies new antigenic domains on glycoprotein B of human cytomegalovirus which are target of neutralizing antibodies. PLoS path 7:e1002172.
  4. Weisel, F.J., U.K. Appelt, A.M. Schneider, J.U. Horlitz, N. van Rooijen, H. Korner, M. Mach, and T.H. Winkler. 2010. Unique requirements for reactivation of virus-specific memory B lymphocytes. J Immunol185:4011-4021.
  5. Wellmann, U., M. Letz, M. Herrmann, S. Angermuller, J.R. Kalden, and T.H. Winkler. 2005. The evolution of human anti-double-stranded DNA autoantibodies. Proc Nat Acad Sci USA 102:9258-9263.

Primary Publications (since 2012)

  • Pfeifle, R., T. Rothe, N. Ipseiz, H.U. Scherer, S. Culemann, U. Harre, J.A. Ackermann, M. Seefried, A. Kleyer, S. Uderhardt, B. Haugg, A.J. Hueber, P. Daum, G.F. Heidkamp, C. Ge, S. Bohm, A. Lux, W. Schuh, I. Magorivska, K.S. Nandakumar, E. Lonnblom, C. Becker, D. Dudziak, M. Wuhrer, Y. Rombouts, C.A. Koeleman, R. Toes, T.H. Winkler, R. Holmdahl, M. Herrmann, S. Bluml, F. Nimmerjahn, G. Schett, and G. Kronke. 2017. Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol 18:104-113.
  • Schmitt, H., S. Sell, J. Koch, M. Seefried, S. Sonnewald, C. Daniel, T.H. Winkler, and L. Nitschke. 2016. Siglec-H protects from virus-triggered severe systemic autoimmunity. J Exp Med 213:1627-1644.
  • Krzyzak, L., C. Seitz, A. Urbat, S. Hutzler, C. Ostalecki, J. Glasner, A. Hiergeist, A. Gessner, T.H. Winkler, A. Steinkasserer, and L. Nitschke. 2016. CD83 Modulates B Cell Activation and Germinal Center Responses. J Immunol196:3581-3594.
  • Sell, S., M. Dietz, A. Schneider, R. Holtappels, M. Mach, and T.H. Winkler. 2015. Control of murine cytomegalovirus infection by gammadelta T cells. PLoS path 11:e1004481.
  • Wiegers, A.K., H. Sticht, T.H. Winkler, W.J. Britt, and M. Mach. 2015. Identification of a neutralizing epitope within antigenic domain 5 of glycoprotein B of human cytomegalovirusJ Virol 89:361-372.
  • Hammersen, J., J. Hou, S. Wunsche, S. Brenner, T. Winkler, and H. Schneider. 2015. A new mouse model of junctional epidermolysis bullosa: the LAMB3 628G>A knockin mouse. Journal invest dermatol 135:921-924.
  • Brachs, S., A. Turqueti-Neves, M. Stein, D. Reimer, B. Brachvogel, M. Bosl, T. Winkler, D. Voehringer, H.M. Jack, and D. Mielenz. 2014. Swiprosin-1/EFhd2 limits germinal center responses and humoral type 2 immunity. Eur J Immunol 44:3206-19.
  • Engels, N., L.M. Konig, W. Schulze, D. Radtke, K. Vanshylla, J. Lutz, T.H. Winkler, L. Nitschke, and J. Wienands. 2014. The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module. Nat comm 5:5456.
  • Lutz, J., K. Dittmann, M.R. Bosl, T.H. Winkler, J. Wienands, and N. Engels. 2015. Reactivation of IgG-switched memory B cells by BCR-intrinsic signal amplification promotes IgG antibody production Nat comm 6:8575.
  • Spindler, N., U. Diestel, J.D. Stump, A.K. Wiegers, T.H. Winkler, H. Sticht, M. Mach, and Y.A. Muller. 2014. Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody. PLoS path 10:e1004377.
  • Hutzler, S., L. Ozgor, Y. Naito-Matsui, K. Klasener, T.H. Winkler, M. Reth, and L. Nitschke. 2014. The ligand-binding domain of Siglec-G is crucial for its selective inhibitory function on B1 cells. J Immunol192:5406-5414.
  • Simonetti, G., M.T. Bertilaccio, T.V. Rodriguez, B. Apollonio, A. Dagklis, M. Rocchi, A. Innocenzi, S. Casola, T.H. Winkler, L. Nitschke, M. Ponzoni, F. Caligaris-Cappio, and P. Ghia. 2014. SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders. Haematologica 99:1356-1364.
  • Schroeder, K., M. Herrmann, and T.H. Winkler. 2013. The role of somatic hypermutation in the generation of pathogenic antibodies in SLE. Autoimmunity 46:121-127.
  • Song, J., Z. Lokmic, T. Lammermann, J. Rolf, C. Wu, X. Zhang, R. Hallmann, M.J. Hannocks, N. Horn, M.A. Ruegg, A. Sonnenberg, E. Georges-Labouesse, T.H. Winkler, J.F. Kearney, S. Cardell, and L. Sorokin. 2013. Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival. Proc Nat Acad Sci USA110: 2915-2924.
  • Spindler, N., P. Rucker, S. Potzsch, U. Diestel, H. Sticht, L. Martin-Parras, T.H. Winkler, and M. Mach. 2013. Characterization of a discontinuous neutralizing epitope on glycoprotein B of human cytomegalovirus. J Virol 87:8927-8939.
  • Stein, M.F., S. Lang, T.H. Winkler, A. Deinzer, S. Erber, D.M. Nettelbeck, E. Naschberger, R. Jochmann, M. Sturzl, R.K. Slany, T. Werner, A. Steinkasserer, and I. Knippertz. 2013. Multiple interferon regulatory factor and NF-kappaB sites cooperate in mediating cell-type- and maturation-specific activation of the human CD83 promoter in dendritic cells. Mol Cell Biol33:1331-1344.
  • Wiede, F., P.D. Fromm, I. Comerford, E. Kara, J. Bannan, W. Schuh, C. Ranasinghe, D. Tarlinton, T. Winkler, S.R. McColl, and H. Korner. 2013. CCR6 is transiently upregulated on B cells after activation and modulates the germinal center reaction in the mouse. Immun Cell Biol91:335-339.
  • Schietke, R.E., T. Hackenbeck, M. Tran, R. Gunther, B. Klanke, C.L. Warnecke, K.X. Knaup, D. Shukla, C. Rosenberger, R. Koesters, S. Bachmann, P. Betz, G. Schley, J. Schodel, C. Willam, T. Winkler, K. Amann, K.U. Eckardt, P. Maxwell, and M.S. Wiesener. 2012. Renal tubular HIF-2alpha expression requires VHL inactivation and causes fibrosis and cysts. PloS one 7:e31034.