Group Thomas Winkler

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Selection processes in B-lymphocytes

Research projects

Our research focus lies on the selection processes at different stages of the development of B-lymphocytes. We investigate the genetic mechanisms for the early development of B-lymphocytes, the mechanisms for the loss of self-tolerance in the autoimmune disease systemic lupus erythematosus and antibody-mediated protection against cytomegalovirus. In our research we predominantly work with mouse models that we also create in our laboratory by the techniques of gene targeting (knock-out mice, knock-in mice, transgenic mice).

Regulation of VDJ - Recombination

During the differentiation of B-lymphocytes the genes for the antibody molecules are assembled in a unique process called VDJ-recombination. VDJ-recombination is responsible for the enormous diversity of antibody molecules. This diversity is necessary to defend all possible invaders of our body. Whereas the molecular mechanism of the VDJ-recombination is understood in very much detail today, the regulation of this process is less well understood. All 7 different antigen-receptor gene loci (3 for immunoglobulins and 4 for T-cell-receptors) use the same VDJ-recombination machinery, but still the expression of the different genes is tighly regulated. Antibody receptors are expressed only on B-lymphocytes and T-cell receptors only on T-lymphocytes. In addition, during development of B-lymphocytes the genes for the heavy chain of the immunoglobulin is recombined before the genes for the light chain and additional regulation exists that only one antigen-receptor is expressed on each B-lymphocyte.
Our research focus is to investigate the accessibility of the immunoglobulin heavy chain genes for the VDJ-recombinase. The epigenetic mechanisms for the regulation of the chromatin state at the immunoglobulin loci is analyzed by modern methods (ChIP-on-ChiP, ChIP-Seq). In addition we try to identify the essential regulatory sequences at the immunoglobulin locus by gene-targeting.

Figure 1: Regulation of VDJ-recombination during B-lymphocyte development (G.Galler)

Mechanisms for the development and pathogenesis of autoantibodies

Autoantibodies against DNA are the hallmark of the autoimmune disease systemic lupus erythematosus (SLE). Our investigations focus on the mechanisms, how these autoantibodies are developing and how these antibodies are involved in the disease.
For our research on SLE we are using mouse models for the disease, either spontaneous mouse models or mouse strains that we developed for specific questions regarding the mechanisms of the disease by gene targeting. At the moment we are following the concept that deregulations of the germinal center reaction can lead to aberrant autoantibody production in SLE. Our investigations focus on a mouse model that is based on an autoantibody derived from a SLE patient.

Figure 2: Indirect immunofluorescence of a monoclonal autoantibody on nuclei of Hep2 cells (left) und direct immunofluorescence of IgG autoantibody deposits in the kidney (right).

Antibody-based immune protection against Cytomegalovirus

Infections with Cytomegalovirus are usually asymptomatic and 50 – 90 % of the human population is persistently infected with this herpes virus. Severe disease becomes apparent when the immune system of the infected individual is suppressed, for example after transplantation. In addition human cytomegalovirus is an important congenital infection.

Our research, which we carry out in close collaboration with the group of Prof. Michael Mach at the Virology Institute aim at the better understanding of humoral immune-responses against the virus to develop new therapeutic concepts and potential therapeutic antibodies for treatment.

For our research we use the human cytomegalovirus (HCMV) as well as its close relative in the mouse, the murine cytomegalovirus (mCMV). In our research projects on mCMV we try to mimic as closely as possible the clinically relevant situation after bone marrow transplantation. In these mouse models we test new antibody-based and cellular therapies. In a cooperation with the Medical Clinic V of the University Erlangen we are developing clinical studies to approve our therapy concepts in patients.

Figure 3: In vivo bioluminescence-imaging of a mouse cytomegalovirus -infection

Publications