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Struktur des IFZ Forschung im IFZ Mitarbeiter Leistungen aus dem IFZ Seminare Stellenangebote Links IFZ-Fördervereinigung Informationen: Ph. D. Thesis (Dr. rer. nat.) |
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KONTAKT IMPRESSUM |
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Forschungsprogramm der Arbeitsgruppe Molekulare Genetik |
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B lymphocytes are the white blood cells that are responsible for the production of antibodies and that play an important role in immune responses against foreign antigens, such as bacteria. Immune responses involving B cells often take place in particular structures in lymph nodes, the germinal centres. B cells that have been selected in immune responses can become long-lived memory B cells that are important to defend the body against future infections against the same antigen ("immunity"). However, B cells may undergo malignant transformation and become tumour cells. Such tumours are called B cell lymphomas or leukemias. The main interest of our group is in the analysis of normal B lymphocyte development and differentiation in the human and the pathogenesis of human B cell lymphomas. The work of our group is foccused on three main topics: molecular characterization of human B cell development, biology and pathogenesis of Epstein-Barr virus (EBV)-associated diseases, pathogenesis of human B cell lymphomas, especially Hodgkin's lymphoma. |
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Normal B cell development |
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For the molecular analysis of normal human B cell subsets, these cells are either isolated by flow cytometry or microdissection from tissue sections. By analysis of rearranged immunoglobulin V region genes we could for example show that a) somatic hypermutation, a process by which immunoglobulin genes are genetically modified, is active in germinal center B cells, b) besides class-switched cells there are also distinct memory B cell subsets in the human expressing IgM (IgM-only and IgM+IgD+CD27+ B cells), c) CD27 represents a marker for human somatically mutated and hence likely memory B cells. Work of our group also provided evidence that aberrant somatic hypermutation is involved in the pathogenesis of human B cell lymphomas, by targeting non-Ig genes (CD95) and by promoting chromosomal translocations. Currently, we continue our work to characterize human memory B cells. Küppers R, Zhao M, Hansmann ML, Rajewsky K (1993) Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 12, 4955-4967. Klein U, Rajewsky K, Küppers R (1998) Human immunoglobulin (Ig) M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated V region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 188, 1679-1689 Müschen M, Re D, Jungnickel B, Diehl V, Rajewsky K, Küppers R (2000) Somatic mutation of the CD95 gene in human B cells as a side-effect of the germinal center reaction. J.Exp. Med., 192, 1833-1839 Goossens T, Klein U, Küppers R (1998) Frequent occurrence of deletions and duplications during somatic hypermutation: Implications for oncogene translocations and heavy chain disease. Proc.Natl.Acad.Sci. USA 95, 2463-2468 |
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EBV biology |
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EBV infects nearly all humans worldwide and after infection establishes a life-long persistence in B cells. Infection by EBV is normally harmless. However, EBV is also involved in the pathogenesis of several diseases, such as infectious mononucleosis and several types of B cell lymphomas. By molecular analysis of single microdissected EBV-infected B cells in the acute viral infection (infectious mononucleosis) we revealed viral strategies for spreading in the immune system. Our current work is focussed on the role EBV has on the differentiation of human germinal centre B cells. Kurth J, Spieker T, Wustrow J, Strickler JG, Hansmann M-L, Rajewsky K, Küppers R (2000) EBV-infected B cells in infectious mononucleosis: Viral strategies for spreading in the B cell compartment and establishing latency. Immunity, 13, 485-495 Kurth J, Hansmann M-L, Rajewsky K, Küppers R (2003) Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction. Proc. Natl. Acad. Sci. USA, 100, 4730-4735 Bechtel D, Kurth J, Unkel C, Küppers R (2005) Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphoma. Blood, 106, 4345-4350 Siemer D, Kurth J, Lang S, Lehnerdt G, Stanelle J, Küppers R. (2008) EBV transformation overrides gene expression patterns of B cell differentiation stages. Mol. Immunol., 45, 3133-3141 |
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Hodgkin's lymphoma |
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Hodgkin's lymphoma is one of the most frequent lymphomas in the Western world. It is characterized by typical tumour cells, the Hodgkin and Reed/Sternberg (HRS) cells, that usually account for only 1% of cells in the lymphoma tissue. The origin and clonality of HRS cells in classical Hodgkin's lymphoma was unclear for a long time. By applying microdissection and single cell PCR techniques that we had established, we showed that HRS cells represent clonal populations of tumour cells in most cases. This technique was also successfully applied to clarify several other issues of HRS cell pathogenesis, such as a potential T cell derivation of HRS cells in rare cases, and the role of somatic mutations in the CD95 gene, the p53 gene and the IB gene in Hodgkin's lymphoma pathogenesis. By generating large scale gene expression profiles from Hodgkin's lymphoma cell lines (both by SAGE and Genechips) and comparing these profiles with those of other B cell lymphomas and normal B cells, we showed that HRS cells lost expression of most known B cell markers and identified genes aberrantly expressed by HRS cells. We also performed global gene expression profiling studies of differential gene expression of microdissected primary lymphoma cells of classical and nodular lymphocyte predominant Hodgkin's lymphomas and identified TNFAIP3 as a novel tumor suppressor gene involved in the pathogenesis of classical Hodgkin lymphoma. Brune V, Tiacci E, Pfeil I, Döring C, Eckerle S, van Noesel CJM, Klapper W, Falini B, von Heydebreck A, Metzler D, Bräuninger A, Hansmann M-L, Küppers R. (2008) Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J. Exp. Med., 205, 2251-2268 Schmitz R, Hansmann M-L, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G, Klapper W, Vater I, Giefing M, Gesk S, Stanelle J, Siebert R, Küppers R (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J. Exp. Med., in press |
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