Deutsches Rheuma-Forschungszentrum Berlin (DRFZ)

Contact information:

Deutsches Rheuma-Forschungszentrum (DRFZ) Berlin 

Charitéplatz 1 

10117 Berlin

Germany

Website: www.drfz.de

Dr. Eva Kreiss

Scientific Coordinator

Phone: +49 (0)30 28460 658

kreiss@drfz.de

Who is who?

PI: Prof. Dr. Andreas Radbruch

Dr. Hyun-Dong Chang

Dr. Mir-Farzin Mashreghi

http://www.drfz.de/en/zellbiologie/

Short summary research:

A key feature of inflammatory rheumatic diseases is an autoreactive, hyperactive immune system. State-of-the-art immunosuppressive therapies efficiently stop progression of the disease but cannot cure it. If the treatment is stopped, the disease usually relapses. We believe that one reason is that the immune system has acquired a memory for the rheumatic inflammation which is refractory to conventional immunosuppressive therapies. It is our goal to understand this “pathogenic” memory and its counterpart, the “protective” immunological memory.

In the past years, we could define cells of the immunological memory. We could demonstrate that plasma cells differentiate to memory plasma cells in the bone marrow, in survival niches organised by dedicated stromal cells. In these niches, the memory plasma cells survive for a long time and continuously secrete antibodies. Apparently, the niches also protect the memory plasma cells from immunosuppressive therapies. We are trying to understand how this protection works at the molecular level. It is our goal to develop strategies for the targeted deletion of autoantibody-secreting memory plasma cells.

Other stromal cells of the bone marrow organise the survival niches for memory T helper (Th) lymphocytes. Until recently, the predominant view has been, that memory Th cells are maintained by homeostatic proliferation and recirculate through the body in search for the cognate antigen. We could show, that after clearing the antigen, memory Th lymphocytes migrate to the bone marrow and settle in their niche and survive as resting cells for extended periods of time. On the other hand, memory Th cells driving chronic rheumatic inflammation are constantly confronted with autoantigens and reactivated. We are investigating how such proinflammatory Th cells are generated, how they proliferate and function, and how they persist. We could recently show, how coordinated signals lead to the differentiation and imprinting of proinflammatory Th cells, how proliferation is regulated by microRNA, and we have identified genes which are specifically expressed in such cells and are important for their survival and function. “Protective” memory Th cells apparently are not requiring these genes. Thus, our results have opened the way for new strategies to target specifically the “pathogenic” immunological memory in rheumatic diseases.

Keywords

Immunological memory 

T cell differentiation 

Biomarkers 

Cytokines 

MicroRNA

Key publications

1. Chu VT, Fröhlich A, Steinhauser G, Scheel T, Roch T, Fillatreau S, Lee JJ, Löhning M, Berek C. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol. 2011 Feb;12(2):151-9. (accepted for publication 6.12.2010)
2. Stittrich AB, Haftmann C, Sgouroudis E, Kühl AA, Hegazy AN, Panse I, Riedel R, Flossdorf M, Dong J, Fuhrmann F, Heinz GA, Fang Z, Li N, Bissels U, Hatam F, Jahn A, Hammoud B, Matz M, Schulze FM, Baumgrass R, Bosio A, Mollenkopf HJ, Grün J, Thiel A, Chen W, Höfer T, Loddenkemper C, Löhning M, Chang HD, Rajewsky N, Radbruch A, Mashreghi MF. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol. 2010 Nov;11(11):1057-62.
3. Neves P, Lampropoulou V, Calderon-Gomez E, Roch T, Stervbo U, Shen P, Kühl AA, Loddenkemper C, Haury M, Nedospasov SA, Kaufmann SH, Steinhoff U, Calado DP, Fillatreau S. Signaling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity. 2010 Nov 24;33(5):777-90.
4. Ziegler S, Huscher D, Karberg K, Krause A, Wassenberg S, Zink A.Trends in treatment and outcomes of rheumatoid arthritis in Germany 1997-2007: results from the National Database of the German Collaborative Arthritis Centres. Ann Rheum Dis. 2010 Oct;69(10):1803-8.
5. Strangfeld A, Hierse F, Rau R, Burmester GR, Krummel-Lorenz B, Demary W, Listing J, Zink A. Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT. Arthritis Res Ther 2010;12(1):R5.
6. Schulz EG, Mariani L, Radbruch A, Höfer T. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12. Immunity. 2009 May;30(5):673-83.
7. Tokoyoda K, Zehentmeier S, Hegazy AN, Albrecht I, Grün JR, Löhning M, Radbruch A. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity. 2009 May;30(5):721-30.
8. Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, Zink A. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF (alpha) agents. JAMA 2009 Feb 18;301(7):737-44.
9. Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, Mei H, Radtke H, Gromnica-Ihle E, Burmester GR, Arnold R, Radbruch A, Hiepe F. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood. 2009 Jan 1;113(1):214-23.

Partner knowledge base:

Core Facilities

The Core Facilities at the DRFZ provide all researchers with access to the most advanced equipment and technologies. It encompasses the flow cytometry and cell sorting unit, Regine-von-Ramin Laboratory for Molecular Rheumatology, Central Laboratory, Bioinformatics, Immune Monitoring, and Imaging. These facilities consist of scientific equipments that are used among all the research groups at the DRFZ to collect and analyze data, allowing researchers to conduct studies at the molecular and cellular level.

Information on ongoing large projects

international projects

EU Projects

ERC advanced grant IMMEMO

Leibniz-Network

ImmunoMemory

National projects