Cell Biology

Immunological memory as driver of rheumatic inflammation

Radbruch

Introduction

Chronic immune reactions are a key feature of inflammatory rheumatic diseases. Current stateof-the-art immunosuppressive therapies are able to stop disease progression and maintain remission. However these therapies do not induce a therapy-free remission, i.e. discontinuation of treatment leads to relapse of disease.

From the experimental therapy of immunoablation and regeneration of a patient´s immune system from their own progenitor cells, also termed “autologous stem cell transplantation”, with about 20 years of experience at the Charité and DRFZ, we know that most if not all patients have an immunological memory driving the rheumatic inflammation, and this memory is refractory to conventional therapy. It is the aim of our group to identify the cells impersonating this pathogenic immunological memory, understand their development, their persistence, and their resistance to current therapies. From such an understanding new options should emerge for their selective therapeutic targeting and the
induction of therapy-free remission.

In a basic approach, we have revisited the current concepts on how immunological memory is organized. We have developed the novel concept of a compartmentalized immunological memory in which the long-term memory to systemic antigens is maintained in the bone marrow, while the memory cells found in circulation are rather short-lived. We have identified a new type of memory cell, the memory plasma cell, secreting protective or pathogenic antibodies. We could show that reticular mesenchymal stromal cells of the bone marrow organize dedicated survival niches in which antigen-experienced lymphocytes differentiate into memory cells and persist as cells resting in terms of activation, proliferation, and mobility, as long as they are provided with survival signals. In such niches, memory cells are also protected from conventional therapies targeting activated immune cells. We are identifying the specific survival signals for different types of memory cells. Such signals and their receptors qualify as novel and selective therapeutic targets. At present we are collaborating with the group of Falk Hiepe to identify and target (pathogenic) memory plasma cells.

How can we distinguish pathogenic from protective memory cells? For memory T helper (Th) lymphocytes we could show that pathogenic memory Th lymphocytes initiate and drive inflammation through chemokines recruiting inflammatory effector cells, like macrophages and granulocytes. In chronic inflammation, pathogenic memory Th lymphocytes adapt to repeated reactivation. We have identified such molecular adaptations, e.g. expression of the genes Hopx, Twist1 and the microRNA miR-148a. Together with the group of Mir-Farzin Mashreghi we are now testing synthetic, membrane-permeable oligonucleotides for the inhibition of these vital adaptations, and thus the selective targeting of pathogenic memory Th lymphocytes.

Selected Publications

1. Zimmermann J, Hübschmann T, Schattenberg F, Schumann J, Durek P, Riedel R, Friedrich M, Glauben R, Siegmund B, Radbruch A, Müller S, Chang HD. High-resolution microbiota flow cytometry reveals dynamic colitis-associated changes in fecal bacterial composition. Eur J Immunol. 2016 May;46(5):1300-3. doi: 10.1002/eji.201646297. PubMed PMID: 26909672.

2. Zimmermann J, Kühl AA, Weber M, Grün JR, Löffler J, Haftmann C, Riedel R, Maschmeyer P, Lehmann K, Westendorf K, Mashreghi MF, Löhning M, Mack M, Radbruch A, Chang HD. T-bet expression by Th cells promotes type 1 inflammation but is dispensable for colitis. Mucosal Immunol. 2016 Feb 17. doi: 10.1038/mi.2016.5. [Epub ahead of print] PubMed PMID: 26883725

3. Alp ÖS, Radbruch A. The lifestyle of memory CD8(+) T cells. Nat Rev Immunol. 2016 Apr;16(4):271. doi: 10.1038/nri.2016.32. PubMed PMID: 26996198.

4. Sercan Alp Ö, Durlanik S, Schulz D, McGrath M, Grün JR, Bardua M, Ikuta K, Sgouroudis E, Riedel R, Zehentmeier S, Hauser AE, Tsuneto M, Melchers F, Tokoyoda K, Chang HD, Thiel A, Radbruch A. Memory CD8(+) T cells colocalize with IL-7(+) stromal cells in bone marrow and rest in terms of proliferation and transcription. Eur J Immunol. 2015 Apr;45(4):975-87. doi: 10.1002/eji.201445295. Epub 2015 Feb 27. PubMed PMID: 25639669; PubMed Central PMCID: PMC4415462

5. Haftmann C, Stittrich AB, Zimmermann J, Fang Z, Hradilkova K, Bardua M, Westendorf K, Heinz GA, Riedel R, Siede J, Lehmann K, Weinberger EE, Zimmel D, Lauer U, Häupl T, Sieper J, Backhaus M, Neumann C, Hoffmann U, Porstner M,  Chen W, Grün JR, Baumgrass R, Matz M, Löhning M, Scheffold A, Wittmann J, Chang HD, Rajewsky N, Jäck HM, Radbruch A, Mashreghi MF. miR-148a is upregulated by Twist1 and Tbet and promotes Th1-cell survival by regulating the  proapoptotic gene Bim. Eur J Immunol. 2015 Apr;45(4):1192-205. doi: 10.1002/eji.201444633. PubMed PMID: 25486906; PubMed Central PMCID: PMC4406154.

Members

Group leader
Prof. Dr. rer. nat. Andreas Radbruch

Scientists
Dr. rer. nat. Hyun-Dong Chang
Dr. rer. nat. Jun Dong
Mairi McGrath PhD
Dr. rer. nat. Özen Sercan
Dr. rer. nat. Claudia Giesecke
Dr. rer nat. Pawel Durek
Elodie Mohr PhD

Ph.D. students
Daniel Schulz
Richard Addo
René Riedel
Francesco Siracusa
Kerstin Westendorf
Melanie Weber
Jakob Zimmermann
Carla Cendon
Haider Abid
Stefanie Schmidt
Weijie Du
Alexander Beller
Kristyna Hradilkova
Sandra Naundorf

Bachelor/Diploma/Master students
Cora Claeden
Katharina Werner
Darya Malko
Cassandra Steinkraus
MarlenSchulze
Sarah Schiele
Jessica Dysarz
Melanie Klingauf
Alexander Schmidt
Josefine Spalding

Technicians
Katrin Lehmann

Others
Sarah Schimmelpfennig
Darya Malko

Cooperation partners

Miltenyi Biotec GmbH, Bergisch Gladbach
Dr. Andreas Bosio, Dr. Ute Bissels, Dr. Anne Richter

Charité – Universitätsmedizin Berlin
Prof. Dr. Gerd-Rüdiger Burmester, Klinik für Rheumatologie und klinische Immunologie
Dr. Tobias Alexander, Klinik für Rheumatologie und klinische Immunologie, Charité-Universitätsmedizin Berlin
Dr. Anja Kühl, Medizinische Klinik I
Prof. Dr. Thomas Dörner, Klinik für Rheumatologie und klinische Immunologie
Prof. Dr. Georg Duda, Julius Wolff Institut für Biomechanik und Muskuloskeletale Regeneration
Dr. Thomas Häupl, Klinik für Rheumatologie und klinische Immunologie
Prof. Dr. Falk Hiepe, Klinik für Rheumatologie und klinische Immunologie
Silvia Pade, Klinik für Rheumatologie und klinische Immunologie
Prof. Dr. Alexander Scheffold, Klinik für Rheumatologie und klinische Immunologie
Prof. Dr. Britta Siegmund, Medizinische Klinik I
Prof. Dr. Jochen Sieper, Medizinische Klinik I
Prof. Dr. Klemens Budde, Dr. Mareen Matz, Nephrologie

Further partners
Prof. Dr. Fritz Melchers, Max Planck Institut für Infektionsbiologie, Berlin
Dr. Wei Chen, Max-Delbrück-Centrum für Molekulare Medizin und Berlin Institute for Medical Systems Biology, Berlin
Prof. Dr. Steffen Gay, Zentrum für Experimentelle Rheumatologie, Universitätspital Zürich
Prof. Dr. Hans-Martin Jäck, Molekulare Immunologie, Universitätsklinikum Erlangen
Prof. Dr. Thomas Kamradt, Institut für Immunologie, Universitätsklinikum, Friedrich-Schiller-Universität, Jena
Prof. Dr. Susann Müller, Helmholtz Institut für Umweltforschung, Leipzig
Prof. Dr. Toshinori Nakayama, Department of Immunology, Chiba University, Chiba, Japan
Prof. Dr. Nikolaus Rajewsky, Max-Delbrück-Centrum für Molekulare Medizin und Berlin Institute for Medical Systems Biology, Berlin
Prof. Dr. Andreas Thiel, Berlin-Brandenburg Center for Regenerative Therapies BCRT, Berlin
Prof. Dr. Kai Wucherpfennig, Dana-Farber Cancer Institute, Boston, MA, USA
Prof. Dr. Michael Lohoff, Institut für Medizinische Mikrobiologie, Philipps University Marburg

Prof. Dr. rer. nat. Andreas Radbruch

Deutsches Rheuma-Forschungszentrum Berlin
Cell Biology
Charitéplatz 1
10117 Berlin
Gemany

Phone +49 (0)30 28460-601
Fax +49 (0)30 28460-603
radbruch@drfz.de

Keywords
Immunological memory
Chronic inflammation
T lymphocytes
B lymphocytes
Plasma cells

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