Immunological memory is a driver of rheumatic inflammation
We usually only get “childhood diseases” once and thereafter, we are protected from them by an “immunological memory” for the rest of our lives. In the case of inflammatory rheumatic diseases, this immunological memory is directed against the patient’s own body. Our group is investigating how memory lymphocytes control chronic inflammation, how they contribute to therapy refractoriness, and how we can selectively target pathogenic memory lymphocytes.
In recent years, we have identified memory plasma cells secreting autoantibodies as a major determinant of rheumatic disease refractoriness towards conventional immunosuppressive therapies. Memory plasma cells secrete copious amounts of (auto-)antibodies and persist in dedicated niches in the bone marrow and inflamed tissues organised by stromal cells. Their lifestyle as terminally-differentiated, non-migratory, and quiescent cells makes them refractory to therapies. However, memory plasma cell survival is conditional on signals provided to them in their niches. Understanding the signals required for memory plasma cells to survive will allow us to selectively address these cells therapeutically and to develop successful strategies for the treatment of refractory rheumatic disease.
We have developed a synthetic niche which mimics the survival niche of memory plasma cells in the bone marrow. We have discovered that the memory plasma cells need direct contact with stroma cells and a second signal, the cytokines APRIL or BAFF, to survive. Contact with stroma cells activates the PI3 kinase signalling pathway, while APRIL activates the NF-κB signaling pathway in the plasma cells. If either of the two signalling pathways is blocked pharmacologically, the plasma cells die, both in vitro and in vivo.
A second type of memory lymphocyte that controls chronic inflammation is the memory T-helper (Th) lymphocyte. Th cells secrete cytokines and chemokines, which stimulate inflammatory reactions and attract and activate granulocytes and phagocytes, inducing and maintaining inflammation. As with memory plasma cells, we have originally found that memory T lymphocytes also persist in bone marrow in dedicated niches, resting in terms of mobility and proliferation, and maintaining functional long-term systemic memory. We can show that memory Th lymphocytes specific for childhood diseases are present in the bone marrow of elderly humans, but are no longer detectable among circulating memory Th lymphocytes. Following booster vaccination, antigen-reactive memory CD4+ T lymphocytes are rapidly mobilised into the blood to mount fast and effective secondary immune responses.
For pathogenic memory T lymphocytes found primarily in inflamed tissues of patients with rheumatic diseases, we have identified the transcription factor Twist1 as critical regulator of molecular adaptations allowing the pathogenic memory Th cells to persist and function in the inflamed tissue. We could show that Twist1 promotes the survival by inducing the microRNA miR-148a which downregulates the pro-apoptotic factor Bim. Twist1 also regulates the energy metabolism of pathogenic Th cells by switching them from glycolysis to complete dependence on fatty acid oxidation. By targeting miR-148a using antagomirs or pharmacological inhibition of fatty acid oxidation, we can selectively eliminate such pathogenic Th lymphocytes.
It is our overall aim to identify and target the immunological memory for rheumatic inflammation while preserving the protective memory to ultimately achieve long-term therapy-free remission in these diseases.
Prof. Dr. rer. nat Andreas Radbruch
Jun Dong, PhD
Dr. rer. nat. Marta Ferreira Gomes
Elodie Mohr, PhD
Charité – Universitätsmedizin Berlin, Germany:
- Dr. Gerd-Rüdiger Burmester, Klinik für Rheumatologie und klinische Immunologie
- Tobias Alexander, Klinik für Rheumatologie und klinische Immunologie
- Anja Kühl, Medizinische Klinik I
- Dr. Thomas Dörner, Klinik für Rheumatologie und klinische Immunologie
- Dr. Georg Duda, Julius Wolff Institut für Biomechanik und Muskuloskeletale Regeneration
- Thomas Häupl, Klinik für Rheumatologie und klinische Immunologie
- Dr. Falk Hiepe, Klinik für Rheumatologie und klinische Immunologie
- Silvia Pade, Klinik für Rheumatologie und klinische Immunologie
- Dr. Britta Siegmund, Medizinischen Klinik für Gastroenterologie, Infektiologie und Rheumatologie
- Dr. Klemens Budde, Dr. Mareen Matz, Nephrologie
- Andreas Bosio, Dr. Ute Bissels, Dr. Anne Richter, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
- Dr. Alexander Scheffold, Universitätsklinikum Schleswig-Holstein, Germany
- Wei Chen, Max-Delbrück-Centrum für Molekulare Medizin und Berlin Institute for Medical Systems Biology, Berlin, Germany
- Dr. Steffen Gay, Zentrum für Experimentelle Rheumatologie, Universitätspital Zürich, Switzerland
- Dr. Hans-Martin Jäck, Molekulare Immunologie, Universitätsklinikum Erlangen, Germany
- Dr. Thomas Kamradt, Institut für Immunologie, Universitätsklinikum, Friedrich-Schiller-Universität, Jena, Germany
- Dr. Toshinori Nakayama, Department of Immunology, Chiba University, Chiba, Japan
- Dr. Nikolaus Rajewsky, Max-Delbrück-Centrum für Molekulare Medizin und Berlin and Institute for Medical Systems Biology, Berlin, Germany
- Dr. Andreas Thiel, Berlin-Brandenburg Center for Regenerative Therapies BCRT, Berlin, Germany
- Dr. Kai Wucherpfennig, Dana-Farber Cancer Institute, Boston, MA, USA
- Dr. Michael Lohoff, Institut für Medizinische Mikrobiologie, Philipps University Marburg, Germany
Hradilkova, K, Maschmeyer P, Westendorf K, Schliemann H, Husak O, von Stuckrad SL, Kallinich T, Minden K, Durek P, Grün JR, Chang HD, Radbruch A. T helper lymphocytes of chronic inflammation are maintained by fatty acid oxidation and adapt to it through Twist1. Arth Rheumatol. 2019. doi: 10.1002/art.40939
Siracusa F, Durek P, McGrath MA, Sercan-Alp Ö, Rao A, Du W, Cendón C, Chang HD, Heinz GA, Mashreghi MF, Radbruch A, Dong J. CD69+ memory T lymphocytes of the bone marrow and spleen express the signature transcripts of tissue-resident memory T lymphocytes. Eur J Immunol. 2019 Jan 23. doi: 10.1002/eji.201847982
Chang HD, Tokoyoda K, Radbruch A. Immunological memories of the bone marrow. Immunol Rev. 2018 May;283(1):86-98. doi: 10.1111/imr.12656. Review.
Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, Mashreghi MF. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo. J Autoimmun. 2018 May;89:41-52. doi:10.1016/j.jaut.2017.11.005.
Siracusa F, McGrath MA, Maschmeyer P, Bardua M, Lehmann K, Heinz G, Durek P, Heinrich FF, Mashreghi MF, Chang HD, Tokoyoda K, Radbruch A. Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow. Proc Natl Acad Sci U S A. 2018 Jan 22. pii: 201715618. doi: 10.1073/pnas.1715618115.