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Immunological memory is a driver of rheumatic inflammation

Introduction
Members
Cooperation partners
Selected Publications
Third Party Funding

Cell Biology

We usually get “childhood diseases” only once and thereafter, we are protected from them by an “immunological memory” for the rest of our lives. In inflammatory rheumatic diseases the 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 target them, at best selectively.

In the past, we have identified memory plasma cells secreting pathogenic autoantibodies as a critical driver of chronic rheumatic, antibody-mediated inflammation, and as an unmet therapeutic target, a cell that is refractory to conventional therapies. Memory plasma cells secrete copious amounts of (auto-) antibodies and persist in dedicated niches organised by stromal cells in the bone marrow and inflamed tissues. We have now analysed how stromal cells maintain plasma cells in more detail. Direct contact between stromal cell and plasma cell activates the PI3 kinase signalling pathway in memory plasma cells, inactivating Foxo1/3, and preventing apoptosis induced by mitochondrial (metabolic) stress, i.e. activation of caspases 3 and 7. A second signal, provided by the cytokine APRIL, and mediated by the NFkB signaling pathway, is required to prevent apoptosis induced by stress of the endoplasmic reticulum, i.e.  activation of caspase 12. The cell-contact dependency of plasma cell persistence raises the question whether protective and pathogenic plasma cells may differ in the molecular composition of the contact, as already indicated by the work of the Tokoyoda group at the DRFZ, offering therapeutic options for the selective ablation of pathogenic plasma cells.

Memory B lymphocytes are the precursors of memory plasma cells and an essential component of the reactive immunological memory. Surprisingly little is known about them. We have now determined that switched memory B cells survive in spleen and bone marrow, and at least in the bone marrow, they are docked on to stromal cells similar to memory plasma cells. Single cell transcriptome and antibody repertoire analyses identified six different switched memory B cell populations. The functional roles of these populations and their relation to pathogenic memory B lymphocytes of rheumatic inflammation remains to be clarified.

A third type of memory lymphocyte is the memory T lymphocyte. These cells essentially control immune reactions, e.g. they are required for the generation of memory plasma cells. Again, a substantial fraction of protective memory T lymphocytes is maintained in the bone marrow, individually docked on to stromal cells. Pathogenic memory T lymphocytes, on the other hand, are found primarily in inflamed tissues of patients with rheumatic diseases. They secrete cytokines and chemokines, which stimulate inflammatory reactions and attract and activate granulocytes and phagocytes, inducing and maintaining chronicity of inflammation. In order to survive in the hostile environment of an inflamed tissue, pathogenic memory T lymphocytes have to adapt to the milieu. One such critical adaptation is the expression of  the transcription factor Twist1. Twist1 promotes the survival by inducing expression of the microRNA miR-148a which downregulates the pro-apoptotic factor Bim. In children with Juvenile Idiopathic Arthritis, in particular PD1+ T helper cells isolated from the synovial fluid express TWIST1. And here we can show that Twist1 also regulates the energy metabolism of pathogenic Th cells, making them entirely dependent on fatty acid oxidation. Molecular adaptations of pathogenic memory T lymphocytes thus qualify as unique targets for their selective therapeutic ablation.

Keywords
Immunological memory
Chronic rheumatic inflammation
Plasma cell
Memory lymphocyte

Leitung
Scientific Director Prof. Dr. Andreas Radbruch Phone +49 (0)30 28 460-601 durez@drfz.de more
Continue to Members

Group leader
Prof. Dr. rer. nat Andreas Radbruch

Scientists
Jun Dong, PhD
Dr. rer nat Pawel Durek
Dr. rer. nat. Marta Ferreira Gomes
Elodie Mohr, PhD

PhD students
Rebecca Cornelis
Weijie Du
Chaofan Fan
Lukas Heiberger
Jinchan Li
Sandra Naundorf

Bachelor/Diploma/Master
Mona Massoud
Ravisha Rawal
Lara Tavernari

Students
Tina Lai
Ramonique Lim
Sofia Uhlig

Continue to Cooperation partners

Charité – Universitätsmedizin Berlin, Germany:

  • Gerd-Rüdiger Burmester, Klinik für Rheumatologie und klinische Immunologie
  • Tobias Alexander, Klinik für Rheumatologie und klinische Immunologie
  • Anja Kühl, Medizinische Klinik I
  • Thomas Dörner, Klinik für Rheumatologie und klinische Immunologie
  • Georg Duda, Julius Wolff Institut für Biomechanik und Muskuloskeletale Regeneration
  • Thomas Häupl, Klinik für Rheumatologie und klinische Immunologie
  • Falk Hiepe, Klinik für Rheumatologie und klinische Immunologie
  • Silvia Pade, Klinik für Rheumatologie und klinische Immunologie
  • Britta Siegmund, Medizinischen Klinik für Gastroenterologie, Infektiologie und Rheumatologie
  • Klemens Budde, Dr. Mareen Matz, Nephrologie

Andere / Others

  • Andreas Bosio, Dr. Ute Bissels, Dr. Anne Richter, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
  • Alexander Scheffold, Universitätsklinikum Schleswig-Holstein, Germany
  • Wei Chen, Max-Delbrück-Centrum für Molekulare Medizin und Berlin Institute for Medical Systems Biology, Berlin, Germany
  • Steffen Gay, Zentrum für Experimentelle Rheumatologie, Universitätspital Zürich, Switzerland
  • Hans-Martin Jäck, Molekulare Immunologie, Universitätsklinikum Erlangen, Germany
  • Thomas Kamradt, Institut für Immunologie, Universitätsklinikum, Friedrich-Schiller-Universität, Jena, Germany
  • Toshinori Nakayama, Department of Immunology, Chiba University, Chiba, Japan
  • Nikolaus Rajewsky, Max-Delbrück-Centrum für Molekulare Medizin und Berlin and Institute for Medical Systems Biology, Berlin, Germany
  • Andreas Thiel, Berlin-Brandenburg Center for Regenerative Therapies BCRT, Berlin, Germany
  • Kai Wucherpfennig, Dana-Farber Cancer Institute, Boston, MA, USA
  • Michael Lohoff, Institut für Medizinische Mikrobiologie, Philipps University Marburg, Germany
Continue to Selected Publications
  • Maschmeyer P, Chang HD, Cheng Q, Mashreghi MF, Hiepe F, Alexander T, Ich Radbruch A. Immunological memory in rheumatic inflammation – a roadblock to tolerance induction. Nat Rev Rheumatol. 2021 Apr 6. doi: 10.1038/s41584-021-00601-6.
  • Ferreira-Gomes M, Kruglov A, Durek P, Heinrich F, Tizian C, Heinz GA, Pascual-Reguant A, Du W, Mothes R, Fan C, Frischbutter S, Habenicht K, Budzinski L, Ninnemann J, Jani PK, Guerra GM, Lehmann K, Matz M, Ostendorf L, Heiberger L, Chang HD, Bauherr S, Maurer M, Schönrich G, Raftery M, Kallinich T, Mall MA, Angermair S, Treskatsch S, Dörner T, Corman VM, Diefenbach A, Volk HD, Elezkurtaj S, Winkler TH, Dong J, Hauser AE, Radbruch H, Witkowski M, Melchers F, Radbruch A, Mashreghi MF. SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nat Commun. 2021 Mar 30;12(1):1961. doi: 10.1038/s41467-021-22210-3. PMID: 33785765.
  • Maschmeyer P, Heinz GA, Skopnik CM, Lutter L, Mazzoni A, Heinrich F, von Stuckrad SL, Wirth LE, Tran CL, Riedel R, Lehmann K, Sakwa I, Cimaz R, Giudici F, Mall MA, Enghard P, Vastert B, Chang HD, Durek P, Annunziato F, van Wijk F, Radbruch A, Kallinich T, Mashreghi MF. Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ. Eur J Immunol. 2020 Dec 9. doi: 10.1002/eji.202048797. Epub ahead of print. PMID: 33296081.
  • Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, Enghard P, Richter U, Biesen R, Schneider U, Knebel F, Burmester G, Radbruch A, Mei HE, Mashreghi MF, Hiepe F, Alexander T. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149-1155. doi: 10.1056/NEJMoa2023325. PMID: 32937047.
  • Romero-Olmedo AJ, Schulz AR, Huber M, Brehm CU, Chang HD, Chiarolla CM, Bopp T, Skevaki C, Berberich-Siebelt F, Radbruch A, Mei HE, Lohoff M. Deep phenotypical characterization of human CD3+ CD56+ T cells by mass cytometry. Eur J Immunol. 2021 Mar;51(3):672-681. doi: 10.1002/eji.202048941. Epub 2020 Dec 15. PMID: 33231295.
  • Cornelis R, Hahne S, Taddeo A, Petkau G, Malko D, Durek P, Thiem M, Heiberger L, Peter L, Mohr E, Klaeden C, Tokoyoda K, Siracusa F, Hoyer BF, Hiepe F, Mashreghi MF, Melchers F, Chang HD, Radbruch A. Stromal Cell-Contact Dependent PI3K and APRIL Induced NF-κB Signaling Prevent Mitochondrial- and ER Stress Induced Death of Memory Plasma Cells. Cell Rep. 2020 Aug 4;32(5):107982. doi: 10.1016/j.celrep.2020.107982. PMID: 32755576; PMCID: PMC7408492.
  • Riedel R, Addo R, Ferreira-Gomes M, Heinz GA, Heinrich F, Kummer J, Greiff V, Schulz D, Klaeden C, Cornelis R, Menzel U, Kröger S, Stervbo U, Köhler R, Haftmann C, Kühnel S, Lehmann K, Maschmeyer P, McGrath M, Naundorf S, Hahne S, Sercan-Alp Ö, Siracusa F, Stefanowski J, Weber M, Westendorf K, Zimmermann J, Hauser AE, Reddy ST, Durek P, Chang HD, Mashreghi MF, Radbruch A. Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow. Nat Commun. 2020 May 22;11(1):2570. doi: 10.1038/s41467-020-16464-6. PMID: 32444631; PMCID: PMC7244721.
  • Beller A, Kruglov A, Durek P, von Goetze V, Werner K, Heinz GA, Ninnemann J, Lehmann K, Maier R, Hoffmann U, Riedel R, Heiking K, Zimmermann J, Siegmund B, Mashreghi MF, Radbruch A, Chang HD. Specific microbiota enhances intestinal IgA levels by inducing TGF-β in T follicular helper cells of Peyer’s patches in mice. Eur J Immunol. 2020 Feb 17. doi: 10.1002/eji.201948474.
  • Minden K, Radbruch A, Burmester GR, Strangfeld A. Das Was, Wie und Warum in der rheumatologischen Versorgung [The what, the how and the why in rheumatological research]. Z Rheumatol. 2020 Dec;79(10):967-968. German. doi: 10.1007/s00393-020-00908-x. Epub 2020 Dec 1. PMID: 33258973.
  • Alexander T, Badoglio M, Henes J, Heesen C, Arnold R, Radbruch A, Snowden JA, Hiepe F. Autologe hämatopoetische Stammzelltransplantation bei Autoimmunerkrankungen : Aktuelle Indikationen und Wirkungsweise, ein Review der EBMT Autoimmune Diseases Working Party (ADWP) [Autologous hematopoietic stem cell transplantation for autoimmune diseases : Current indications and mode of action, a review on behalf of the EBMT Autoimmune Diseases Working Party (ADWP)]. Z Rheumatol. 2020 Jun;79(5):419-428. German. doi: 10.1007/s00393-020-00795-2. PMID: 32356079.
  • Sarkander J, Hojyo S, Mursell M, Yamasaki Y, Wu TY, Tumes DJ, Miyauchi K, Tran CL, Zhu J, Löhning M, Hutloff A, Mashreghi MF, Kubo M, Radbruch A, Tokoyoda K. Enhanced Cell Division Is Required for the Generation of Memory CD4 T Cells to Migrate Into Their Proper Location. Front Immunol. 2020 Jan 15;10:3113. doi: 10.3389/fimmu.2019.03113. PMID: 32010148; PMCID: PMC6974474.
  • 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, Hoyer B, Alexander T, Khodadadi L, Mei H, Dörner T, Hiepe F, Burmester GR, Radbruch A. Pathogenic memory plasma cells in autoimmunity. Curr Opin Immunol. 2019 Dec;61:86-91. doi: 10.1016/j.coi.2019.09.005.
  • Cheng Q, Pelz A, Taddeo A, Khodadadi L, Klotsche J, Hoyer BF, Alexander T, Thiel A, Burmester GR, Radbruch A, Hiepe F, Selective depletion of plasma cells in vivo based on the specificity of their secreted antibodies. Eur J Immunol. 2019 Nov 12. doi: 10.1002/eji.201948144
  • Cossarizza A, Chang HD, Radbruch A et al Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). Eur J Immunol. 2019 Oct;49(10):1457-1973. doi: 10.1002/eji.201970107.
  • Addo RK, Heinrich F, Heinz GA, Schulz D, Sercan-Alp Ö, Lehmann K, Tran CL, Bardua M, Matz M, Löhning M, Hauser AE, Kruglov A, Chang HD, Durek P, Radbruch A, Mashreghi MF.Single-cell transcriptomes of murine bone marrow stromal cells reveal niche-associated heterogeneity. Eur J Immunol. 2019 Sep;49(9):1372-1379. doi: 10.1002/eji.201848053. Epub 2019 Jun 7.
  • 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.
Continue to Third Party Funding
  • TRR130 Teilprojekt 16 (Radbruch/Chang): Deciphering the Survival Code of Memory Plasma Cells and Memory B Cells
  • TRR241 Teilprojekt B03 (Chang/Radbruch): The intestinal epithelial cells in the dialogue between microbiota and the immune system
  • EU H2020 IMI2 RTCure: WP3 (Project leader Chang/Radbruch)
  • EU H2020 IMI2 3TR
  • BMBF Forschungsverbund Neuroimpa (Neuroimmunologie und Schmerz)
  • DFG 389687267 (Radbruch/Dong)

 

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