Prof. Dr. Andreas Radbruch

Deutsches Rheuma-Forschungszentrum Berlin
Ein Institut der Leibniz Gemeinschaft
Charitéplatz 1
10117 Berlin  

Tel. +49 (0) 30 28460 601
radbruch@drfz.de

Dr. Hyun-Dong Chang

Deutsches Rheuma-Forschungszentrum Berlin
Ein Institut der Leibniz Gemeinschaft
Charitéplatz 1
10117 Berlin  

Tel. +49 (0) 30 28460 761
chang@drfz.de

Project summary:

Deciphering the survival code of memory plasma cells and memory B cells

Two essential components of antibody-mediated immunity are memory plasma cells and memory B cells. Both, memory plasma cells and memory B cells, can be maintained over decades and provide the basis for longterm protection against recurrent pathogens but also for therapy-refractory immunopathology in autoimmune diseases. For memory plasma cells, it has been shown that their survival in bone marrow is conditional on provision of multiple survival signals in dedicated niches organized by bone marrow stromal cells.

In the last funding period, we have been able to establish for the first time a synthetic niche which provides the plasma cells with their physiological survival signals and allows us to maintain and study memory plasma cells ex vivo.

In the current funding period, we will elucidate the molecular signalling network which governs differentiation of precursors into memory plasma cells and their survival. We will use the synthetic niche for memory plasma cells to (1) determine which molecular networks determine the competence for a short-lived plasma blast to become a long-lived memory plasma cells, and (2) decipher redundant and non-redundant survival signals, and determine how their signals are integrated. Lastly, we will (3) also characterize the survival niche of memory B cells and establish a synthetic niche for memory B cells, to elucidate the signals required for memory B cell maintenance.

Deciphering the survival code of memory plasma cells and memory B cells
Fig. 1
Publications P 16:

Ostendorf, L., Burns, M., Durek, P., Heinz, G.A., Heinrich, F., Garantziotis, P., Enghard, P., Richter, U., Biesen, R., Schneider, U., Knebel, F., Burmester, G., Radbruch, A., Mei, H.E., Mashreghi, M.F., Hiepe, F. and Alexander, T. (2020). Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N. Engl. J. Med. 383, 1149-1155.

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, B., Hiepe, F., Mashreghi, M.F., Melchers, F., Chang, H.D.*, and Radbruch, A.*. (2020). Stromal cell-contact dependent PI3K and APRIL induced NF-kB signalling complement each other to prevent mitochondrial- and endoplasmatic reticulum-stress induced cell death of bone marrow plasma cells. Cell Rep. 32, 107982. # equal contribution, *equal contribution

Riedel, R., Addo, R., Ferreira-Gomes, M., Heinz, G.A., 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, A.E., Reddy, S.T., Durek, P., Chang, H.D.*, Mashreghi, M.F.*, and Radbruch, A.*. (2020). Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow. Nat. Commun. 11, 2570.   *equal contribution

Chang, H.D., Tokoyoda, K., Hoyer, B., Alexander, T., Khodadadi, L., Mei, H., Dörner, T., Hiepe, F., Burmester, G.R., and Radbruch, A. (2019). Pathogenic memory plasma cells in autoimmunity. Curr. Opin. Immunol. 61, 86-91.

Addo, R.K., Heinrich, F., Heinz, G.A., Schulz, D., Sercan-Alp, Ö., Lehmann, K., Tran, C.L., Bardua, M., Matz, M., Löhning, M., Hauser, A.E., Kruglov, A., Chang, H.D., Durek, P., Radbruch, A., and Mashreghi, M.F. (2019). Single-cell transcriptomes of murine bone marrow stromal cells reveal niche-associated heterogeneity. Eur. J. Immunol. 49, 1372-1379.

Tonon, S., Mion, F., Dong, J., Chang, H.D., Dalla, E., Scapini, P., Perruolo, G., Zanello, A., Dugo, M., Cassatella, M.A., Colombo, M.P., Radbruch, A., Tripodo, C., and Pucillo, C.E. (2019). IL-10-producing B cells are characterized by a specific methylation signature. Eur J Immunol 49, 1213-1225.

Chang, H.D., Tokoyoda, K., Radbruch, A. (2018) Immunological memories of the bone marrow. Immunol. Rev. 283, 86-98.

Siracusa, F., McGrath, M.A., Maschmeyer, P., Bardua, M., Lehmann, K., Heinz, G., Durek, P., Heinrich, F.F., Mashreghi, M.F., Chang, H.D., Tokoyoda, K., and Radbruch, A. (2018). Nonfollicular reactivation of bone marrow resident memory CD4 T cells in immune clusters of the bone marrow. Proc. Natl. Acad. Sci. USA 115, 1334-1339.

Taddeo, A., Gerl, V., Hoyer, B.F., Chang, H.D., Kohler, S., Schaffert, H., Thiel, A., Radbruch, A., and Hiepe, F. (2015). Selection and depletion of plasma cells based on the specificity of the secreted antibody. Eur. J. Immunol. 45, 317-319.