Prof. Dr. Hans-Martin Jäck
Abteilung für Molekulare Immunologie
Medizinische Klinik III
Nikolaus-Fiebiger-Zentrum
Friedrich-Alexander-Universität Erlangen-Nürnberg
Glückstr. 6
91054 Erlangen
Tel. +49 (0) 9131 85 35913
hans-martin.jaeck@fau.de
Dr. rer. nat. Wolfgang Schuh
Abteilung für Molekulare Immunologie
Medizinische Klinik III
Nikolaus-Fiebiger-Zentrum
Friedrich-Alexander-Universität Erlangen-Nürnberg
Glückstr. 6
91054 Erlangen
Tel. +49 (0) 9131 85 39339
wolfgang.schuh@uk-erlangen.de
microRNA-controlled generation and maintenance of humoral memory
The generation of immunological memory after successful vaccination is essential for long-lasting protection against future infections. Our long-term goal is to identify the molecular circuits that control antibody-mediated memory with the aim of developing new treatments to either maintain physiologic or remove pathologic memory B cells and antibody-secreting plasma cells. In this funding period, we will elucidate how one class of small interfering non-coding RNAs, the so-called microRNAs (miRNAs), regulates and fine-tunes the differentiation and survival of memory B cells and long-lived plasma cells. In the first section, we will address the importance of miRNAs in generating memory B cells and plasma cells. For this purpose, we have already established a transgenic knock-in mouse line with a floxed DGCR8 allele encoding an essential subunit of the nuclear miRNA processing complex. miRNA synthesis can now be conditionally ablated in vivo at various stages of B cell development by breeding our floxed DGCR8 knock-in mouse to mouse strains that produce B cell-restricted Cre recombinase either before or after the establishment of plasma cells and memory B cells. In the second section, we will identify miRNAs that control the development of plasma cells via the in vitro reconstitution of DGCR8-deficient mature B cells with miRNAs that are upregulated during B cell activation. In the last section, we will elucidate the mechanisms by which miR-148a, a plasma cell signature miRNA, orchestrates the differentiation of B cells into plasma cells through B cell-specific Cre-mediated ablation and determining mRNA target profiles. These studies will provide new molecular insights into the regulatory circuits that control the production of antibodies. Our findings could potentially lead to new avenues for diagnosing or treating diseases associated with aberrant plasma cell development, e.g., primary antibody deficiencies, plasma cell malignancies, and autoimmune disorders.
Steinmetz, T.D., Schlotzer-Schrehardt, U., Hearne, A., Schuh, W., Wittner, J., Schulz, S.R., Winkler, T.H., Jäck, H.M., and Mielenz, D. (2020). TFG is required for autophagy flux and to prevent endoplasmic reticulum stress in CH12 B lymphoma cells. Autophagy 1-19, doi: 10.1080/15548627.2020.1821546.
Schuh, W., Mielenz, D., and Jäck, H.M. (2020). Unraveling the mysteries of Plasma Cells. Adv. Immunol. 146, 57-107.
Cossarizza, A., Chang, H.-D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W.W., ... Jäck, H.M., … Schuh, W., … et al. (2019). Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). Eur. J. Immunol. 49, 1457-1973.
Cvetkovic, L., Perisic, S., Titze, J., Jäck, H.M., and Schuh, W. (2019). The Impact of Hyperosmolality on Activation and Differentiation of B Lymphoid Cells. Front. Immunol. 10, 828.
Urbanczyk, S., Stein, M., Schuh, W., Jäck, H.M., Mougiakakos, D., and Mielenz, D. (2018). Regulation of Energy Metabolism during Early B Lymphocyte Development. Int. J. Mol. Sci. 19, 2192.
Haberland, K., Ackermann, J.A., Ipseiz, N., Culemann, S., Pracht, K., Englbrecht, M., Jäck, H.M., Schett, G., Schuh, W.*, and Krönke, G*. (2018). Eosinophils are not essential for maintenance of murine plasma cells in the bone marrow. Eur. J. Immunol. 48, 822-828. *authors contributed equally
Meinzinger, J., Jäck, H.M., and Pracht, K. (2018). miRNA meets plasma cells "How tiny RNAs control antibody responses". Clin. Immunol. 186, 3-8.
Friedrich, M., Pracht, K., Mashreghi, M.-F., Jäck, H.M., Radbruch, A., and Seliger, B. (2017). The role of the miR-148/-152 family in physiology and disease. Eur. J. Immunol. 47, 2026-2038.
Schmitt, V., Hahn, M., Kastele, V., Wagner, O., Wiendl, M., Derer, A., Taddeo, A., Hahne, S., Radbruch, A., Jäck, H.M., Schuh, W., Mielenz, D., Gay, S., Schett, G., Hueber, A. J., and Frey, S. (2017). Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts. Eur. J. Immunol. 47, 2101-2112.
Pracht, K., Meinzinger, J., Daum, P., Schulz, S. R., Reimer, D., Hauke, M., Roth, E., Mielenz, D., Berek, C., Corte-Real, J., Jäck, H.M.*, and Schuh, W.* (2017). A new staining protocol for detection of murine antibody-secreting plasma cell subsets by flow cytometry. Eur. J. Immunol. 47, 1389-1392. *authors contributed equally
Brandl, A., Daum, P., Brenner, S., Schulz, S.R., Yap, D.Y., Bosl, M.R., Wittmann, J., Schuh, W., and Jäck, H.M. (2016). The microprocessor component, DGCR8, is essential for early B-cell development in mice. Eur J Immunol 10.1002/eji.201646348.
Herglotz, J., Unrau, L., Hauschildt, F., Fischer, M., Kriebitzsch, N., Alawi, M., Indenbirken, D., Spohn, M., Muller, U., Ziegler, M., Schuh, W., Jäck, H.M., and Stocking, C.(2016). Essential control of early B-cell development by Mef2 transcription factors. Blood 127, 572-581.
Zambrano, K., Jerome, V., Freitag, R., Buchholz, R., Jäck, H.M., Hubner, H., and Schuh, W. (2016). Prolonged Ex vivo expansion and differentiation of naive murine CD43(-) B splenocytes. Biotechnol Prog 32, 978-989.
Liu, P., Baumgart, M., Groth, M., Wittmann, J., Jäck, H.M., Platzer, M., Tuckermann, J.P., and Baschant, U. (2016). Dicer ablation in osteoblasts by Runx2 driven cre-loxP recombination affects bone integrity, but not glucocorticoid-induced suppression of bone formation. Sci Rep 6, 32112.
Porstner, M., Winkelmann, R., Daum, P., Schmid, J., Pracht, K., Corte-Real, J., Schreiber, S., Haftmann, C., Brandl, A., Mashreghi, M.F., Gelse K., Hauke M., Wirries I., Zwick M., Roth E., Radbruch A., Wittmann J., and Jäck H.-M. (2015). miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2. Eur J Immunol 45, 1206-1215.
Haftmann, C., Stittrich, A.B., Zimmermann, J., Fang, Z., Hradilkova, K., Bardua, M., Westendorf, K., Heinz, G.A., Riedel, R., Siede, J., Lehmann K., Weinberger E.E., Zimmel D., Lauer U., Häupl T., Sieper J., Backhaus M., Neumann C., Hoffmann U., Porstner M., Chen W., Grün J.R., Baumgrass R., Matz M., Löhning M., Scheffold A., Wittmann J., Chang H.D., Rajewsky N., Jäck H.-M., Radbruch A., and Mashreghi M.F. (2015). miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim. Eur J Immunol 45, 1192-1205.
Weber, J.P., Fuhrmann, F., Feist, R.K., Lahmann, A., Al Baz, M.S., Gentz, L.J., Vu Van, D., Mages, H.W., Haftmann, C., Riedel, R., Grün, J.R., Schuh, W., Kroczek, R.A., Radbruch, A., Mashregi, M.F., and Hutloff, A. (2015). ICOS maintains the T follicular helper cell phenotype by down-regulating Kruppel-like factor 2. J Exp Med 212, 217-233.