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Jürgen Ruland - Immune Signals and Cancer
My lab has a long standing interest in the molecular pathogenesis of lymphomas. Based on the functional characterization of recurrent chromosomal translocation in human MALT lymphomas, we identified the long sought-after molecular link that antigen receptors on lymphocytes utilize to activate the transcription factor NF κB. We discovered that the adapter protein BCL10 forms signaling complexes that couple antigen receptor proximal events in T and B cells to canonical NF-κB control. In these settings, BCL10 collaborates with MALT1 and CARD11 to assemble a complex that is essential for adaptive immunity. Loss-of-function mutations lead to immunodeficiency as we have demonstrated and gain-of-function alterations are recurrently observed in various B and also T cell lymphomas. We have also shown that this pathway operates in other immune cell lineages. Moreover, we have discovered that the proteolytic activity of the MALT1 paracaspase is key for the survival of human diffuse large B cell lymphoma (DLBCL) cells, leading to the development of MALT1 inhibitors as anti-lymphoma drugs in academia and industry. We have engineered clinically relevant murine models of human B and T cell lymphoma and utilized these to dissect lymphoma pathogenesis. Using in vivo genetic screens, my group identified the inhibitory receptor PD-1 as a key tumor suppressor in T-cell lymphoma with the respective implications for PD-1 checkpoint inhibition in the clinic.
In addition to the contributions described above, I discovered several signaling pathways in the innate immune cells, which are critical for host defense against fungi, viruses and bacteria, and the regulation of sterile inflammatory responses. In this context, I identified the adapter protein CARD9 as a key regulator of pattern recognition receptor (PRR) signaling and in particular of C-type lectin receptor pathways. Here, CARD9 cooperates with the tyrosine kinase SYK, PKCd and the inflammasomes to create protective pro-inflammatory immune responses. Based on these results, my group identified the first and major human immunodeficiency leading to high susceptibility to fungal infections. In addition, I discovered two intracytoplasmatic nucleic sensing pathways that mediate inflammatory responses upon RNA or DNA virus detection and identified Clec12a as a transmembrane receptor that detects uric acid crystals upon sterile cell death. These findings provided important insights into the regulation of the innate immune system with relevance of immune deficiency research, vaccine development, and understanding of inflammatory diseases. Ongoing work analyses these innate immune pathways in tumor microenvironments.
Prof. Ruland studied medicine in Giessen and Pittsburgh with a degree in pharmacology. After medical and research work at TUM, Freiburg University, the Ontario Cancer Institute and the AMGEN Research Institute at the University of Toronto, he became head of a junior research group of the German Cancer Aid at TUM in 2003. He completed his postdoctoral studies in medicine in 2005 and served as professor of molecular immunology at TUM from 2010 to 2012. In 2012, he was appointed professor of clinical chemistry at TUM. He is member of the National Academy of Sciences Leopoldina, the Bavarian Academy of Sciences and Humanities and the German Cancer Aid committee for promoting young medical professionals and scientists. He is the spokesperson for the SFB 1335 "Aberrant Immune Signals in Cancer" and successfully raised his second ERC Advanced Grant in 2019.
- Gottfried Wilhelm Leibniz Prize (2021)
- ERC Advanced Grant (2013 & 2019)
- Member of the Bavarian Academy of Sciences and Humanities (2016)
- Member of the National Academy of Sciences Leopoldina (2015)
- Advanced Investigator Award from the European Research Council (2013)
- Paul Martini Prize from the Paul Martini Foundation (2010)
- William Warner Award for Cancer Research from the William Warner Foundation (2010)
- Science Award (Wissenschaftspreis) from the Arbeitsgemeinschaft für Internistische Onkologie (2007)
- Artur-Pappenheim Award from the Deutsche Gesselschaft für Hämatologie und Onkologie (2006)
Alankus, B., Ecker, V., Vahl, N., Braun, M., Weichert, W., Macher-Goppinger, S., Gehring, T., Neumayer, T., Zenz, T., Buchner, M., Ruland, J. (2021). Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia. J Exp Med 218.
Ruland, J., Hartjes, L. (2019). CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nat Rev Immunol 19, 118-134.
Wartewig, T., Kurgyis, Z., Keppler, S., Pechloff, K., Hameister, E., Ollinger, R., Maresch, R., Buch, T., Steiger, K., Winter, C., Rad, R., and Ruland, J. (2017). PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552, 121-125.
Roth, S., Rottach, A., Lotz-Havla, A. S., Laux, V., Muschaweckh, A., Gersting, S. W., Muntau, A. C., Hopfner, K. P., Jin, L., Vanness, K., Petrini, J. H., Drexler, I., Leonhardt, H. and Ruland, J. (2014). Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1beta production. Nat Immunol 15, 538-545.
Neumann, K., Castineiras-Vilarino, M., Hockendorf, U., Hannesschlager, N., Lemeer, S., Kupka, D., Meyermann, S., Lech, M., Anders, H.J., Kuster, B., Busch, D.H., Gewies, A., Naumann, R., Groß, O. and Ruland, J. (2014). Clec12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. Immunity 40, 389-399.
Strasser, D., Neumann, K., Bergmann, H., Marakalala, J.M., Guler, R., Rojowska, A., Hopfner, K., Brombacher, F., Urlaub, H., Baier, G., Brown, G. Leitges, M., and Ruland, J. (2012) Syk-coupled C-type lectin receptors engage PKCdelta to elicit Card9 mediated innate immunity. Immunity 36, 32-42.
Poeck, H., Bscheider, M., Gross, O., Finger, K., Hannesschläger, K., Schlee, M., Rebsamen, M., Rothenfusser, S., Akira, S., Endres, S., Peschel, C., Hartmann, G., Hornung, V., and Ruland, J. (2010) Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol. 11, 63-69.
Gross, O., Poeck, H., Bscheider, M., Dostert, C., Hannesschläger, N., Endres, S., Hartmann, G., Tardivel, A., Schweighoffer, E., Tybulewicz, V., Mocsai, A., Tschopp, J., and Ruland, J. (2009) Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433-436.
Gross, O., Gewies, A., Finger, K., Schäfer, M., Sparwasser, T., Peschel, C., Förster, I., and Ruland, J. (2006) Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651-656.
Ruland, J., Duncan, G. S., Elia, A., del Barco Barrantes, I., Nguyen, L., Plyte, S., Millar, D. G., Bouchard, D., Wakeham, A., Ohashi, P. S., and Mak, T. W. (2001). Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. Cell 104, 33-42.
Prof. Jürgen Ruland
Technical University of Munich
School of Medicine
Institute for Clinical Chemistry and Pathobiochemistry
Tel: +49 89 4140 4751