Visual Universitätsmedizin Mainz

Neuroimmunology

Traditionally, research into Multiple Sclerosis has focused on the mechanisms occurring in the peripheral immune system. Only recently have approaches been developed to explore the damage mechanisms of the central nervous system itself. In this area, we have been able to make significant contributions to the explanation of neurodegenerative mechanisms of the central nervous system (see Siffrin et al. Trends Neurosci 2010; Liblau et al. Trends Neurosci 2013; Zipp et al. JAMA Neurol 2013). The crosstalk of the immune and nervous systems plays a role not only in acute inflammation (e.g., in meningitis; Hoffmann et al., J Clin Invest 2007), but also in classical chronic inflammation (Multiple Sclerosis), as well as in stroke (Jolivel et al., Acta Neuropathol 2015) and neurodegenerative diseases (Zipp et al., Trends Neurosci 2006; “The Brain as a Target of Inflammatory Processes” supported by the German Research Council; DFG; CRC-TRR 43).

Our current research focuses in particular on Multiple Sclerosis, which we conduct within our Collaborative Research Center “Initation/effector vs. regulatory mechanisms in multiple sclerosis - progress towards tackling the diseases” (DFG: CRC-TR-128), together with colleagues in Muenster and Munich. We endeavor to closely align our experimental strategies with our clinical studies as an integral part of our overall research strategy (Roep et al Nat Med 2012).

Neurobiological questions regarding the regulation of neuronal cell damage in the inflamed brain on the one hand (Diestel et al., J Exp Med 2003; Prozorovski et al., Nat Cell Biol 2008; Siffrin et al., Immunity 2010), and immunoregulatory questions of defense and autoimmunity on the other (Aktas et al., J Exp Med 2003Wandinger et al., Lancet 2003Aktas et al., J Immunol 2004; Schulze-Topphoff et al., Nat Med 2009; Jolivel et al. Brain 2013; Hoppmann et al. Brain 2015), are central to our research activities. To address these questions, we employ T-cell and brain-slice cultures as well as animal models of Experimental Autoimmune Encephalitis (EAE) together with two-photon live imaging. Here, we exploit this model of neuroinflammation to gain insight into inflammatory neuronal injury occurring in the brain. In Multiple Sclerosis, where chronic inflammation of the brain occurs, both immunoregulatory and neuroprotective therapeutic approaches have much potential. We have shown that an important damage mechanism for neurons  is clearly the death ligand TRAIL (Nitsch et al., Lancet 2000; Dörr et al., J Neurosci 2002) (Aktas et al., Neuron 2005; Vogt et al., Ann Neurol 2009), which also plays a role in tumor defense. Very recently we also reported on a repair mechanism: in collaboration with an American research group, we demonstrated that lymphocytes, which migrate to the point of damage in the central nervous system, directly affect the outgrowth of nerve fibers via the cytokine interleukin-4 (Walsh et al., J Clin Invest 2015). We wish to better understand these adaptive response and repair/regeneration processes at the crosstalk of the immune and nervous systems, with the hope of exploiting them in novel treatment strategies.

One of our main goals is the development of therapeutic strategies and identification of diagnostic and prognostic markers of the disease course in neurological illnesses. Especially in the area of genetic markers, we are involved in national and international networks (IMSGC, Nature 2011IMSGC, Nat Genetics 2013Lill, IMSGC, Brain 2013), as well as being a member of the German Competence Network for Multiple Sclerosis (KKNMS; German Ministry of Education and Research; BMBF). In early phase-II studies, we are attempting to transfer our experimental therapeutic approaches directly to the clinic. An example of the development of diagnostic markers is a collaboration to establish an Aquaporin-4 antibody test for the diagnosis of Neuromyelitis Optica (Paul et al., PLoS Med 2007).

A further focus is the use of magnetic resonance techniques for the characterization of early inflammatory lesions and neuronal damage, which represent an important outcome parameter for diseases of the brain and spinal cord in humans as well as facilitating translation (Würfel et al., Brain 2004 and Brain 2008; Bellmann-Strobl et al., Neurology 2009; Droby et al., NeuroImage 2015). Difficult to diagnose inflammatory conditions, which are a key area of our activities, can often lead to novel concepts in diagnosis and therapy (Dörr et al., Lancet Neurol 2008; Hoffmann et al., J Clin Invest 2007; Vogt et al., Ann Neurol 2009).

Methods

For more information on the methods used in our group, please contact frauke.zipp@unimedizin-mainz.de

Selected publications

Vogelaar CF*, Mandal S*, Lerch S*, Birkner K, Birkenstock J, Bühler U, Schnatz A, Raine CS, Bittner S, Vogt J, Kipnis J, Nitsch R, Zipp F. 2018. Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation. Sci Transl Med 10(430): eaao2304. * equally contributing

Larochelle C*, Uphaus T*, Broux B, Gowing E, Paterka M, Michel L, Dudvarski Stankovic N, Bicker F, Lemaitre F, Prat A§, Schmidt MMH§, Zipp F§. 2018. EGFL7 reduces CNS inflammation in mouse. Nat Commun 9(1): 819. *,§ equally contributing

Paterka M, Siffrin V, Voss JO, Werr J, Hoppmann N, Gollan R, Belikan P, Bruttger J, Birkenstock J, Esplugues E, Yogev N, Flavell RA, Bopp T, Zipp F. 2016. Gatekeeper role of antigen-presenting CD11c+ cells in neuroinflammation. EMBO Journal 35(1): 89-101.

Ulges A, Witsch E, Pramanik G, Klein M, Birkner K, Bühler U, Wasser, B, Luessi, F, Stergiou N, Dietzen S, Brühl T-J, Bohn T, Bündgen G, Kunz H, Waisman A, Schild H, Schmitt E, Zipp F§, Bopp T§. 2016. Protein kinase CK2 governs the molecular decision between encephalitogenic TH17 cell and Treg cell development.  Proc Natl Acad Sci USA 113(36): 10145-50. § equally contributing

Larochelle C, Uphaus T, Prat A, Zipp F. 2016. Secondary progression in multiple sclerosis: neuronal exhaustion or distinct pathology? Trends Neurosci 39(5): 325-339

Ellwardt E, Walsh JT, Kipnis J, Zipp F. 2016. Understanding the Role of T Cells in CNS Homeostasis. Trends Immunol 37(2): 154-65.


Walsh, J. T., Hendrix, S., Boato, F., Smirnov, I., Zheng, J., Lukens, J. R., Gadani, S., Hechler, D., Golz, G., Rosenberger, K., Kammertons, T., Vogt, J., Vogelaar, C., Siffrin, V., Radjavi, A., Fernandez-Castaneda, A., Gaultier, A., Gold, R., Kanneganti, T. D., Nitsch, R., Zipp §, F., and Kipnis §, J. 2015. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. J Clin Invest 125: 699-714. § equally contributing.

 

Methner, A., and Zipp, F. 2013. Multiple sclerosis in 2012: Novel therapeutic options and drug targets in MS. Nat Rev Neurol 9: 72-73.


Liblau, R. S., Gonzalez-Dunia, D., Wiendl, H., and Zipp, F. 2013. Neurons as targets for T cells in the nervous system. Trends Neurosci 36: 315-324.


IMSGC (Zipp F as part of strategy group). 2013. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 45: 1353-1360.


Roep, B. O., Buckner, J., Sawcer, S., Toes, R., and Zipp, F. 2012. The problems and promises of research into human immunology and autoimmune disease. Nat Med 18: 48-53.


IMSGC (Zipp F as part of strategy group). 2011. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476: 214-219.


Siffrin, V., Vogt, J., Radbruch, H., Nitsch, R., and Zipp, F. 2010. Multiple sclerosis - candidate mechanisms underlying CNS atrophy. Trends Neurosci 33: 202-210.


Siffrin, V., Radbruch, H., Glumm, R., Niesner, R., Paterka, M., Herz, J., Leuenberger, T., Lehmann, S. M., Luenstedt, S., Rinnenthal, J. L., Laube, G., Luche, H., Lehnardt, S., Fehling, H. J., Griesbeck, O., and Zipp, F. 2010. In vivo imaging of partially reversible th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 33: 424-436.


Schulze-Topphoff, U., Prat, A., Prozorovski, T., Siffrin, V., Paterka, M., Herz, J., Bendix, I., Ifergan, I., Schadock, I., Mori, M. A., Van Horssen, J., Schroter, F., Smorodchenko, A., Han, M. H., Bader, M., Steinman, L., Aktas, O., and Zipp, F. 2009. Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system. Nat Med 15: 788-793.


Prozorovski, T., Schulze-Topphoff, U., Glumm, R., Baumgart, J., Schroter, F., Ninnemann, O., Siegert, E., Bendix, I., Brustle, O., Nitsch, R., Zipp §, F., and Aktas §, O. 2008. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10: 385-394. § equally contributing.


Hoffmann, O., Priller, J., Prozorovski, T., Schulze-Topphoff, U., Baeva, N., Lunemann, J. D., Aktas, O., Mahrhofer, C., Stricker, S., Zipp §, F., and Weber §, J. R. 2007. TRAIL limits excessive host immune responses in bacterial meningitis. J Clin Invest 117: 2004-2013. § equally contributing.


Zipp, F., and Aktas, O. 2006. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 29: 518-527.


Aktas, O., Smorodchenko, A., Brocke, S., Infante-Duarte, C., Schulze Topphoff, U., Vogt, J., Prozorovski, T., Meier, S., Osmanova, V., Pohl, E., Bechmann, I., Nitsch, R., and Zipp, F. 2005. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46: 421-432.


Wandinger, K. P., Lunemann, J. D., Wengert, O., Bellmann-Strobl, J., Aktas, O., Weber, A., Grundstrom, E., Ehrlich, S., Wernecke, K. D., Volk, H. D., and Zipp, F. 2003. TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 361: 2036-2043.


Diestel, A., Aktas, O., Hackel, D., Hake, I., Meier, S., Raine, C. S., Nitsch §, R., Zipp §, F., and Ullrich §, O. 2003. Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J Exp Med 198: 1729-1740. § equally contributing.


Aktas, O., Waiczies, S., Smorodchenko, A., Dorr, J., Seeger, B., Prozorovski, T., Sallach, S., Endres, M., Brocke, S., Nitsch, R., and Zipp, F. 2003. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 197: 725-733.


Nitsch, R., Bechmann, I., Deisz, R. A., Haas, D., Lehmann, T. N., Wendling, U., and Zipp, F. 2000. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 356: 827-828.


Zipp, F., Weil, J. G., and Einhaupl, K. M. 1999. No increase in demyelinating diseases after hepatitis B vaccination. Nat Med 5: 964-965.