Neuroimmunology

We carry out research into neuropsychiatric diseases involving inflammation, with a particular focus multiple sclerosis.

Mechanisms of immune and nervous system crosstalk

Traditionally, research into multiple sclerosis has focused on the mechanisms occurring in the peripheral immune system. However, it has recently become clear that damage processes within the nervous system itself and crosstalk between the immune and nervous systems may be independently and thus even more crucial. We use different experimental models, in vivo life imaging and human samples to study health, pathology and develop therapeutic concepts.

Collaborative strategies for therapeutic translation

One of our goals is to identify pathology and prognostic markers of the disease course in neurological illnesses. Especially in the area of genetic markers, we are heavily involved in national and international networks (e.g. Governance Group International Multiple Sclerosis Consortium, Executive Board Member of German Competence Network for Multiple Sclerosis (KKNMS)), which are making important advances.

Imaging, networks and behaviour

Further foci are therapeutic response markers and the use of magnetic resonance imaging 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. Difficult to diagnose inflammatory conditions, which are a key area of our activities, can often lead to novel concepts in pathology and therapy. 

Research Networks 

In addition to the networks mentioned above, we are members of the CRC 128, and CRC 1080, as well as Focus Program Translational Neuroscience (FTN), the Research Center for Immunotherapy (FZI) and the Rhine-Main Neuroscience Network (rmn2). Frauke Zipp is also a member of the International Women in Multiple Sclerosis (iWiMS) network, the MS International Federation (MSIF), the International Society of Neuroimmunology (ISNI), the German Multiple Sclerosis Society (DMSG) and the International Progressive MS Alliance (PMSA).

Methods

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

Referenzen

Bittner S, Pape K, Klotz L, Zipp F. (2023) Implications of immunometabolism for smouldering MS pathology and therapy. Nat Rev Neurol Online ahead of print.

Zipp F., Bittner S., Schafer D.P. 2023 Cytokines as emerging regulators of central nervous system synapses. Immunity. 56(5):914-925

Hanuscheck, N., Thalman, C., Domingues, M., Schmaul, S., Muthuraman, M., Hetsch, F., Ecker, M., Endle, H., Oshaghi, M., Martino, G., Kuhlmann, T., Bozek, K., van Beers, T., Bittner, S., von Engelhardt, J., Vogt, J., Vogelaar, C., Zipp, F.2022.Interleukin-4 receptor signaling modulates neuronal network activity. J Exp Med; 219(6): e20211887

Bitar, L.*, Uphaus T.*, Thalman, C.*, Muthuraman, M., Gyr, L., Ji, H., Domingues M., Endle, H., Groppa, S., Steffen, F., Koirala, N., Fan, W., Ibanez, L., Heitsch, L., Cruchaga, C., Lee, J., Kloss, F., Bittner S., Nitsch^§, R., Zipp^§, F., Vogt^§, J.2022. Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke. Science Translational Medicine, Vol 14, Issue 641
*equally contributing first authors, ^§equally contributing senior authors

Engel, S., Zipp, F.2022. Preventing disease progression in multiple sclerosis—insights from large real-world cohorts. Genome Med 14, 41. 

Bittner S & Zipp F.2021. A lymphocyte-glia connection sets the pace for smoldering Inflammation. Cell; 184(23): 5696-5698.

Bittner S, Oh J, Havrdova EK, Tintore M, Zipp F.2021. The potential of serum neurofilament as biomarker for multiple sclerosis. Brain; 144(19): 2954-2963.

Wasser B*, Luchtman D*, Löffel J, Robohm K, Birkner K, Stroh A, Vogelaar CF, Zipp F^§, Bittner S^§.2020. CNS-localized myeloid cells capture living invading T cells during neuroinflammation. J Exp Med; 217(6): e20190812. *equally contributing, ^§equally contributing and corresponding

Birkner K, Wasser B, Ruck T, Thalman C, Luchtman D, Pape K, Schmaul S, Bitar L, Krämer-Albers EM, Stroh A, Meuth S, Zipp F^§, Bittner S^§.2020. ß1-Integrin- and KV1.2 Channel-Dependent Signaling Stimulates Glutamate Release From Th17 Cells. J Clin Invest; 130(2):715-732.  ^§ equally contributing and corresponding

International Multiple Sclerosis Genetics Consortium*.2019. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science; 365: eaav7188. *FZ in governance group

Pape K, Tamouza R, Leboyer M, Zipp F.2019. Immunoneuropsychiatry - novel perspectives on brain disorders. Nat Rev Neurol; 15: 317-328.

Ellwardt E*, Pramanik G*, Luchtman D, Novkovic T, Rosales Jubal E, Vogt J, Arnoux I, Vogelaar CF, Mandal S, Schmalz M, Barger Z, Ruiz de Azua I, Kuhlmann T, Lutz B, Mittmann T, Bittner S, Zipp F^§, Stroh A^§. 2018. Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis. Nat Neurosci 21(10):1392-1403. *equally contributing, ^§equally contributing and corresponding 

Bittner S, Zipp F.2018. AAN unveils new guidelines for MS disease-modifying therapy. Nat Rev Neurol; 14(7): 384-386. 

International Multiple Sclerosis Genetics Consortium*.2018. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell; 175: 1–9. *FZ in governance

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.