Prof. Dr. Anja Erika Hauser
Professor for Immunodynamics
and Intravital Microscopy
Charité University Medicine Berlin
Dr. Helena Radbruch
Institut für Neuropathologie
Charité University Medicine Berlin
Analysis of B cell dynamics in chronic neuroinflammation
In the first funding period of the TRR130, we detected non-proliferating plasma cells (CD138+Ki67-) in the brain of MS patients. To follow up on this, we investigated the life span of plasma cells and B cells within chronically inflamed CNS in a mouse model. We found long-lived plasma cells in the vicinity of CXCL12-expressing astrocytes, consistent with our finding that plasma cell survival niches are composed of various cell types, depending on the tissue in which they reside. We plan to further characterize cerebral plasma cell niches with respect to their cellular and molecular composition.
Regarding the pathogenicity of plasma cells in the CNS, we could show that monoclonal antibodies cloned from patients induce a prolonged increase in intracellular calcium levels in brain slice cultures, indicative of neuronal dysfunction. In parallel, we could detect an increase in neuronal NADPH oxidase (NOX) activation in these co-cultures. We hypothesize that autoantibodies can induce the production of reactive oxygen species in the tissue, ultimately leading to neuronal destruction. Based on our data on the persistence of plasma cells and B cells in the CNS and the ability of antibodies to induce neuronal dysfunction and NOX-activation, we plan to determine in the next funding period whether soluble antibodies are able to induce a switch towards a pro-inflammatory phenotype in CNS-resident cells such as neurons, microglia, or astrocytes. We want to investigate whether this effect is evident even without the presence of overt inflammatory cell infiltrates in the CNS, as these infiltrates disappear in patients with chronic MS.
This project aims to understand the cellular and molecular mechanisms leading to chronic neuroinflammation by identifying the phenotype and localization of B cell subsets involved, and by dissecting their contribution to MS pathogenesis. Ultimately, this may help to identify strategies in order to stop disease progression in chronic neuroinflammation.
Radbruch H., R. Mothes, D. Bremer, S. Seifert, J. Pohlan, L. Ostendorf, R. Guenther, R. Leben, W. Stenzel, R. Niesner, and A. E. Hauser. 2017. Analyzing NADPH-oxidase activation in aging and vascular amyloid pathology. Frontiers Immunol., in press
Wunsch, M., S. Jabari, B. Voussen, M. Enders, S. Srinivasan, F. Cossais, T. Wedel, M. Boettner, A. Schwarz, L. Weyer, O. Gocer, M. Schroeter, M. Maeurer, M. Woenckhaus, K. Pollok, H. Radbruch, L. Klotz, C. J. Scholz, J. Nickel, A. Friebe, K. Addicks, S. Ergun, P. V. Lehmann, and S. Kuerten. 2017. The enteric nervous system is a potential autoimmune target in multiple sclerosis. Acta Neuropathol 134: 281-295.
Bremer, D., F. Pache, R. Gunther, J. Hornow, V. Andresen, R. Leben, R. Mothes, H. Zimmermann, A. U. Brandt, F. Paul, A. E. Hauser, H. Radbruch, and R. Niesner. 2016. Longitudinal Intravital Imaging of the Retina Reveals Long-term Dynamics of Immune Infiltration and Its Effects on the Glial Network in Experimental Autoimmune Uveoretinitis, without Evident Signs of Neuronal Dysfunction in the Ganglion Cell Layer. Front Immunol. 7: 642.
Kreye, J., N. K. Wenke, M. Chayka, J. Leubner, R. Murugan, N. Maier, B. Jurek, L. T. Ly, D. Brandl, B. R. Rost, A. Stumpf, P. Schulz, H. Radbruch, A. E. Hauser, F. Pache, A. Meisel, L. Harms, F. Paul, U. Dirnagl, C. Garner, D. Schmitz, H. Wardemann, and H. Pruss. 2016. Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain 139: 2641-2652.
Radbruch, H., D. Bremer, R. Guenther, Z. Cseresnyes, R. Lindquist, A. E. Hauser, and R. Niesner. 2016. Ongoing Oxidative Stress Causes Subclinical Neuronal Dysfunction in the Recovery Phase of EAE. Frontiers Immunol. 7: 92
Lemke, A., M. Kraft, K. Roth, R. Riedel, D. Lammerding, and A. E. Hauser. 2016. Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice. Mucosal Immunol. 9: 83-97.
Mossakowski, A. A., J. Pohlan, D. Bremer, R. Lindquist, J. M. Millward, M. Bock, K. Pollok, R. Mothes, L. Viohl, M. Radbruch, J. Gerhard, J. Bellmann-Strobl, J. Behrens, C. Infante-Duarte, A. Mahler, M. Boschmann, J. L. Rinnenthal, M. Fuchtemeier, J. Herz, F. C. Pache, M. Bardua, J. Priller, A. E. Hauser, F. Paul, R. Niesner, and H. Radbruch. 2015. Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation. Acta neuropathologica.
Radbruch, H., D. Bremer, R. Mothes, R. Gunther, J. L. Rinnenthal, J. Pohlan, C. Ulbricht, A. E. Hauser, and R. Niesner. 2015. Intravital FRET: Probing Cellular and Tissue Function in Vivo. International journal of molecular sciences 16: 11713-11727.
Zehentmeier, S., Z. Cseresnyes, J. Escribano Navarro, R. A. Niesner, and A. E. Hauser. 2015. Automated quantification of hematopoietic cell - stromal cell interactions in histological images of undecalcified bone. Journal of visualized experiments : JoVE.
Zehentmeier, S., K. Roth, Z. Cseresnyes, O. Sercan, K. Horn, R. A. Niesner, H. D. Chang, A. Radbruch, and A. E. Hauser. 2014. Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells. Eur J Immunol 44: 2306-2317.