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.
Jumaa, H., Caganova, M., McAllister, E.J., Hoenig, L., He, X., Saltukoglu, D., Brenker, K., Kohler, M., Leben, R., Hauser, A.E., Niesner, R., Rajewsky, K., Reth, M., and Jellusova, J. (2020). Immunoglobulin expression in the endoplasmic reticulum shapes the metabolic fitness of B lymphocytes. Life Sci. Alliance 3, e202000700.
Lindquist, R.L., Niesner, R.A., and Hauser, A.E. (2019). In the Right Place, at the Right Time: Spatiotemporal Conditions Determining Plasma Cell Survival and Function. Front. Immunol. 10, 788.
Mothes, R., Ulbricht, C., Leben, R., Gunther, R., Hauser, A.E., Radbruch, H., and Niesner, R. (2020). Teriflunomide Does Not Change Dynamics of Nadph Oxidase Activation and Neuronal Dysfunction During Neuroinflammation. Front. Mol. Biosci. 7, 62.
Holzwarth, K., Kohler, R., Philipsen, L., Tokoyoda, K., Ladyhina, V., Wahlby, C., Niesner, R.A., and Hauser, A.E. (2018). Multiplexed fluorescence microscopy reveals heterogeneity among stromal cells in mouse bone marrow sections. Cytometry A. 93, 876-888.
Lindquist, R.L., Bayat-Sarmadi, J., Leben, R., Niesner, R., and Hauser, A.E. (2018). NAD(P)H Oxidase Activity in the Small Intestine Is Predominantly Found in Enterocytes, Not Professional Phagocytes. Int. J. Mol. Sc. 19, 1365.
Zhang, Y., Tech, L., George, L.A., Acs, A., Durrett, R.E., Hess, H., Walker, L.S.K., Tarlinton, D.M., Fletcher, A.L., Hauser, A.E., and Toellner, K.M. (2018). Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells. J. Exp. Med. 215, 1227-1243.
Pollok, K., Mothes, R., Ulbricht, C., Liebheit, A., Gerken, J.D., Uhlmann, S., Paul, F., Niesner, R., Radbruch, H.*, and Hauser, A.E.* (2017). The chronically inflamed central nervous system provides niches for long-lived plasma cells. Acta neuropathologica communications 5, 88.
Radbruch, H., Mothes, R., Bremer, D., Seifert, S., Kohler, R., Pohlan, J., Ostendorf, L., Gunther, R., Leben, R., Stenzel, W., Niesner, R.A.* and Hauser, A.E.* (2017). Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology. Front. Immunol. 8, 844.
Reismann, D., Stefanowski, J., Gunther, R., Rakhymzhan, A., Matthys, R., Nutzi, R., Zehentmeier, S., Schmidt-Bleek, K., Petkau, G., Chang, H.D., Naundorf, S., Winter, Y., Melchers, F., Duda G., Hauser, A.E.*, and Niesner*, R. A. (2017). Longitudinal intravital imaging of the femoral bone marrow reveals plasticity within marrow vasculature. Nat. Commun. 8, 2153.
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.