Prof. Dr. Reinhard Voll
Klinik für Rheumatologie und Klinische Immunologie
& Centre for Clinical Immunodeficiency (CCI)
Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
Hugstetter Str. 55
The plasma cell: Culprit and therapeutic target in antibody-mediated diseases
Autoantibodies crucially contribute to the pathogenesis of multiple human diseases including autoimmune haemolytic anaemia, myasthenia gravis and systemic lupus erythematosus (SLE). Refractory disease courses are frequent and may be caused by secretion of pathogenic antibodies from long-lived plasma cells (PC), which are resistant to conventional treatments. We demonstrated that proteasome inhibitors can eliminate PC including long-lived ones and ameliorate lupus-like disease in mice. Recently, we identified long-lived PC within inflamed kidneys of NZB/W F1 lupus mice. Approximately half of those renal PC was reactive with double stranded, native DNA or nucleolin, a markedly higher percentage than in spleen and bone marrow.
This project aims (I) to investigate the mechanisms of PC survival and differentiation at sites of inflammation and (II) to develop strategies to re-establish a non-autoimmune PC memory.
The key questions to be addressed are:
(1) Are PC against other “lupus” autoantigens also enriched in inflamed kidneys, and if so, which mechanisms drive this enrichment? For this purpose we will compare frequencies of autoantibody producing cells by ELISPOT assays and investigate migration after adoptive transfer.
(2) What is the cellular and molecular nature of the “inflammatory PC survival niches”? Are there specific environmental effects on PC and antibodies? To identify molecules and cells mediating PC survival in inflamed tissues, we will use immunohistochemistry, intravital microscopy, flow cytometry, KO-mice and cytokine antagonists.
(3) How can we efficiently deplete autoreactive PC and replace them with harmless/useful PC? In order to increase efficacy and reduce toxicity of proteasome inhibitors we will explore combination therapies based on proteasome inhibition together with antagonists of survival factors such as APRIL. After depletion, we will try to occupy PC survival niches with non-autoreactive PC by vaccination and adoptive cell transfer strategies.
Understanding the mechanisms of PC survival in affected organs will allow the development of new treatment strategies for antibody-mediated diseases.
A. After antigen stimulation B cells can differentiate into antibody producing plasma cells. Plasma cells are either short lived and die within a few days, or can become long lived, if they find specialized survival niches. Long-lived plasma cells can be found in bone marrow and spleen, and in inflamed kidneys or other sites of chronic inflammation.
B. Immunohistochemical staining of plasma cells (red) within an inflamed kidney of a NZB/W F1 lupus mouse.
Rizzi, M., Lorenzetti, R., Fischer, K., Staniek, J., Janowska, I., Troilo, A., Strohmeier, V., Erlacher, M., Kunze, M., Bannert, B., Kyburz, D., Voll, R.E., Venhoff, N., and Thiel, J. (2016). Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J Autoimmun doi: 10.1016/j.jaut.2016.10.005.
Alexander, T., Sarfert, R., Klotsche J., Kühl, A.A., Rubbert-Roth, A., Lorenz, H.M., Rech, J., Hoyer, B.F., Cheng, Q., Waka, A., Taddeo, A., Wiesener, M., Schett, G., Burmester, G.R., Radbruch, A., Hiepe, F., and Voll, R.E. (2015). The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 74,1474-1478.
Hiepe, F., Alexander, T., and Voll, R.E. (2015). [Plasma cells]. Z Rheumatol 74, 20-25. (Review)
Medgyesi, D., Hobeika, E., Biesen, R., Kollert, F., Taddeo, A., Voll, R.E., Hiepe, F., and Reth, M. (2014). The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity. J Exp Med 211, 427-440.
Nikolova-Ganeva, K.A., Gesheva, V.V., Todorov, T.A., Voll, R.E., Vassilev, T.L. (2013). Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice. Clin Exp Immunol 174, 221-228.
Hainz, N., Thomas, S., Neubert, K., Meister, S., Benz, K., Rauh, M., Daniel, C., Wiesener, M., Voll, R.E., and Amann, K. (2012). The proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulointerstitial architecture. Nephron Exp Nephrol 120, e47-58.
Starke, C., Frey, S., Wellmann, U., Urbonaviciute, V.,Herrmann, M., Amann, K., Schett, G., Winkler, T., and Voll, R.E. (2011). High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kid-neys of NZB/W F1 lupus mice. Eur J Immunol 41, 2107-2112.
Lang, V.R., Mielenz, D., Neubert, K., Böhm, C., Schett, G., Jäck H.M., Voll, R.E.*, and Meister, S.* (2010). The early marginal zone B cell-initiated T-independent type 2 response resists the proteasome inhibitor bortezomib. J Immunol 185, 5637-5647. (* equal contribution)
Meister, S., Frey, B., Lang, V.R., Gaipl, U.S., Schett, G., Schlötzer-Schrehardt, U., and Voll, R.E. (2010). Calci-um channel blocker verapamil enhances endoplasmic reticulum stress and cell death induced by pro-teasome inhibition in myeloma cells. Neoplasia 12, 550-561.
Neubert, K., Meister, S., Moser, K., Weisel, F., Maseda, D., Amann, K., Wiethe, C., Winkler, T.H., Kalden, J.R., Manz, R.A., and Voll, R.E. (2008). The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nature Med 14, 748-755.