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.
Schramm, M. A., Venhoff, N., Wagner, D., Thiel, J., Huzly, D., Craig-Mueller, N., Panning, M., Hengel, H., Kern, W.V., and Voll, R.E. (2020). COVID-19 in a Severely Immunosuppressed Patient With Life-Threatening Eosinophilic Granulomatosis With Polyangiitis. Front. Immunol. 11, 2086.
Freudenhammer, M., Voll, R.E., Binder, S.C., Keller, B., and Warnatz, K. (2020). Naive- and Memory-like CD21(low) B Cell Subsets Share Core Phenotypic and Signaling Characteristics in Systemic Autoimmune Disorders. J. Immunol. 205, 2016-2025.
Troilo, A., Wehr, C., Janowska, I., Venhoff, N., Thiel, J., Rawluk, J., Frede, N., Staniek, J., Lorenzetti, R., Schleyer, M.T., Herget, G.W., Konstantinidis, L., Erlacher, M., Proietti, M., Camacho-Ordonez, N., Voll, R.E., Grimbacher, B., Warnatz, K., Salzer, U., and Rizzi, M. (2020). Nonpermissive bone marrow environment impairs early B-cell development in common variable immunodeficiency. Blood 135, 1452-1457.
van Dam, L.S., Osmani, Z., Kamerling, S.W.A., Kraaij, T., Bakker, J.A., Scherer, H.U., Rabelink, T.J., Voll, R.E., Alexander, T., Isenberg, D.A., van Kooten, C., and Teng, O. (2020). A reverse translational study on the effect of rituximab, rituximab plus belimumab, or bortezomib on the humoral autoimmune response in SLE. Rheumatology (Oxford) 59, 2734-2745.
Eichhorst, A., Daniel, C., Rzepka, R., Sehnert, B., Nimmerjahn, F., Voll, R.E., and Chevalier, N. (2019). Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases. Int. J. Mol. Sci. 20, 3234.
Schaffer, S., Maul-Pavicic, A., Voll, R.E., and Chevalier, N. (2019). Optimized isolation of renal plasma cells for flow cytometric analysis. J. Immunol. Methods 474, 112628.
Lorenzetti, R., Janowska, I., Smulski, C.R., Frede, N., Henneberger, N., Walter, L., Schleyer, M.T., Huppe, J.M., Staniek, J., Salzer, U., Voll, R.E., Venhoff, N., Thiel, J., and Rizzi, M. (2019). Abatacept modulates CD80 and CD86 expression and memory formation in human B-cells. J. Autoimmun. 101, 145-152.
Alexander, T., Sarfert, R., Klotsche, J., Kuhl, 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.