Immunomodulatory approaches targeting autoreactive B lineage cells while leaving protective B memory intact
B Cell Memory
The Dörner Lab researches on translational rheumatologic/clinical immunology research with a foscus on B lineage cells in autoimmunity. Based on the original identification of the plasma cell/plasmablast marker CD27++ as identifier of antibody producing cells and marker of disease activity in adult and juvenile SLE, ongoing research addresses abnormalities of B cell subsets from naïve towards plasma cell differentiation in autoimmune conditions. For comparison, the group studies characteristics of (auto)antigen specific plasmablast and memory B cells upon vaccination versus active autoimmune disease. Such studies address potential molecular differences between autoreactive and protective B and plasma cells which would candidate as selective target in treatment autoimmunity. Moreover, such differences can serve as biomarkers for disease activity, prognosis and/or therapeutic response.
After the original identification of unique CD19- plasma cells implying that human bone marrow plasma cells are several heterogeneous subsets, current studies address this heterogeneity by their detailed molecular and functional characteristics. In this context and within a collaborative project with Prof. Klaus Rajewsky’s group at the MDC, we apply state of the art CRISPR/Cas9 technology to identify molecular differences between normal plasma cells and autoimmune plasma cells from SLE patients that can provide the basis for innovative molecular therapies.
In contrast to the conventional view that B lineage cells in autoimmunity are hyperresponsiveness, we originally found hyporesponsive or anergic post-activated (APA) B lineage cells in SLE, RA and Sjögren’s based on their reduced cytokine production, TLR and especially BCR responses. Most notable and with the most striking differences, BCR activation resulted in substantially reduced protein tyrosine kinase phosphorylation of downstream molecules (Syk, BTK and PLCg-2) together with increased expression of certain surface molecules such as CD22 connected to SHP-1, a receptor related phosphatase. Overall, APA B cells carry characteristically increased protein tyrosine phosphatase which is controlled by CD40 dependent transcription. Activation of CD40 results in reduced phosphatase activity and overcomes APA B cell abnormalities including normalization of BCR responses.
Various studies on the mechanism of innovative B cell therapeutics are underway in collaboration with the Charite Research Organization and our lab which provide insights into the underlying disease and disease mechanisms and therapeutic consequences on certain lymphocytes in relation to clinical responses. Here innovative therapeutics targeting B lineage cells beyond anti-CD20 targeting hold promise for more selective and effective treatments for systemic inflammatory diseases.
Systemic lupus erythematosus (SLE)
Rheumatoid arthritis (RA)
Primary Sjögren‘s syndrome (pSS)
Prof. Dr. med. Thomas Dörner
Andreia C. Lino, PhD
Dr. rer. nat. Annika Glenzer (graduated 1/2021)
Van Duc Dang, PhD
Dr. med. Eva V. Schrezenmeier
Dr. med. Ana-Luisa Stefanski
Dr. med. Marie Lettau
Dr. rer.nat. Sarah Y. Weißenberg (graduated 11/2020)
Dr. Mariele Gatto (graduated 4/2020)
Franziska Szelinski, M. Sc.
Hector Rincon, M. Sc.
Le Tuna Anh
- Prof. Dr. Jörn Walter, Saarland University, Department of Genetics and Epigenetics, Saarbrücken, Germany
- Prof. Dr. Lars Rönnblom, Uppsala University, Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala, Sweden
- Prof. Dr. Marie Wahren-Herlenius, Karolinska Institute, Stockholm, Sweden
- Prof. Dr. Peter Lipsky, RILITE Research Institute, Charlottesville, VA, USA
- Prof. Simon Fillatreau, PhD, Institute Necker – Inserm, Paris, France
- Prof. Dr. Hans-Peter Brezinschek, Medical Faculty, University Graz, Austria
- Prof. Klaus Rajewsky, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
- Dr. Van Trung Chu, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
- Prof. Changchun Xiao, Xiamen University, Xiamen, China
- Prof. Dr. Klaus Warnatz, Research Group “Human B-cell immunodeficiency”, Center for Chronic Immunodeficiency at Center for Translational Cell Research at the University Freiburg, Germany
- Prof. Mikael Benson, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Lettau M, Wiedemann A, Schrezenmeier EV, Giesecke-Thiel C, Dörner T. Human CD27+ memory B cells colonize a superficial follicular zone in the palatine tonsils with similarities to the spleen. A multicolor immunofluorescence study of lymphoid tissue. PLoS One. 2020 Mar 18;15(3):e0229778.
- Weißenberg SY, Szelinski F, Schrezenmeier E, Stefanski AL, Wiedemann A, Rincon-Arevalo H, Welle A, Jungmann A, Nordström K, Walter J, Imgenberg-Kreuz J, Nordmark G, Rönnblom L, Bachali P, Catalina MD, Grammer AC, Lipsky PE, Lino AC, Dörner T. Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases. Front Immunol. 2019 Sep 24;10:2136.
- Aue A, Szelinski F, Weißenberg SY, Wiedemann A, Rose T, Lino AC, Dörner T. Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility. Rheumatology (Oxford). 2020 Nov 1;59(11):3435-3442.
- Giesecke C, Meyer T, Durek P, Maul J, Preiß J, Jacobs JFM, Thiel A, Radbruch A, Ullrich R, Dörner T. (2018). Simultaneous Presence of Non- and Highly Mutated Keyhole Limpet Hemocyanin (KLH)-Specific Plasmablasts Early after Primary KLH Immunization Suggests Cross-Reactive Memory B Cell Activation. J Immunol 200(12): 3981-3992.
- Dörner T, Posch MG, Li Y, Petricoul O, Cabanski M, Milojevic JM, Kamphausen E, Valentin MA, Simonett C, Mooney L, Hüser A, Gram H, Wagner FD, Oliver SJ. Treatment of primary Sjögren’s syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis. 2019 May;78(5):641-647.
- Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, Simon Q, Thalmensi J, Baures A, Flühler V, Sakwa I, Stervbo U, Ries S, Jouneau L, Boudinot P, Tsubata T, Adachi T, Hutloff A, Dörner T, Zimber-Strobl U, de Vos AF, Dahlke K, Loh G, Korniotis S, Goosmann C, Weil JC, Reynaud CA, Kaufmann SHE, Walter J, Fillatreau S. LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Immunity 2018;49(1):120-133.e9.
- Dörner T, Szelinski F, Lino AC, Lipsky PE. Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus. RMD Open. 2020 Jul;6(2):e001258.
- Wiedemann A, Lettau M, Wirries I, Jungmann A, Salhab A, Gasparoni G, Mei HE, Perka C, Walter J, Radbruch A, Lino AC, Dörner T. Human IgA-Expressing Bone Marrow Plasma Cells Characteristically Upregulate Programmed Cell Death Protein-1 Upon B Cell Receptor Stimulation. Front Immunol. 2021 Feb 12;11:628923.
- Wiedemann A, Lino AC, Dörner T. B cell subset distribution in human bone marrow is stable and similar in left and right femur. PLoS One; 2019; 14: e0212525.
- Stefanski A-L, Wiedemann A, Reiter K, Lino AC, Dörner T. Enhanced PD-1 and diminished PD-L1 expression mark post-activated lupus B cells. Arthritis Rheumatol. 2019 Sep;71(9):1539-1544.
- Fillatreau S, Manfroi B, Dörner T. Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nat Rev Rheumatol. 2021 Feb;17(2):98-108.
- Dörner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet. 2019; 393(10188):2344-2358
- Dörner T, Burmester GR. PRIME Cells Predicting Rheumatoid Arthritis Flares. N Engl J Med. 2020 Oct 15;383(16):1595.
- Dörner T, Tanaka Y, Petri MA, Smolen JS, Wallace DJ, Dow ER, Higgs RE, Rocha G, Crowe B, Benschop RJ, Byers NL, Silk ME, de Bono S, Fantini D, Hoffman RW. Baricitinib-associated changes in global gene expression during a 24-week phase II clinical systemic lupus erythematosus trial implicates a mechanism of action through multiple immune-related pathways. Lupus Sci Med. 2020 Oct;7(1):e000424.