Immunomodulatory approaches targeting autoreactive B lineage cells while leaving protective B memory intact
B Cell Memory
The group focuses on translational rheumatologic/clinical immunology research with a tracking record on B lineage cells in autoimmunity. Based on the original identification of the plasma cell/plasmablast marker CD27++ as marker of disease activity in adult and juvenile SLE ongoing research addresses abnormalities of B cell subsets for detailed pathogenic insights of B cell differentiation as well as diagnostic and prognostic purposes. In close connection, the group studies characteristics of (auto)antigen specific plasmablast and memory B cells during vaccination and in autoimmune diseases addressing particular autoreactive and immunoregulatory plasma cells.
After the original identification of heterogeneous plasma cell subsets in the human bone marrow including mature CD19- plasma cells current studies address molecular and functional characteristics of plasma cell subsets in the human bone marrow. Presently, in the framework of a collaborative project with groups 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 hyperresponsiveness of B lineage cells in autoimmunity, we originally found hyporesponsive B lineage cells in SLE, RA and Sjögren’s based on their reduced cytokine production, TLR and BCR responses. On the molecular level, reduced protein tyrosine kinase phosphorylation of Syk, BTK and PLCg-2 and distinct expression of certain surface molecules such as CD22 connected to SHP-1 as membrane phosphatase have been found. In this context, increased intracellular protein tyrosine phosphatase regulated by CD40 dependent transcription was found and is subject of further research for therapeutic purposes.
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 their mechanism of action including their impact on long-lived plasma cells in humans and the relation of clinical response and memory B cell kinetics.
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. Eva V. Schrezenmeier
Dr. Ana-Luisa Stefanski
Dr. Marie Lettau
Dr. Thomas Rose
Annika Wiedemann, Dipl.-Ing.
Sarah Y. Weißenberg, M. Sc.
Franziska Szelinski, M. Sc.
Hector Rincon, M. Sc.
Dr. Mariele Gatto
Finn Moritz Wilkens
- 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
- Lisney AR, Szelinski F, Reiter K, Burmester GR, Rose T, Dörner T. (2017). High maternal expression of SIGLEC1 on monocytes as a surrogate marker of a type I interferon signature is a risk factor for the development of autoimmune congenital heart block. Ann Rheum Dis76(8): 1476-1480.
- Schrezenmeier E, Jayne D, Dörner T. (2018) Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives. J Am Soc Nephrol.Mar;29(3):741-758. doi: 10.1681/ASN.2017040367.
- 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 Immunol200(12): 3981-3992.
- 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 (2018) LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Jul 17;49(1):120-133.e9.
- Schrezenmeier E, Weißenberg SY, Stefanski A-L, Szelinski F, Wiedemann A, Lino AC, Dörner T(2019) Postactivated B cells in systemic lupus erythematosus: update on translational aspects and therapeutic considerations. Curr Opin Rheumatol. Mar;31(2):175-184.
- Gatto M, Wiedemann A, Nomovi N, Reiter K, Schrezenmeier E, Rose T, Lino AC, Valentino S, Ghirardello A, Dörner T, Doria A. (2019) Circulating Pentraxin3-specific B cells are Decreased in Lupus Nephritis. Front Immunol.Jan 25;10:29.
- Stefanski A-L, Wiedemann A, Reiter K, Lino AC, Dörner T. (2019) Enhanced PD-1 and diminished PD-L1 expression mark post-activated lupus B cells. Arthritis Rheumatol.
- Wiedemann A, Lino AC, Dörner T. (2019) B cell subset distribution in human bone marrow is stable and similar in left and right femur. PLoS One;14: e0212525.
- Dörner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet. 2019; 393(10188):2344-2358